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Nanostructured carriers as innovative tools for cancer diagnosis and therapy

Chiara Martinelli, Carlotta Pucci, Gianni Ciofani

APL Bioengineering · 2019 · Review · CC BY

doi:10.1063/1.5079943

Abstract

Cancer accounts for millions of deaths every year and, due to the increase and aging of the world population, the number of new diagnosed cases is continuously rising. Although many progresses in early diagnosis and innovative therapeutic protocols have been already set in clinical practice, still a lot of critical aspects need to be addressed in order to efficiently treat cancer and to reduce several drawbacks caused by conventional therapies. Nanomedicine has emerged as a very promising approach to support both early diagnosis and effective therapy of tumors, and a plethora of different inorganic and organic multifunctional nanomaterials have been ad hoc designed to meet the constant demand for new solutions in cancer treatment. Given their unique features and extreme versatility, nanocarriers represent an innovative and easily adaptable tool both for imaging and targeted therapy purposes, in order to improve the specific delivery of drugs administered to cancer patients. The current review reports an in-depth analysis of the most recent research studies aiming at developing both inorganic and organic materials for nanomedical applications in cancer diagnosis and therapy. A detailed overview of different approaches currently undergoing clinical trials or already approved in clinical practice is provided.

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From PubMed Central, U.S. National Library of Medicine, as current on Oct 25, 2026. Paragraph numbers are ours, so an answer can point at one.

INTRODUCTION

Cancer is one of the main causes of death worldwide and, according to the World Health Organization, the number of cancer-related deaths is going to increase up to approximately 13.2 million people a year by 2030. Currently, cancer treatments rely on chemotherapy, radiotherapy, and surgery. Unfortunately, these approaches are not specific, since they can attack both tumor and healthy tissues, causing adverse side effects to already debilitated patients (e.g., nausea, hair loss, weakness, and immuno-depression).

Aggressive tumors proliferate by creating new vessels in the surrounding tissues through a process termed angiogenesis. This vasculature shows several abnormalities in the number of endothelial cells and tridimensional structure, and the gaps between neighboring cells are larger than in physiological conditions, resulting in enhanced permeability. Moreover, tumor tissues lack an efficient lymphatic drainage system. All these phenomena are at the origin of the “enhanced permeability and retention” (EPR) effect, thanks to which some drugs can accumulate more easily around tumor tissues with respect to healthy ones. However, due to the augmented pressure at the core of the tumor mass, common drugs penetrate with many difficulties and are mostly retained at the periphery.

For these reasons, there is an increasing and urgent need for designing new tools capable of improving diagnosis and reducing the severe reactions correlated with conventional therapies. Recently, researchers are putting a lot of effort in creating drugs that univocally target cancer cells and are highly bioavailable, in order to decrease the administration doses and to prevent undesired cytotoxicity and drug resistance. In the last two decades, a branch of nanotechnology, namely nanomedicine, emerged as an innovative way to exploit nanomaterials for human health, including cancer treatment. Nanomedicine allows performing early diagnosis, curing with minimal side effects, and evaluating the efficacy of the treatments in a non-invasive way.

Nanoparticles are colloidal systems very small in size (from 1 up to 1000 nm), with a high surface-to-volume ratio, and morphology and properties dependent on the components and on the preparation protocols. They can be used as therapeutic agents (magnetic nanoparticles generating hyperthermia, for instance), as drug carriers, or as contrast agents for imaging purposes. To be exploited in biomedical applications, nanomaterials must be biocompatible, well characterized, and stable in vivo. Nanoparticles can be easily engineered to enhance their selectivity and efficacy towards tumor cells, and present several advantages compared to traditional plain chemotherapeutic agents: they can (i) encapsulate hydrophobic molecules, increasing their solubility/biocompatibility and their retention time in tumoral leaky vasculature; (ii) be conjugated with targeting ligands for diagnostic and therapeutic purposes, improving intracellular penetration and enhancing specificity towards a selected target; and (iii) release the drug in a stable and controlled manner. Nowadays, several kinds of nanomaterials are under investigation for clinical purposes, ranging from inorganic to organic nanocarriers, and many of them have already been accepted or are under evaluation.

In this review, we will provide an overview of the main nanoparticles that are currently tested for potential exploitation in nanomedicine; applications to biological models and their current status in the clinical context will be also described, highlighting their impact as cancer nanotheranostic agents.

NANOPARTICLES FOR NANOMEDICAL APPLICATIONS

Usually, nano-biomaterials are synthesized from inorganic metals or polymers and lipids; therefore, they can be generally classified as inorganic or organic (Fig. 1).

Inorganic nanoparticles

This class of nanoparticles is composed of inorganic compounds, like metal oxides or pure metals; some relevant examples are described in the following.

Nanoshells are spherical particles composed of a dielectric core (silica, in general) surrounded by a thin layer of metal. This structure makes them strongly resonate with light at specific wavelengths, and the resonance can be tuned in a large spectrum of wavelength by manipulating the shell thickness and the nanoparticle size. Nanoshells can either absorb or scatter light; absorbing nanoshells are mainly used to generate hyperthermia, whereas scattering ones are used as contrast agents.

Silica nanoparticles have an easily tunable mesoporous structure and a high surface/volume ratio that ensure a high loading capacity and a homogeneous distribution of drugs or imaging agents. The solid framework composed of Si-O bonds is extremely resistant to degradation or external stresses. Moreover, they have lower toxicity and higher biocompatibility compared to other metal oxides.

Gold nanoparticles have peculiar optical and electrical properties, low toxicity, and potential biodegradability. Moreover, gold chemistry is relatively easy, and the synthesis can be performed by following simple procedures, with good yields in terms of quantity and monodispersity. Gold nanoparticles have been investigated as a delivery system for therapeutic agents, in photodynamic therapy for the treatment of cancer, or in diagnostics to detect biomarkers for different kinds of diseases.

Quantum dots (QDs) are a class of small nanoparticles (2–50 nm in diameter) consisting of a semiconducting material, with specific electronic and optical properties, due to their high surface-to-volume ratio. The final size plays an important role in these properties: for this reason, QDs can be synthesized with a core-shell structure, in order to block the size of the internal core to the desired radius. Moreover, if the shell is made of a different semiconductor with a higher band gap, QDs properties can be tuned. QDs have intense fluorescence, resistance to photobleaching, and high sensitivity for detection; thus, they are often exploited for imaging purposes. However, they can also be used as drug carriers in theranostic applications.

Iron oxide nanoparticles can mainly have superparamagnetic or ferromagnetic properties, even though superparamagnetic ones are preferred in nanomedicine. In these systems, the stimulation with a magnetic field will produce the alignment of magnetic domains with the applied field. When removed, the magnetisation of superparamagnetic particles reverts to zero, and heat is released because of relaxation processes (Brownian and/or Neel relaxations); conversely, in ferromagnetic systems, the magnetisation does not spontaneously revert to zero, but a specific magnetic field (coercivity field) is needed. Heat generation is used for tumor thermal ablation through hyperthermia. Nanotherm®, a formulation of iron oxide nanoparticles of around 15 nm coated with aminosilane, has obtained approval for the treatment of glioblastoma.

Nanoparticles of cerium oxide (nanoceria) are also under investigation for the treatment of tumors, by combining their antioxidant properties to an efficient entrapment of chemotherapeutic agents in their porous structure.

Organic nanoparticles

Liposomes are made of phospholipids, lipids, and cholesterol. Due to their amphiphilic nature, phospholipids spontaneously self-assemble in water, forming spherical structures in which the hydrophilic “head” faces towards the solvent, and the hydrophobic “tails” form the lipid bilayer. Liposomes can have one or more lipid bilayers, but they all enclose an aqueous core, mimicking the morphology of cell membranes, and they can encapsulate both hydrophilic and hydrophobic drugs. An outer layer of poly(ethylene glycol) (PEG) is often necessary to enhance their stealth stability. PEG is known to provide steric stabilization, extended blood circulation, and reduced uptake from the mononuclear phagocyte system. Doxil®, Myocet® or DaunoXome® are liposomal formulations already approved by the Food and Drug Administration (FDA) for chemotherapy.

Polymersomes are morphological analogous of conventional liposomes, but they are composed of synthetic amphiphilic block copolymers. An amphiphilic block copolymer consists of two or more blocks of different polymers linked together by covalent bonds; one of the blocks is a hydrophilic polymer, usually PEG, and the other one can be any biocompatible polymer, such as poly(lactic acid), poly(lactic-co-glycolic acid), polystyrene, or polycaprolactone. Block copolymers can be designed to have specific properties in order to obtain nanoparticles with the desired features. Polymersomes possess higher stability, higher mechanical resistance, and reduced permeability compared to liposomes.

Micelles are spherical aggregates made of amphiphilic macromolecules where the hydrophilic part is facing the solvent, while the hydrophobic tails are confined in the core. Contrary to liposomes, micelles encapsulate hydrophobic drugs in the hydrophobic core, whereas hydrophilic drugs can be adsorbed or chemically attached to the outer shell, usually made of PEG or poly(vinyl alcohol). The hydrophilic shell increases the solubility and the stability of the nanoparticles in aqueous environments. The critical micelle concentration of amphiphilic polymers is usually very low, therefore dilution in vivo is not an issue for the stability of the aggregates.

Polymer nanoparticles are either solid spheres or nanocapsules composed by biocompatible and biodegradable polymers such as poly(lactide), poly(lactide-co-glycolide), and poly (ε-caprolactone), or natural polymers like chitosan, alginate, gelatin, and albumin. Chitosan nanoparticles are known to form electrostatic complexes with DNA, being thus very promising for non-viral gene therapy. Nanogels are polymeric nanoparticles where the polymers cross-link in a porous network that ensures high drug entrapment efficiency. The cross-linking can be obtained through a chemical reaction with the formation of covalent bonds, or through non-covalent interactions (physical cross-linking). In the latter case, stability in vivo must be carefully evaluated before final application.

Dendrimers are a class of polymers with a peculiar structure characterized by a central core—an atom or group of atoms—and multiple branches that end with several terminal functional groups. The branches extend symmetrically and radially from the core forming an overall globular shape. The advantage of dendrimers is that their architecture can be controlled with high precision, giving rise to well-defined and monodisperse objects. Moreover, their synthesis is extremely versatile, and either natural or synthetic polymers can be used as starting materials. Hydrophilic or hydrophobic drugs can be incorporated in the core of the dendrimers, depending on the nature of the monomers composing the macromolecule.

Solid lipid nanoparticles (SLNs) are made of lipids that are solids at body temperature (fatty acids, steroids, waxes, monoglycerides, diglycerides, or triglycerides). A small percentage of surfactants or polymeric stabilizers in the aqueous solution are needed during the preparation because of the high hydrophobicity of lipids. The kind of lipids and surfactants used in the formulation will affect the physicochemical properties of the particles. PEGylated lipids are often included in the formulation to impart steric stability and to allow for functionalization. Hydrophobic drugs are encapsulated during the fabrication, whereas hydrophilic drugs need to be either chemically attached to the components or dissolved in the hydrophilic PEG shell. Compared to liposomes, lipid nanoparticles ensure a higher drug stability and prolonged release because of their crystalline structure. Moreover, with respect to other organic nanoparticles, they do not need organic solvents during their fabrication, making them safer to use. However, the high crystallinity of solid lipid nanoparticles can cause low drug loading efficiency and/or very slow drug release profiles. For this reason, nanostructured lipid carriers (NLCs), that include one or more lipids liquid at room temperature (like oleic acid, for example), are often preferred. Depending on the amount of liquid lipid, its insertion will give rise to amorphous or partially crystalline solid matrices, increased drug release rates, and facilitated drug encapsulation during the preparation step.

FUNCTIONALIZATION, TARGETING AND TRIGGERED RELEASE

A current challenge in nanomedicine is the synthesis of nanoparticles that are selective for a specific target. This accomplishment would reduce the side effects of the treatment and, at the same time, would increase its efficacy. The concept of site-specific drugs was suggested by the Nobel laureate Paul Ehrlich, who developed the concept of “magic bullet” referring to drugs able to kill specific microbes without harming the rest of the body. Since then, this view has been extended to other areas of medicine.

Because of their size, nanoparticles tend to accumulate more in tumor tissues with respect to normal ones due to the enhanced permeability and retention (EPR) effect. Passive targeting relies on the fact that tumors have a leaky vasculature, different pH, and different local temperature, and are devoid of an efficient lymphatic drainage system [Fig. 2(a)]. For example, lipid-based nanovectors can reach tumor sites regardless of their surface, and can easily enter lymphatic circulation. Passive targeting, however, suffers from several limitations, such as a difficult control of the process, which may induce multi-drug resistance (MDR), a poor drug diffusion, and aspecific accumulation in liver and spleen. Targeted drug delivery has solved some of these drawbacks, allowing to specifically reach tumor cells, accumulate the vectors locally into the tumor microenvironment, and efficiently release the drug at the desired site, without perturbing healthy tissues. This can be achieved through two different approaches: (i) active targeting [Fig. 2(b)] and (ii) triggered release [Fig. 2(c)].

Active targeting aims at “programming” the nanocarriers to target specific cells after extravasation. It relies on the molecular recognition (ligand-receptor or antigen-antibody interactions) of the diseased cells through specific receptors that are overexpressed on them, but that are instead normally or minimally expressed on healthy cells. The ligand must have a high affinity for its receptor, and the interaction must be able to trigger receptor-mediated endocytosis, after which the intracellular release can be favored by acidic pH or enzymes. If the affinity between the ligand and receptor is too strong, however, the penetration of the carrier might be hindered.

Nanocarriers for active targeting need to be functionalized with ligands that bind specific receptors on the cell membrane. The strategies for the functionalization are different and depend on the nature of the materials involved. A ligand can be either adsorbed onto the particle surface (biotin-streptavidin interactions, for instance) or covalently bound to one of the components of the nanoparticles, normally poly(ethylene glycol). In the second case, the conjugation can occur before or after the preparation of the nanoparticles: the size of the ligand is crucial in the choice of one of these two methods. Large ligands are usually attached after the formation of the carrier, because they could alter the hydrophilic/lipophilic balance of the component, changing the condition in which the self-assembly takes place. For small ligands, instead, both ways can be exploited. The second approach, however, has some drawbacks: purification procedures, like centrifugation or filtration, may affect the stability and the features of the nanoparticles, and it is more difficult to demonstrate a successful conjugation with conventional techniques.

Different kinds of ligands can be used to target cancer cells, and one of the simplest molecule that can be exploited at this aim is folic acid. It belongs to the vitamin B family, and is essential for nucleotide biosynthesis, while its receptor is overexpressed in several tumors, especially in ovarian and endometrial cancers. PEG-coated polymeric nanoparticles coupled to folic acid have been developed. More recently, poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles carrying paclitaxel and functionalized with folic acid were able to efficiently transport the drug in Caco-2 cells, paving the way to the delivery of drugs with poor oral bioavailability. Another study demonstrated that folate-decorated chitosan nanoparticles were able to univocally deliver ligustrazine to cancer cells overexpressing folate receptors. Concerning cancer imaging, many studies have shown that superparamagnetic iron oxide nanoparticles conjugated to folic acid can be exploited as contrast agents for magnetic resonance imaging (MRI). The advantages of using small ligands are their low costs and easy handling. The same applies for carbohydrates, like galactose, lactose, or mannose, among others, that specifically bind to asialoglycoprotein receptors and to C-type lectin receptors overexpressed in cancer cell membranes. Solid lipid nanoparticles loaded with doxorubicin have been mannosylated and tested for drug release ability and cytotoxicity in A549 cells.

Another category of targeting ligands includes peptides and proteins. Peptides are short chains of amino acids that can be easily synthesized to have a particular sequence. They are stable for long time and reduce undesired effects on the immune system. Moreover, being small, they do not alter the physicochemical properties of the nanoparticles. Cell penetrating peptides (CPPs) are often exploited to increase the permeability of the nanoparticles. However, since they are not specific for a particular receptor, they are often coupled with other ligands. Angiopep-2 is a peptide derived from the Kunitz domain of aprotinin that efficiently binds to low-density lipoprotein receptor-related protein-1 (LRP1) of endothelial cells in the blood-brain barrier (BBB). For this reason, it is often used to target cancer cells in the brain. Apolipoproteins (Apos) interact with low-density lipoprotein receptors as well, and they are used for the same purpose. Transferrin receptors (TfRs) are also overexpressed on solid tumors, especially in glioblastoma multiforme cells, and on the epithelial cells of the BBB, due to increased iron uptake required for cancer cell proliferation.

Antibodies are a special class of proteins with a typical “Y” shape, where the tips have a specific amino acid sequence called antigen-binding fragment (Fab), that univocally binds an antigen. This kind of interaction is highly specific and strong, making antibodies the most effective ligands. Even though their high molecular weight can affect the physicochemical properties of the nanoparticles or compromise the protection of the PEG layer, just a very small amount of antibody is needed to target a specific site. The production of conventional antibodies is difficult and expensive; therefore, antibody fragments containing the Fab region are often preferred, because they are safer against non-specific binding and can be easily engineered. Human serum albumin nanoparticles carrying loperamide have been successfully conjugated to monoclonal antibodies that specifically bind the transferrin receptor. The delivery was revealed to be efficient, and the drug was transported across the blood-brain barrier. Recent studies showed that immunoliposomes can accumulate in the brain endothelium thanks to transferrin receptor targeting.

Finally, a new class of ligands is represented by small synthetic single-stranded RNA or DNA oligonucleotides (normally composed of 20–60 nucleotides), called aptamers, that can form specific shapes (helices or single-stranded loops). They are extremely versatile, and can bind different kind of targets—proteins, inorganic molecules, and cells—with a high selectivity. For this reason, they are considered an equivalent of antibodies, but their preparation is much simpler and cheaper, additionally to not showing any sign of toxicity.

Triggered release is intended as the localized release of drugs induced by a stimulus that alters the structure of the nanocarrier. The main advantage of this type of system is that it is highly specific and can be activated “on demand” without perturbing healthy tissues. Triggers can be internal, such as variations in pH, redox conditions, and ionic strength, or external, such as temperature, ultrasounds, magnetic fields, and ultraviolet/near-infrared (UV/NIR) radiation. Nanocarriers can be designed to be responsive to these stimuli and to achieve enhanced release of their cargo in a precise location. Moreover, external stimuli such as local hyperthermia and UV/NIR light can enhance the permeability of blood vessels and favor deep tissue penetration. Finally, ultrasounds can induce release of contrast agents at the tumor site, while magnetic fields can locally drive nanocarriers, thus triggering drug release through hyperthermia.

NANOCARRIERS FOR DIAGNOSIS

One of the main difficulties related to cancer diagnosis is the low sensitivity of conventional equipment. Tumors start to be detectable when they are already around 1 cm3 in size, a stage at which they are already able to spread in surrounding tissues, potentially creating metastatic lesions. Tissue biopsies for cancer diagnosis provide information regarding the tumor grade and its histological features, but fail to detect early stage lesions.

Recently, molecular imaging procedures have been improved to detect early stage cancer and to monitor the tumor at the genomic level in a noninvasive way, in order to predict its evolution, and to find the best personalized therapeutic strategy. Many innovative approaches exploit the unique features of nanoparticles like their small size, the ability to travel along human vessels, and their specificity mediated by conjugation to targeting molecules. Nanocarriers can be designed and modified to reach both cell surface proteins and intracellular molecules by means of endocytosis. The vast majority of nanomaterials used for cancer diagnosis are based on inorganic metals, like gold, silica, quantum dots, and iron oxide nanoparticles.

Nanoshells have been widely exploited as imaging agents, due to their optical resonance properties and their scattering and absorption features. In particular, they have been developed as contrast agents for optical coherence tomography (OCT). Nanoshells have been also modified by antibody conjugation, in order to target specific tumor cell receptors for cancer imaging. Gold nanorods and nanocages have been successfully used as contrast agents for photoacoustic imaging in vivo, while mesoporous silica nanoparticles are currently used for optical and magnetic resonance imaging: a multifunctional nanovector has been for example developed able to encapsulate therapeutic or imaging agents and to achieve targeted delivery in cancer cells.

Quantum dots represent the ideal tool for cancer imaging because of their unique absorption and emission spectra, negligible photobleaching, and stable fluorescence. They have been conjugated to streptavidin-IgG to detect extra- and intracellular molecules, and proved to be more photostable than conventional fluorophores. In a recent study, PEGylated quantum dots were conjugated to the anti-HER2 antibody and localized in specific tumor cells. QD toxicity still raises some concerns and several studies are ongoing in order to address this point. In 2012, a pilot study performed on primates demonstrated no evident toxicity up to 90 days post-injection, but further investigations are necessary to clarify the persistence of heavy metals in the body.

Superparamagnetic iron oxide nanoparticles (SPIONs) have been applied for cancer diagnosis due to their intrinsic magnetism and the possibility to be visualized by magnetic resonance imaging. Dextran-coated SPIONs have been used in vitro and in vivo as MRI contrast agents. They can be targeted by applying an external magnetic field and/or by functionalization with specific ligands. Efficient coupling to antibodies has provided localization in specific tumor models in vivo. SPIONs encapsulated within a polyacrylamide matrix and functionalized with poly(ethylene glycol) have been efficiently uptaken by tumor cells. Magnetic nanoparticles conjugated to fluorophores, chemotherapeutics or photosensitizing agents can also be exploited as theranostic devices to visualize cancer cells and simultaneously kill them (Fig. 3).

NANOCARRIERS FOR THERAPY

A plethora of organic nanomaterials are currently under evaluation or have been already accepted for cancer therapy. Liposomes are highly biocompatible and stable, protecting cargoes from degradation. Many chemotherapeutic agents have been loaded into liposomes and delivered to cancer cells; moreover, liposomes have also been proposed as carriers for gene delivery and silencing, providing encouraging results both in vitro and in vivo. Many efforts have been devoted to enhance the drug release efficiency, by making them responsive to specific stimuli, like ultrasounds, light, and hyperthermia for triggered release.

Polymersomes are widely exploited for drug encapsulation and targeted delivery because of their high stability and biocompatibility. Usually, drug release is triggered upon external condition variations, like pH and redox potential, or by the presence of a magnetic field. Polymersomes made of poly(N-vinylpyrrolidone) (PVP), as a hydrophilic component, and poly(dimethylsiloxane) (PDMS), as a hydrophobic part, are a common example of these kind of systems. Recently, PVP-b-PDMS polymersomes conjugated to tumor necrosis factor alpha (TNF-alpha) have been successfully tested for in vivo delivery. Poly(butadiene-ethylene oxide) polymersomes loaded with paclitaxel have been demonstrated to be able to release this drug in a prolonged and stable way, with no significant cellular toxicity. Block copolymers can be also labeled with fluorescent molecules for in vivo studies, and loaded with photosensitizers for photodynamic therapy. Moreover, lipophilic anticancer drugs, amphiphilic dyes, and membrane proteins have been enveloped in polymersome membranes.

Micelles are widely used as carriers of lipophilic molecules due to their high versatility and biocompatibility. Micelles can be efficiently designed in order to be responsive to different external stimuli, such as temperature and pH. High concentrations of drugs can be intracellularly delivered through endocytosis. Micelles have been effectively functionalized with an antibody directed against the epidermal growth factor receptor (EGFR), a glycoprotein overexpressed in several tumors. Micelles targeted to ανβ3 integrin, a regulator of cancer angiogenesis, have been reported. In recent studies, the local release of drugs from micellar nanoparticles has been achieved by exploiting the sensitivity of mitochondria to high temperatures. A recent preclinical study demonstrated that Genexol-PM, a paclitaxel-loaded micelle approved by the FDA, was more efficient as a radiosensitizer than plain taxol in murine models of non-small-cell lung carcinoma.

Polymeric nanoparticles are highly stable in the gastrointestinal environment and allow controlled drug release. They can be functionalized for targeted delivery, and many kinds of molecules, drugs, and nucleic acids can be loaded. Chitosan nanoparticles demonstrated to be effective in releasing siRNAs both in vitro and in vivo. Efficient oxaliplatin delivery was obtained using hyaluronic acid-chitosan nanoparticles. Polymer nanocarriers can be also made responsive to temperature and sensitive to pH changes.

Dendrimers possess a branched structure that can be easily modified for high specific targeting. PEGylated poly(methylmetacrylate) (PMMA) dendrimers have been exploited in B16F10 melanomas. Poly-L-lysine (PLL) dendrimers/doxorubicin complexes were able to induce anti-angiogenic responses in in vivo tumor models. Interestingly, dendrimers have been extensively used to deliver contrast agents for MRI imaging in glioma cells.

Lipid nanoparticles are ideal for encapsulating hydrophobic drugs, while hydrophilic molecules can be linked to their surface. Many research studies have focused on designing solid lipid nanoparticles for delivery to cancer cells, but also as non-viral gene carrier systems. To this end, lipid-coated lipoplexes were fabricated to carry antisense oligonucleotides to the liver endothelial cells. Since lipid nanoparticles can the cross the blood-brain barrier, they are good candidates for brain tumor targeting. Etoposide encapsulated in transferrin-conjugated nanostructured lipid carriers efficiently targeted acute myelogenous leukemia cells, and induced cytotoxicity in human gastric cancer cell lines and on tumor animal models. NLCs delivering lapachone and doxorubicin were able to overcome multidrug resistance in breast cancer experimental models. Co-delivery of paclitaxel and indocyanine green was also successful in combining chemo- and photodynamic therapy in vitro and in vivo. Delivery of an epidermal growth factor receptor (EGFR) inhibitor showed evident cytotoxicity in human hepatocellular carcinoma cells. NLCs have been also modified to obtain reduced immunogenicity and longer bioavailability, and to enhance their pharmacokinetic profiles in vivo. Finally, NLCs have been recently shown to be extremely efficient tools for combining conventional chemotherapy to hyperthermia treatments, by loading their core with chemotherapeutics and SPIONs (Fig. 4).

CANCER NANOMEDICINES: FROM BASIC RESEARCH TO CLINICAL TRANSLATION

Nanomedical devices are continuously developed and optimized in order to enhance the solubility and the bioavailability of small molecules and drugs, and to specifically deliver active drugs to diseased tissues. Approximately 250 nano-based drugs have been commercialized or are under investigation in clinical trials, and this number is constantly growing. Since the 1970s, 1 to 7 nanomedicines are FDA-approved each year. The submissions for approval include: liposomes (33%), nanocrystals (23%), emulsions (14%), iron-polymer complexes (9%), micelles (6%), and others (drug-protein complexes, drug-polymer complexes, and polymeric nanoparticles, 15%). Nanomedicine covered about 15% of the total pharmaceutical market in 2014 and is predicted to increase up to 22% in 2019 with an overall estimated business of 293.1 billion dollars by 2022, according to BCC Research. Oncology represents the largest area of nanomedicine market (about 35%), while other sectors involve neurological diseases, infections, and inflammatory and cardiovascular diseases. Several nanomedicines have been already approved by the FDA and by the European Medicines Agency (EMA) for cancer diagnosis and therapy (Table I), and many of them are currently undergoing clinical trial evaluation, possibly entering the market in the next future.

Clinical translation of chemicals is subjected to many regulatory and manufactory rules before definitive approval. The approval process for a single new drug costs around 1 billion dollars and it might take 10–15 years. In spite of their simple composition, many of the chemical/physical properties of nanoparticles remain critical. In vivo performance has to be carefully evaluated before introducing a new product in the industrial manufacturing process.

Far in 1995, doxorubicin-loaded PEGylated liposomes (Doxil) were approved for acquired immune deficiency syndrome (AIDS)-associated Kaposi's sarcoma treatment. This formulation improved doxorubicin tolerability in patients and reduced collateral effects. After that, other liposomes developed to treat infections (Ambisome®), metastatic breast cancer (Myocet), and pancreatic ductal adenocarcinoma in combination with 5-fluorouracil and leucovorin (MM-398) were approved. New multifunctional liposomal nanoparticles are currently in the clinical trial phase, such as ThermoDox®, a formulation made of thermosensitive lipids that allows for a site-specific release of doxorubicin in response to high temperature. Other non-lipid-based FDA-approved nanoformulations include albumin-bound paclitaxel particles (Abraxane®), indicated for metastatic breast cancer and recently for pancreatic ductal adenocarcinoma, and an engineered protein combining interleukin-2 and diphtheria toxins for the treatment of non-Hodgkin's peripheral T-cell lymphomas (Ontak®). Nevertheless, other promising polymeric nanosystems such as BIND-014, a polymer micelle incorporating docetaxel, poliglumex (a paclitaxel-polyglutamic acide conjugate), and CRLX101 (a cyclodextrin-PEG copolymer encapsulating camptothecin), are under clinical trials.

Regarding inorganic nanoparticles, up until now, just some formulations containing superparamagnetic iron oxide nanoparticles (SPIONs) have been approved for clinical use for iron deficiency in anemic patients (Feraheme®), for the treatment of glioblastoma using local tissue hyperthermia (Nanotherm™), or as imaging agents (Feridex®/Endorem®). Other inorganic nanoparticles such as NBTXR3 (a radiosensitizer combined to radiotherapy after intravenous injection or intratumoral administration, AGulX), Cornell dots (silica nanoparticles for imaging applications), and a few gold nanoparticles are under clinical trials. Regarding active targeting, only a minor number of nanovectors is investigated in clinical trials, for example immunoliposomes directed against EGFR and polymeric nanoparticles for prostate cancer treatment, or products investigated for cardiovascular diseases or immunological tissue targeting. Actually, Ontak is the only active targeting nanomedicine that has been approved by the FDA.

CONCLUSIONS AND FUTURE PERSPECTIVES

Nowadays, nanomedicine represents one of the most promising and advanced field of biomedical research, combining nanotechnology and medicine to design agents with improved efficacy and safety for human health. In the last decade, many kinds of nanomaterials have been introduced in the biomedical field, in particular for cancer diagnosis and therapy. Ranging from inorganic to organic nanoparticles, the materials and the formulation procedures that are available for their fabrication are several, achieving high versatility, controllable size and shape, possibility to be functionalized for targeted therapy and to be loaded with several drugs and active molecules. Nevertheless, there is still room for improvement, as some aspects like cytotoxicity, immunogenicity, and low biocompatibility need to be addressed in a more extensive manner, especially for inorganic systems and for some of synthetic polymers.

In this review, we presented the most significant nanomaterials currently investigated and evaluated for clinical applications, and explored the most recent innovations in cancer diagnosis and therapy. We also discussed how nanocarriers are able to reach human organs by passive targeting, exploiting the EPR effect. However, due to a non-specific accumulation in the tumor tissues, active targeting has become the new trend in nanomedicine. By exploiting molecules overexpressed just on the cancer cell surface, in fact, active targeting has reached a high level of precision and selectivity, guaranteeing the exclusive uptake of nanoparticles in tumor cells. Future research studies will help in elucidating the molecular and the cellular mechanisms that mark healthy from pathological cells, giving a boost to the design of highly performant nano-delivery systems as tools for treating cancer. Finally, future improvements in nanomaterial characterization procedures will meet the most relevant issues required for the eventual approval of nano-drugs in clinical practice.

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    C. J. Kearney and D. J. Mooney, “ Macroscale delivery systems for molecular and cellular payloads,” Nat. Mater. 12(11), 1004 (2013 ).

    Not in our library10.1038/nmat3758

  14. 14.

    A. Albanese, P. S. Tang, and W. C. W. Chan, “ The effect of nanoparticle size, shape, and surface chemistry on biological systems,” Annu. Rev. Biomed. Eng. 14, 1 (2012 ).

    Not in our library10.1146/annurev-bioeng-071811-150124

  15. 15.

    H. Maeda, “ Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity,” Adv. Drug Delivery Rev. 91, 3 (2015 ).

    Not in our library10.1016/j.addr.2015.01.002

  16. 16.

    L. E. Gerlowski and R. K. Jain, “ Microvascular permeability of normal and neoplastic tissues,” Microvasc. Res. 31(3), 288 (1986 ).

    Not in our library10.1016/0026-2862(86)90018-x

  17. 17.

    O. C. Farokhzad and R. Langer, “ Impact of nanotechnology on drug delivery,” ACS Nano 3(1), 16 (2009 ).

    Not in our library10.1021/nn900002m

  18. 18.

    P. Burgess, P. B. Hutt, O. C. Farokhzad et al., “ On firm ground: IP protection of therapeutic nanoparticles,” Nat. Biotechnol. 28(12), 1267 (2010 ).

    Not in our library10.1038/nbt.1725

  19. 19.

    T. Sun, Y. S. Zhang, B. Pang et al., “ Engineered nanoparticles for drug delivery in cancer therapy,” Angew. Chem.-Int. Ed. Engl. 53(46), 12320 (2014 ).

    Not in our library10.1002/anie.201403036

  20. 20.

    K. B. Sutradhar and M. L. Amin, “ Nanotechnology in cancer drug delivery and selective targeting,” ISRN Nanotechnol. 2014, 1

    Not in our library10.1155/2014/939378

  21. 21.

    M. Srinivasan, M. Rajabi, and S. Mousa, “ Multifunctional nanomaterials and their applications in drug delivery and cancer therapy,” Nanomaterials 5(4), 1690 (2015 ).

    Not in our library10.3390/nano5041690

  22. 22.

    L. Bregoli, D. Movia, J. D. Gavigan-Imedio et al., “ Nanomedicine applied to translational oncology: A future perspective on cancer treatment,” Nanomedicine 12(1), 81 (2016 ).

    Not in our library10.1016/j.nano.2015.08.006

  23. 23.

    T. S. Hauck and W. C. W. Chan, “ Gold nanoshells in cancer imaging and therapy: Towards clinical application,” Nanomedicine 2(5), 735 (2007 ).

    Not in our library10.2217/17435889.2.5.735

  24. 24.

    J. G. Morton, E. S. Day, N. J. Halas, and J. L. West, “ Nanoshells for photothermal cancer therapy,” Methods Mol. Biol. 624, 101 (2010 ).

    Not in our library10.1007/978-1-60761-609-2

  25. 25.

    C. Bharti, N. Gulati, U. Nagaich, and A. Pal, “ Mesoporous silica nanoparticles in target drug delivery system: A review,” Int. J. Pharm. Invest. 5(3), 124 (2015 ).

    Not in our library10.4103/2230-973x.160844

  26. 26.

    E. E. Connor, J. Mwamuka, A. Gole et al., “ Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity,” Small 1(3), 325 (2005 ).

    Not in our library10.1002/smll.200400093

  27. 27.

    N. S. Abadeer and C. J. Murphy, “ Recent progress in cancer thermal therapy using gold nanoparticles,” J. Phys. Chem. C 120(9), 4691 (2016 ).

    Not in our library10.1021/acs.jpcc.5b11232

  28. 28.

    S. D. Brown, P. Nativo, J.-A. Smith et al., “ Gold nanoparticles for the improved anticancer drug delivery of the active component of oxaliplatin,” J. Am. Chem. Soc. 132(13), 4678 (2010 ).

    Not in our library10.1021/ja908117a

  29. 29.

    T. Stuchinskaya, M. Moreno, M. J. Cook et al., “ Targeted photodynamic therapy of breast cancer cells using antibody-phthalocyanine-gold nanoparticle conjugates,” Photochem. Photobiol. Sci. 10(5), 822 (2011 ).

    Not in our library10.1039/c1pp05014a

  30. 30.

    M. Cordeiro, F. F. Carlos, P. Pedrosa et al., “ Gold nanoparticles for diagnostics: Advances towards points of care,” Diagnostics 6(4), E43 (2016 ).

    Not in our library10.3390/diagnostics6040043

  31. 31.

    A. M. Smith and S. Nie, “ Next-generation quantum dots,” Nat. Biotechnol. 27(8), 732 (2009 ).

    Not in our library10.1038/nbt0809-732

  32. 32.

    C. T. Matea, T. Mocan, F. Tabaran et al., “ Quantum dots in imaging, drug delivery and sensor applications,” Int. J. Nanomed. 12, 5421 (2017 ).

    Not in our library10.2147/ijn.s138624

  33. 33.

    A. Hervault and N. T. K. Thanh, “ Magnetic nanoparticle-based therapeutic agents for thermo-chemotherapy treatment of cancer,” Nanoscale 6(20), 11553 (2014 ).

    Not in our library10.1039/c4nr03482a

  34. 34.

    C. L. Dennis and R. Ivkov, “ Physics of heat generation using magnetic nanoparticles for hyperthermia,” Int. J. Hyperthermia 29(8), 715 (2013 ).

    Not in our library10.3109/02656736.2013.836758

  35. 35.

    C. Sanchez, P. Belleville, M. Popall, and L. Nicole, “ Applications of advanced hybrid organic-inorganic nanomaterials: From laboratory to market,” Chem. Soc. Rev. 40(2), 696 (2011 ).

    Not in our library10.1039/c0cs00136h

  36. 36.

    J. Das, Y. J. Choi, J. W. Han et al., “ Nanoceria-mediated delivery of doxorubicin enhances the anti-tumour efficiency in ovarian cancer cells via apoptosis,” Sci. Rep. 7(1), 9513 (2017 ).

    Not in our library10.1038/s41598-017-09876-w

  37. 37.

    C. Tapeinos, M. Battaglini, M. Prato et al., “ CeO2 nanoparticles-loaded pH-responsive microparticles with antitumoral properties as therapeutic modulators for osteosarcoma,” ACS Omega 3, 8952 (2018 ).

    Not in our library10.1021/acsomega.8b01060

  38. 38.
    Preparation, Characterization, and Preliminary In Vitro Testing of Nanoceria-Loaded Liposomes · 2017
    Not checked
  39. 39.

    M. Gulati, M. Grover, S. Singh, and M. Singh, “ Lipophilic drug derivatives in liposomes,” Int. J. Pharm. 165, 129 (1998 ).

    Not in our library10.1016/s0378-5173(98)00006-4

  40. 40.

    M. L. Immordino, F. Dosio, and L. Cattel, “ Stealth liposomes: Review of the basic science, rationale, and clinical applications, existing and potential,” Int. J. Nanomed. 1(3), 297 (2006 ).

    Not in our library10.1023/a:1020134521778

  41. 41.

    M. Markman, “ Pegylated liposomal doxorubicin in the treatment of cancers of the breast and ovary,” Expert Opin. Pharmacother. 7(11), 1469 (2006 ).

    Not in our library10.1517/14656566.7.11.1469

  42. 42.

    R. D. Hofheinz, S. U. Gnad-Vogt, U. Beyer, and A. Hochhaus, “ Liposomal encapsulated anti-cancer drugs,” Anticancer Drugs 16(7), 691 (2005 ).

    Not in our library10.1097/01.cad.0000167902.53039.5a

  43. 43.

    Y. Malam, M. Loizidou, and A. M. Seifalian, “ Liposomes and nanoparticles: Nanosized vehicles for drug delivery in cancer,” Trends Pharmacol. Sci. 30(11), 592 (2009 ).

    Not in our library10.1016/j.tips.2009.08.004

  44. 44.

    J. M. Rabanel, J. Faivre, S. F. Tehrani et al., “ Effect of the polymer architecture on the structural and biophysical properties of PEG-PLA nanoparticles,” ACS Appl. Mater. Interfaces 7(19), 10374 (2015 ).

    Not in our library10.1021/acsami.5b01423

  45. 45.

    S. Mishra, A. De, and S. Mozumdar, “ Synthesis of thermoresponsive polymers for drug delivery,” Methods Mol. Biol. 1141, 77 (2014 ).

    Not in our library10.1007/978-1-4939-0363-4

  46. 46.

    N. Gundogdu and M. Cetin, “ Chitosan-poly (lactide-co-glycolide) (CS-PLGA) nanoparticles containing metformin HCl: Preparation and in vitro evaluation,” Pak. J. Pharm. Sci. 27(6), 1923 (2014 ).

    Not in our library

  47. 47.

    W. Xiong, L. Peng, H. Chen, and Q. Li, “ Surface modification of MPEG-b-PCL-based nanoparticles via oxidative self-polymerization of dopamine for malignant melanoma therapy,” Int. J. Nanomed. 10, 2985 (2015 ).

    Not in our library10.2147/ijn.s79605

  48. 48.

    X. Zhang and P. Zhang, “ Polymersomes in nanomedicine—A review,” Curr. Med. Chem. 13(2), 124 (2017 ).

    Not in our library10.2174/1573413712666161018144519

  49. 49.

    B. M. Discher, Y. Y. Won, D. S. Ege et al., “ Polymersomes: Tough vesicles made from diblock copolymers,” Science 284(5417), 1143 (1999 ).

    Not in our library10.1126/science.284.5417.1143

  50. 50.

    J. F. Le Meins, O. Sandre, and S. Lecommandoux, “ Recent trends in the tuning of polymersomes’ membrane properties,” Eur. Phys. J. E 34(2), 14 (2011 ).

    Not in our library10.1140/epje/i2011-11014-y

  51. 51.
    Stealth Properties to Improve Therapeutic Efficacy of Drug Nanocarriers · 2013
    No notice
  52. 52.

    M. L. Adams, A. Lavasanifar, and G. S. Kwon, “ Amphiphilic block copolymers for drug delivery,” J. Pharm. Sci. 92(7), 1343 (2003 ).

    Not in our library10.1002/jps.10397

  53. 53.

    A. Nasir, A. Kausar, and A. Younus, “ A review on preparation, properties and applications of polymeric nanoparticle-based materials,” Polym.-Plast. Technol. Eng. 54(4), 325 (2015 ).

    Not in our library10.1080/03602559.2014.958780

  54. 54.

    J. C. Fernandes, M. J. Tiera, and F. M. Winnik, “ Chitosan nanoparticles for non-viral gene therapy,” in Polysaccharides for Drug Delivery and Pharmaceutical Applications, ACS Symposium Series Vol. 934 (ACS, 2006 ), Chap. 9, pp. 177.

    Not in our library

  55. 55.

    E. Baghdan, S. R. Pinnapireddy, B. Strehlow et al., “ Lipid coated chitosan-DNA nanoparticles for enhanced gene delivery,” Int. J. Pharm. 535(1-2), 473 (2018 ).

    Not in our library10.1016/j.ijpharm.2017.11.045

  56. 56.

    W. Gao, Y. Zhang, Q. Zhang, and L. Zhang, “ Nanoparticle-hydrogel: A hybrid biomaterial system for localized drug delivery,” Ann. Biomed. Eng. 44(6), 2049 (2016 ).

    Not in our library10.1007/s10439-016-1583-9

  57. 57.

    E. R. Gillies and J. M. J. Fréchet, “ Dendrimers and dendritic polymers in drug delivery,” Drug Discovery Today 10(1), 35 (2005 ).

    Not in our library10.1016/s1359-6446(04)03276-3

  58. 58.

    P. Kesharwani, K. Jain, and N. K. Jain, “ Dendrimer as nanocarrier for drug delivery,” Prog. Polym. Sci. 39(2), 268 (2014 ).

    Not in our library10.1016/j.progpolymsci.2013.07.005

  59. 59.

    A. S. Waghmare, N. D. Grampurohit, M. V. Gadhave et al., “ Solid lipid nanoparticles: A promising drug delivery system,” Int. Res. J. Pharm. 3(4), 100 (2012 ).

    Not in our library

  60. 60.

    J. Liu, Y. Xiao, and C. Allen, “ Polymer-drug compatibility: A guide to the development of delivery systems for the anticancer agent, ellipticine,” J. Pharm. Sci. 93(1), 132 (2004 ).

    Not in our library10.1002/jps.10533

  61. 61.

    R. H. Müller, M. Radtke, and S. A. Wissing, “ Nanostructured lipid matrices for improved microencapsulation of drugs,” Int. J. Pharm. 242(1-2), 121 (2002 ).

    Not in our library10.1016/s0378-5173(02)00180-1

  62. 62.

    F. Tamjidi, M. Shahedi, J. Varshosaz, and A. Nasirpour, “ Nanostructured lipid carriers (NLC): A potential delivery system for bioactive food molecules,” Innovative Food Sci. Emerging Technol. 19, 29 (2013 ).

    Not in our library10.1016/j.ifset.2013.03.002

  63. 63.

    K. Strebhardt and A. Ullrich, “ Paul Ehrlich’s magic bullet concept: 100 Years of progress,” Nat. Rev. Cancer 8(6), 473 (2008 ).

    Not in our library10.1038/nrc2394

  64. 64.

    N. Alasvand, A. M. Urbanska, M. Rahmati et al., “ Therapeutic nanoparticles for targeted delivery of anticancer drugs,” in Multifunctional Systems for Combined Delivery, Biosensing and Diagnostics (Elsevier, 2017 ), pp. 245.

    Not in our library

  65. 65.

    M. Upreti, A. Jyoti, and P. Sethi, “ Tumor microenvironment and nanotherapeutics,” Transl. Cancer Res. 2(4), 309 (2013 ).

    Not in our library10.3978/j.issn.2218-676x.2013.08.11

  66. 66.

    S. Cai, Q. Yang, T. R. Bagby, and M. L. Forrest, “ Lymphatic drug delivery using engineered liposomes and solid lipid nanoparticles,” Adv. Drug Delivery Rev. 63(10-11), 901 (2011 ).

    Not in our library10.1016/j.addr.2011.05.017

  67. 67.

    S. Barua and S. Mitragotri, “ Challenges associated with penetration of nanoparticles across cell and tissue barriers: A review of current status and future prospects,” Nano Today 9(2), 223 (2014 ).

    Not in our library10.1016/j.nantod.2014.04.008

  68. 68.

    K. Cho, X. Wang, S. Nie et al., “ Therapeutic nanoparticles for drug delivery in cancer,” Clin. Cancer Res. 14(5), 1310 (2008 ).

    Not in our library10.1158/1078-0432.ccr-07-1441

  69. 69.

    J. K. Mills and D. Needham, “ Targeted drug delivery,” Expert Opin. Ther. Pat. 9(11), 1499 (1999 ).

    Not in our library10.1517/13543776.9.11.1499

  70. 70.

    V. P. Torchilin, “ Passive and active drug targeting: Drug delivery to tumors as an example,” Handb. Exp. Pharmacol. 197, 3 (2010 ).

    Not in our library10.1007/978-3-642-00477-3

  71. 71.

    S. Xu, B. Z. Olenyuk, C. T. Okamoto, and S. F. Hamm-Alvarez, “ Targeting receptor-mediated endocytotic pathways with nanoparticles: Rationale and advances,” Adv. Drug Delivery Rev. 65(1), 121 (2013 ).

    Not in our library10.1016/j.addr.2012.09.041

  72. 72.

    D. Hymel and B. R. Peterson, “ Synthetic cell surface receptors for delivery of therapeutics and probes,” Adv. Drug Delivery Rev. 64(9), 797 (2012 ).

    Not in our library10.1016/j.addr.2012.02.007

  73. 73.

    H. Hillaireau and P. Couvreur, “ Nanocarriers’ entry into the cell: Relevance to drug delivery,” Cell. Mol. Life Sci. 66(17), 2873 (2009 ).

    Not in our library10.1007/s00018-009-0053-z

  74. 74.

    R. Vácha, F. J. Martinez-Veracoechea, and D. Frenkel, “ Receptor-mediated endocytosis of nanoparticles of various shapes,” Nano Lett. 11(12), 5391 (2011 ).

    Not in our library10.1021/nl2030213

  75. 75.

    M. Perfézou, A. Turner, and A. Merkoçi, “ Cancer detection using nanoparticle-based sensors,” Chem. Soc. Rev. 41(7), 2606 (2012 ).

    Not in our library10.1039/c1cs15134g

  76. 76.

    V. P. Torchilin, “ Recent advances with liposomes as pharmaceutical carriers,” Nat. Rev. Drug Discovery 4(2), 145 (2005 ).

    Not in our library10.1038/nrd1632

  77. 77.

    J. Nicolas, S. Mura, D. Brambilla et al., “ Design, functionalization strategies and biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery,” Chem. Soc. Rev. 42(3), 1147 (2013 ).

    Not in our library10.1039/c2cs35265f

  78. 78.

    Y. B. Patil, U. S. Toti, A. Khdair et al., “ Single-step surface functionalization of polymeric nanoparticles for targeted drug delivery,” Biomaterials 30(5), 859 (2009 ).

    Not in our library10.1016/j.biomaterials.2008.09.056

  79. 79.

    D. Sutton, N. Nasongkla, E. Blanco, and J. Gao, “ Functionalized micellar systems for cancer targeted drug delivery,” Pharm. Res. 24(6), 1029 (2007 ).

    Not in our library10.1007/s11095-006-9223-y

  80. 80.

    C. Zhan, B. Gu, C. Xie et al., “ Cyclic RGD conjugated poly(ethylene glycol)-co-poly(lactic acid) micelle enhances paclitaxel anti-glioblastoma effect,” J. Controlled Release 143(1), 136 (2010 ).

    Not in our library10.1016/j.jconrel.2009.12.020

  81. 81.

    S. Senol, A. B. Ceyran, A. Aydin et al., “ Folate receptor α expression and significance in endometrioid endometrium carcinoma and endometrial hyperplasia,” Int. J. Clin. Exp. Pathol. 8(5), 5633 (2015 ).

    Not in our library

  82. 82.

    B. Stella, S. Arpicco, M. T. Peracchia et al., “ Design of folic acid-conjugated nanoparticles for drug targeting,” J. Pharm. Sci. 89(11), 1452 (2000 ).

    Not in our library10.1002/1520-6017(200011)89:11<1452::aid-jps8>3.0.co;2-p

  83. 83.

    E. Roger, S. Kalscheuer, A. Kirtane et al., “ Folic acid functionalized nanoparticles for enhanced oral drug delivery,” Mol. Pharm. 9(7), 2103 (2012 ).

    Not in our library10.1021/mp2005388

  84. 84.

    L. Cheng, H. Ma, M. Shao et al., “ Synthesis of folate-chitosan nanoparticles loaded with ligustrazine to target folate receptor positive cancer cells,” Mol. Med. Rep. (2), 1101 (2017 ).

    Not in our library10.3892/mmr.2017.6740

  85. 85.

    H. Zhang, J. Li, Y. Hu et al., “ Folic acid-targeted iron oxide nanoparticles as contrast agents for magnetic resonance imaging of human ovarian cancer,” J. Ovarian Res. 9, 19 (2016 ).

    Not in our library10.1186/s13048-016-0230-2

  86. 86.

    M.-K. Yoo, I.-K. Park, H.-T. Lim et al., “ Folate–PEG–superparamagnetic iron oxide nanoparticles for lung cancer imaging,” Acta Biomater. 8(8), 3005 (2012 ).

    Not in our library10.1016/j.actbio.2012.04.029

  87. 87.

    L. Li, F. Gao, W. Jiang et al., “ Folic acid-conjugated superparamagnetic iron oxide nanoparticles for tumor-targeting MR imaging,” Drug Delivery 23(5), 1726 (2016 ).

    Not in our library10.3109/10717544.2015.1006404

  88. 88.

    J. H. Han, Y. K. Oh, D. S. Kim, and C. K. Kim, “ Enhanced hepatocyte uptake and liver targeting of methotrexate using galactosylated albumin as a carrier,” Int. J. Pharm. 188(1), 39 (1999 ).

    Not in our library10.1016/s0378-5173(99)00206-9

  89. 89.

    Y. I. Jeong, S. J. Seo, I. K. Park et al., “ Cellular recognition of paclitaxel-loaded polymeric nanoparticles composed of poly(γ-benzyl L-glutamate) and poly(ethylene glycol) diblock copolymer endcapped with galactose moiety,” Int. J. Pharm. 296(1–2), 151 (2005 ).

    Not in our library10.1016/j.ijpharm.2005.02.027

  90. 90.

    H. Yan, T. Kamiya, P. Suabjakyong, and N. M. Tsuji, “ Targeting C-type lectin receptors for cancer immunity,” Front. Immunol. 6, 408 (2015 ).

    Not in our library10.3389/fimmu.2015.00408

  91. 91.

    A. Jain, A. Agarwal, S. Majumder et al., “ Mannosylated solid lipid nanoparticles as vectors for site-specific delivery of an anti-cancer drug,” J. Controlled Release 148(3), 359 (2010 ).

    Not in our library10.1016/j.jconrel.2010.09.003

  92. 92.

    R. C. Ladner, A. K. Sato, J. Gorzelany, and M. De Souza, “ Phage display-derived peptides as therapeutic alternatives to antibodies,” Drug Discovery Today 9(12), 525 (2004 ).

    Not in our library10.1016/s1359-6446(04)03104-6

  93. 93.

    H. Koo, M. S. Huh, I. C. Sun et al., “ In vivo targeted delivery of nanoparticles for theranosis,” Acc. Chem. Res. 44(10), 1018 (2011 ).

    Not in our library10.1021/ar2000138

  94. 94.

    M. Demeule, J. C. Currie, Y. Bertrand et al., “ Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector Angiopep-2,” J. Neurochem. 106(4), 1534 (2008 ).

    Not in our library10.1111/j.1471-4159.2008.05492.x

  95. 95.

    J. Kreuter, D. Shamenkov, V. Petrov et al., “ Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier,” J. Drug Targeting 10(4), 317 (2002 ).

    Not in our library10.1080/10611860290031877

  96. 96.

    L. Recht, C. O. Torres, T. W. Smith et al., “ Transferrin receptor in normal and neoplastic brain tissue: Implications for brain-tumor immunotherapy,” J. Neurosurg. 72(6), 941 (1990 ).

    Not in our library10.3171/jns.1990.72.6.0941

  97. 97.

    T. R. Daniels, E. Bernabeu, J. A. Rodríguez et al., “ The transferrin receptor and the targeted delivery of therapeutic agents against cancer,” Biochim. Biophys. Acta 1820(3), 291 (2012 ).

    Not in our library10.1016/j.bbagen.2011.07.016

  98. 98.
    Antibody fragments as nanoparticle targeting ligands: a step in the right direction · 2017
    No notice
  99. 99.

    P. Carter, “ Improving the efficacy of antibody-based cancer therapies,” Nat. Rev. Cancer 1(2), 118 (2001 ).

    Not in our library10.1038/35101072

  100. 100.

    K. Ulbrich, T. Hekmatara, E. Herbert, and J. Kreuter, “ Transferrin- and transferrin-receptor-antibody-modified nanoparticles enable drug delivery across the blood-brain barrier (BBB),” Eur. J. Pharm. Biopharm. 71(2), 251 (2009 ).

    Not in our library10.1016/j.ejpb.2008.08.021

  101. 101.
    Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma · 2017
    No notice
  102. 102.

    R. C. Conrad, L. Giver, Y. Tian, and A. D. Ellington, “ In vitro selection of nucleic acid aptamers that bind proteins,” Methods Enzymol. 267, 336 (1996 ).

    Not in our library10.1016/s0076-6879(96)67022-0

  103. 103.
    Aptamers: Problems, Solutions and Prospects · 2013
    No notice
  104. 104.

    P. R. Bouchard, R. M. Hutabarat, and K. M. Thompson, “ Discovery and development of therapeutic aptamers,” Annu. Rev. Pharmacol. Toxicol. 50, 237 (2010 ).

    Not in our library10.1146/annurev.pharmtox.010909.105547

  105. 105.

    A. Jhaveri, P. Deshpande, and V. Torchilin, “ Stimuli-sensitive nanopreparations for combination cancer therapy,” J. Controlled Release 190, 352 (2014 ).

    Not in our library10.1016/j.jconrel.2014.05.002

  106. 106.

    Y. Obata, S. Tajima, and S. Takeoka, “ Evaluation of pH-responsive liposomes containing amino acid-based zwitterionic lipids for improving intracellular drug delivery in vitro and in vivo,” J Controlled Release 142(2), 267 (2010 ).

    Not in our library10.1016/j.jconrel.2009.10.023

  107. 107.

    I. F. Tannock and D. Rotin, “ Acid pH in tumors and its potential for therapeutic exploitation,” Cancer Res. 49(16), 4373 (1989 ).

    Not in our library

  108. 108.

    Y. C. Wang, F. Wang, T. M. Sun, and J. Wang, “ Redox-responsive nanoparticles from the single disulfide bond-bridged block copolymer as drug carriers for overcoming multidrug resistance in cancer cells,” Bioconjugate Chem. 22(10), 1939 (2011 ).

    Not in our library10.1021/bc200139n

  109. 109.

    V. Torchilin, “ Multifunctional and stimuli-sensitive pharmaceutical nanocarriers,” Eur. J. Pharm. Biopharm. 71(3), 431 (2009 ).

    Not in our library10.1016/j.ejpb.2008.09.026

  110. 110.

    D. Needham, G. Anyarambhatla, G. Kong, and M. W. Dewhirst, “ A new temperature-sensitive liposome for use with mild hyperthermia: Characterization and testing in a human tumor xenograft model,” Cancer Res. 60(5), 1197 (2000 ).

    Not in our library

  111. 111.

    B. M. Dicheva and G. A. Koning, “ Targeted thermosensitive liposomes: An attractive novel approach for increased drug delivery to solid tumors,” Expert Opin. Drug Delivery 11(1), 83 (2014 ).

    Not in our library10.1517/17425247.2014.866650

  112. 112.

    N. Fomina, C. McFearin, M. Sermsakdi et al., “ UV and near-IR triggered release from polymeric nanoparticles,” J. Am. Chem. Soc. 132(28), 9540 (2010 ).

    Not in our library10.1021/ja102595j

  113. 113.

    A. Schroeder, R. Honen, K. Turjeman et al., “ Ultrasound triggered release of cisplatin from liposomes in murine tumors,” J. Controlled Release 137(1), 63 (2009 ).

    Not in our library10.1016/j.jconrel.2009.03.007

  114. 114.

    K. D. Siegmund, P. Marjoram, Y.-J. Woo et al., “ Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers,” Proc. Natl. Acad. Sci U. S. A. 106(12), 4828 (2009 ).

    Not in our library10.1073/pnas.0810276106

  115. 115.

    M. Yezhelyev, R. Yacoub, and R. O’Regan, “ Inorganic nanoparticles for predictive oncology of breast cancer,” Nanomedicine 4(1), 83 (2009 ).

    Not in our library10.2217/17435889.4.1.83

  116. 116.

    C. Loo, A. Lin, L. Hirsch et al., “ Nanoshell-enabled photonics-based imaging and therapy of cancer,” Technol. Cancer Res. Treat. 3(1), 33 (2004 ).

    Not in our library10.1177/153303460400300104

  117. 117.

    C. Loo, A. Lowery, N. Halas et al., “ Immunotargeted nanoshells for integrated cancer imaging and therapy,” Nano Lett. 5(4), 709 (2005 ).

    Not in our library10.1021/nl050127s

  118. 118.

    M. Eghtedari, A. Oraevsky, J. A. Copland et al., “ High sensitivity of in vivo detection of gold nanorods using a laser optoacoustic imaging system,” Nano Lett. 7(7), 1914 (2007 ).

    Not in our library10.1021/nl070557d

  119. 119.

    X. Yang, S. E. Skrabalak, Z. Y. Li et al., “ Photoacoustic tomography of a rat cerebral cortex in vivo with Au nanocages as an optical contrast agent,” Nano Lett. 7(12), 3798 (2007 ).

    Not in our library10.1021/nl072349r

  120. 120.

    L. S. Wang, L. C. Wu, S. Y. Lu et al., “ Biofunctionalized phospholipid-capped mesoporous silica nanoshuttles for targeted drug delivery: Improved water suspensibility and decreased nonspecific protein binding,” ACS Nano 4(8), 4371 (2010 ).

    Not in our library10.1021/nn901376h

  121. 121.

    U. Resch-Genger, M. Grabolle, S. Cavaliere-Jaricot et al., “ Quantum dots versus organic dyes as fluorescent labels,” Nat. Methods 5(9), 763 (2008 ).

    Not in our library10.1038/nmeth.1248

  122. 122.

    P. Malik, S. Gulia, and R. Kakkar, “ Quantum dots for diagnosis of cancers,” Adv. Mater. Lett. 4(11), 811 (2013 ).

    Not in our library10.5185/amlett.2013.3437

  123. 123.

    X. Wu, H. Liu, J. Liu et al., “ Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots,” Nat. Biotechnol. 21(1), 41 (2003 ).

    Not in our library10.1038/nbt764

  124. 124.

    J. Gao, K. Chen, Z. Miao et al., “ Affibody-based nanoprobes for HER2-expressing cell and tumor imaging,” Biomaterials 32(8), 2141 (2011 ).

    Not in our library10.1016/j.biomaterials.2010.11.053

  125. 125.

    L. Ye, K. T. Yong, L. Liu et al., “ A pilot study in non-human primates shows no adverse response to intravenous injection of quantum dots,” Nat. Nanotechnol. 7(7), 453 (2012 ).

    Not in our library10.1038/nnano.2012.74

  126. 126.

    A. S. Arbab, L. A. Bashaw, B. R. Miller et al., “ Characterization of biophysical and metabolic properties of cells labeled with superparamagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging,” Radiology 229(3), 838 (2003 ).

    Not in our library10.1148/radiol.2293021215

  127. 127.

    H. Choi, S. R. Choi, R. Zhou et al., “ Iron oxide nanoparticles as magnetic resonance contrast agent for tumor imaging via folate receptor-targeted delivery,” Acad. Radiol. 11(9), 996 (2004 ).

    Not in our library10.1016/j.acra.2004.04.018

  128. 128.

    L. Josephson, C. H. Tung, A. Moore, and R. Weissleder, “ High-efficiency intracellular magnetic labeling with novel superparamagnetic-tat peptide conjugates,” Bioconjugate Chem. 10(2), 186 (1999 ).

    Not in our library10.1021/bc980125h

  129. 129.

    M. C. Lamkowsky, M. Geppert, M. M. Schmidt, and R. Dringen, “ Magnetic field-induced acceleration of the accumulation of magnetic iron oxide nanoparticles by cultured brain astrocytes,” J. Biomed. Mater. Res., Part A. 100(2), 323 (2012 ).

    Not in our library10.1002/jbm.a.33263

  130. 130.

    S. Prijic, J. Scancar, R. Romih et al., “ Increased cellular uptake of biocompatible superparamagnetic iron oxide nanoparticles into malignant cells by an external magnetic field,” J. Membr. Biol. 236(1), 167 (2010 ).

    Not in our library10.1007/s00232-010-9271-4

  131. 131.

    J. H. Lee, Y. M. Huh, Y. W. Jun et al., “ Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging,” Nat. Med. 13, 95 (2007 ).

    Not in our library10.1038/nm1467

  132. 132.

    C. G. Hadjipanayis, R. Machaidze, M. Kaluzova et al., “ EGFRvIII antibody-conjugated iron oxide nanoparticles for magnetic resonance imaging-guided convection-enhanced delivery and targeted therapy of glioblastoma,” Cancer Res. 70(15), 6303 (2010 ).

    Not in our library10.1158/0008-5472.can-10-1022

  133. 133.

    B. a Moffat, G. R. Reddy, P. McConville et al., “ A novel polyacrylamide magnetic nanoparticle contrast agent for molecular imaging using MRI,” Mol. Imaging 2(4), 324 (2003 ).

    Not in our library10.1162/153535003322750664

  134. 134.
    Multifunctional Magnetic-fluorescent Nanocomposites for Biomedical Applications · 2008
    No notice
  135. 135.

    A. B. Chinen, C. M. Guan, J. R. Ferrer et al., “ Nanoparticle probes for the detection of cancer biomarkers, cells, and tissues by fluorescence,” Chem. Rev. 115(19), 10530 (2015 ).

    Not in our library10.1021/acs.chemrev.5b00321

  136. 136.

    Z. Wang, Y. Yu, W. Dai et al., “ The use of a tumor metastasis targeting peptide to deliver doxorubicin-containing liposomes to highly metastatic cancer,” Biomaterials 33(33), 8451 (2012 ).

    Not in our library10.1016/j.biomaterials.2012.08.031

  137. 137.

    J. Chen, H. Jiang, Y. Wu et al., “ A novel glycyrrhetinic acid-modified oxaliplatin liposome for liver-targeting and in vitro/vivo evaluation,” Drug Des., Dev. Ther. 9, 2265 (2015 ).

    Not in our library10.2147/dddt.s81722

  138. 138.

    C. N. Landen, A. Chavez-Reyes, C. Bucana et al., “ Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery,” Cancer Res. 65(15), 6910 (2005 ).

    Not in our library10.1158/0008-5472.can-05-0530

  139. 139.

    A. M. Tari, Y. Gutiérrez-Puente, G. Monaco et al., “ Liposome-incorporated Grb2 antisense oligodeoxynucleotide increases the survival of mice bearing bcr-abl-positive leukemia xenografts,” Int. J. Oncol. 31(5), 1243 (2007 ).

    Not in our library

  140. 140.

    M. E. Davis, J. E. Zuckerman, C. H. J. Choi et al., “ Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles,” Nature 464, 1067 (2010 ).

    Not in our library10.1038/nature08956

  141. 141.

    S. L. Huang and R. C. MacDonald, “ Acoustically active liposomes for drug encapsulation and ultrasound-triggered release,” Biochim. Biophys. Acta 1665(1–2), 134 (2004 ).

    Not in our library10.1016/j.bbamem.2004.07.003

  142. 142.

    Y. Ueno, S. Sonoda, R. Suzuki et al., “ Combination of ultrasound and bubble liposome enhance the effect of doxorubicin and inhibit murine osteosarcoma growth,” Cancer Biol. Ther. 12(4), 270 (2011 ).

    Not in our library10.4161/cbt.12.4.16259

  143. 143.

    O. V. Gerasimov, J. A. Boomer, M. M. Qualls, and D. H. Thompson, “ Cytosolic drug delivery using pH- and light-sensitive liposomes,” Adv. Drug Delivery Rev. 38(3), 317 (1999 ).

    Not in our library10.1016/s0169-409x(99)00035-6

  144. 144.

    D. Papahadjopoulos, K. Jacobson, S. Nir, and I. Isac, “ Phase transitions in phospholipid vesicles Fluorescence polarization and permeability measurements concerning the effect of temperature and cholesterol,” BBA 311(3), 330 (1973 ).

    Not in our library10.1016/0005-2736(73)90314-3

  145. 145.

    J. S. Lee and J. Feijen, “ Polymersomes for drug delivery: Design, formation and characterization,” J. Controlled Release 161(2), 473 (2012 ).

    Not in our library10.1016/j.jconrel.2011.10.005

  146. 146.

    Y. Kaneda, Y. Tsutsumi, Y. Yoshioka et al., “ The use of PVP as a polymeric carrier to improve the plasma half-life of drugs,” Biomaterials 25(16), 3259 (2004 ).

    Not in our library10.1016/j.biomaterials.2003.10.003

  147. 147.

    S. Li, B. Byrne, J. E. Welsh, and A. F. Palmer, “ Self-assembled poly(butadiene)-b-poly(ethylene oxide) polymersomes as paclitaxel carriers,” Biotechnol. Prog. 23(1), 278 (2007 ).

    Not in our library10.1002/bp060185z

  148. 148.

    C. Murdoch, K. J. Reeves, V. Hearnden et al., “ Internalization and biodistribution of polymersomes into oral squamous cell carcinoma cells in vitro and in vivo,” Nanomedicine 5(7), 1025 (2010 ).

    Not in our library10.2217/nnm.10.97

  149. 149.

    P. Baumann, V. Balasubramanian, O. Onaca-Fischer et al., “ Light-responsive polymer nanoreactors: A source of reactive oxygen species on demand,” Nanoscale 5, 217 (2013 ).

    Not in our library10.1039/c2nr32380j

  150. 150.

    F. Ahmed, R. I. Pakunlu, G. Srinivas et al., “ Shrinkage of a rapidly growing tumor by drug-loaded polymersomes: PH-triggered release through copolymer degradation,” Mol. Pharm. 3(3), 340 (2006 ).

    Not in our library10.1021/mp050103u

  151. 151.

    G. Battaglia and A. J. Ryan, “ Bilayers and interdigitation in block copolymer vesicles,” J. Am. Chem. Soc. 127(24), 8757 (2005 ).

    Not in our library10.1021/ja050742y

  152. 152.

    R. Stoenescu, A. Graff, and W. Meier, “ Asymmetric ABC-triblock copolymer membranes induce a directed insertion of membrane proteins,” Macromol. Biosci. 4(10), 930 (2004 ).

    Not in our library10.1002/mabi.200400065

  153. 153.

    R. Pelton, “ Temperature-sensitive aqueous microgels,” Adv. Colloid Interface Sci. 85(1), 1 (2000 ).

    Not in our library10.1016/s0001-8686(99)00023-8

  154. 154.

    D. Kim, E. S. Lee, K. Park et al., “ Doxorubicin loaded pH-sensitive micelle: Antitumoral efficacy against ovarian A2780/DOXR tumor,” Pharm. Res. 25(9), 2074 (2008 ).

    Not in our library10.1007/s11095-008-9603-6

  155. 155.

    E. R. Gillies and J. M. J. Fréchet, “ Development of acid-sensitive copolymer micelles for drug delivery,” Pure Appl. Chem. 76(7–8), 1295 (2004 ).

    Not in our library10.1351/pac200476071295

  156. 156.

    J. Vega, S. Ke, Z. Fan et al., “ Targeting doxorubicin to epidermal growth factor receptors by site-specific conjugation of C225 to poly(L-glutamic acid) through a polyethylene glycol spacer,” Pharm. Res. 20(5), 826 (2003 ).

    Not in our library10.1023/a:1023454107190

  157. 157.

    N. Nasongkla, X. Shuai, H. Ai et al., “ cRGD-functionalized polymer micelles for targeted doxorubicin delivery,” Angew. Chem.–Int. Ed. 43(46), 6323 (2004 ).

    Not in our library10.1002/anie.200460800

  158. 158.

    M. D. C. Topp, P. J. Dijkstra, H. Talsma, and J. Feijen, “ Thermosensitive micelle-forming block copolymers of poly(ethylene glycol) and poly(n-isopropylacrylamide,” Macromolecules 115(19), 5913 (1997 ).

    Not in our library10.1021/ma9710803

  159. 159.

    H. Wei, S. X. Cheng, X. Z. Zhang, and R. X. Zhuo, “ Thermo-sensitive polymeric micelles based on poly(N-isopropylacrylamide) as drug carriers,” Prog. Polym. Sci. 34, 893 (2009 ).

    Not in our library10.1016/j.progpolymsci.2009.05.002

  160. 160.

    M. E. Werner, N. D. Cummings, M. Sethi et al., “ Preclinical evaluation of genexol-pm, a nanoparticle formulation of paclitaxel, as a novel radiosensitizer for the treatment of non-small cell lung cancer,” Int. J. Radiat. Oncol. Biol. Phys. 86(3), 463 (2013 ).

    Not in our library10.1016/j.ijrobp.2013.02.009

  161. 161.

    E. M. Pridgen, F. Alexis, and O. C. Farokhzad, “ Polymeric nanoparticle technologies for oral drug delivery,” Clin. Gastroenterol. Hepatol. 12(10), 1605 (2014 ).

    Not in our library10.1016/j.cgh.2014.06.018

  162. 162.

    A. Krishna Sailaja, P. Amareshwar, and P. Chakravarty, “ Chitosan nanoparticles as a drug delivery system,” Res. J. Pharm. Biol. Chem. Sci. 1 (2010 ).

    Not in our library

  163. 163.

    M. A. G. Raja, H. Katas, and T. J. Wen, “ Stability, intracellular delivery, and release of siRNA from chitosan nanoparticles using different cross-linkers,” PLoS One 10(6), 1 (2015 ).

    Not in our library10.1371/journal.pone.0128963

  164. 164.

    M. Malhotra, C. Tomaro-Duchesneau, S. Saha, and S. Prakash, “ Intranasal delivery of chitosan-sirna nanoparticle formulation to the brain,” Methods Mol. Biol. 1141, 233 (2014 ).

    Not in our library10.1007/978-1-4939-0363-4_15

  165. 165.

    A. Jain, S. K. Jain, N. Ganesh et al., “ Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer,” Nanomed. Nanotechnol., Biol. Med. 6(1), 179 (2010 ).

    Not in our library10.1016/j.nano.2009.03.002

  166. 166.

    M. A. Ward and T. K. Georgiou, “ Thermoresponsive polymers for biomedical applications,” Polymers 3(3), 1215 (2011 ).

    Not in our library10.3390/polym3031215

  167. 167.

    P. Andreozzi, E. Diamanti, K. R. Py-Daniel et al., “ Exploring the pH sensitivity of poly(allylamine) phosphate supramolecular nanocarriers for intracellular siRNA Delivery,” ACS Appl. Mater. Interfaces 9, 38242 (2017 ).

    Not in our library10.1021/acsami.7b11132

  168. 168.

    N. Malik, E. G. Evagorou, and R. Duncan, “ Dendrimer-platinate: A novel approach to cancer chemotherapy,” Anticancer Drugs 10(8), 767 (1999 ).

    Not in our library10.1097/00001813-199909000-00010

  169. 169.

    K. T. Al-jamal, N. Rubio, J. Buddle et al., “ Cationic poly-l-lysine dendrimer complexes doxorubicin and delays tumor growth in vitro and in vivo,” ACS Nano 7(3), 1905 (2013 ).

    Not in our library10.1021/nn305860k

  170. 170.

    J. Yang, Y. Luo, Y. Xu et al., “ Conjugation of iron oxide nanoparticles with RGD-modified dendrimers for targeted tumor MR imaging,” ACS Appl. Mater. Interfaces 7(9), 5420 (2015 ).

    Not in our library10.1021/am508983n

  171. 171.

    Y. Zou, G. Zong, Y. H. Ling et al., “ Effective treatment of early endobronchial cancer with regional administration of liposome-p53 complexes,” J. Natl. Cancer Inst. 90(15), 1130 (1998 ).

    Not in our library10.1093/jnci/90.15.1130

  172. 172.

    M. Bartsch, A. H. Weeke-Klimp, E. P. D. Hoenselaar et al., “ Stabilized lipid coated lipoplexes for the delivery of antisense oligonucleotides to liver endothelial cells in vitro and in vivo,” J. Drug Target 90(15), 1130 (2004 ).

    Not in our library10.1080/10611860400013519

  173. 173.

    J. Kreuter, P. Ramge, V. Petrov et al., “ Direct evidence that polysorbate-80-coated poly(butylcyanoacrylate) nanoparticles deliver drugs to the CNS via specific mechanisms requiring prior binding of drug to the nanoparticles,” Pharm. Res. 20(3), 409 (2003 ).

    Not in our library10.1023/a:1022604120952

  174. 174.

    A. Khajavinia, J. Varshosaz, and A. J. Dehkordi, “ Targeting etoposide to acute myelogenous leukaemia cells using nanostructured lipid carriers coated with transferrin,” Nanotechnology 23(40), 405101 (2012 ).

    Not in our library10.1088/0957-4484/23/40/405101

  175. 175.

    H. Jiang, L. Pei, N. Liu et al., “ Etoposide-loaded nanostructured lipid carriers for gastric cancer therapy,” Drug Delivery 23(4), 1379 (2016 ).

    Not in our library10.3109/10717544.2015.1048491

  176. 176.

    X. Li, X. Jia, and H. Niu, “ Nanostructured lipid carriers co-delivering lapachone and doxorubicin for overcoming multidrug resistance in breast cancer therapy,” Int. J. Nanomed. 13, 4107 (2018 ).

    Not in our library10.2147/ijn.s163929

  177. 177.

    X. Ding, X. Xu, Y. Zhao et al., “ Tumor targeted nanostructured lipid carrier co-delivering paclitaxel and indocyanine green for laser triggered synergetic therapy of cancer,” RSC Adv. 7, 35086 (2017 ).

    Not in our library10.1039/c7ra06119f

  178. 178.

    M. Bondì, A. Azzolina, E. Craparo et al., “ Entrapment of an EGFR inhibitor into nanostructured lipid carriers (NLC) improves its antitumor activity against human hepatocarcinoma cells,” J. Nanobiotechnol. 12, 21 (2014 ).

    Not in our library10.1186/1477-3155-12-21

  179. 179.

    L. Jia, J. Shen, D. Zhang et al., “ In vitro and in vivo evaluation of oridonin-loaded long circulating nanostructured lipid carriers,” Int. J. Biol. Macromol. 50(3), 523 (2012 ).

    Not in our library10.1016/j.ijbiomac.2012.01.024

  180. 180.

    X. Zhao, Y. Zhao, L. Geng et al., “ Pharmacokinetics and tissue distribution of docetaxel by liquid chromatography-mass spectrometry: Evaluation of folate receptor-targeting amphiphilic copolymer modified nanostructured lipid carrier,” J. Chromatogr., B 879(31), 3721 (2011 ).

    Not in our library10.1016/j.jchromb.2011.10.015

  181. 181.

    A. Grillone, E. R. Riva, A. Mondini et al., “ Active targeting of sorafenib: Preparation, characterization, and in vitro testing of drug-loaded magnetic solid lipid nanoparticles,” Adv. Healthcare Mater. 4(11), 1681 (2015 ).

    Not in our library10.1002/adhm.201500235

  182. 182.

    C. Tapeinos, A. Marino, M. Battaglini et al., “ Stimuli-responsive lipid-based magnetic nanovectors increase apoptosis in glioblastoma cells through synergic intracellular hyperthermia and chemotherapy,” Nanoscale 11(1), 72 (2018 ).

    Not in our library10.1039/c8nr05520c

  183. 183.

    S. R. D’Mello, C. N. Cruz, M. L. Chen et al., “ The evolving landscape of drug products containing nanomaterials in the United States,” Nat. Nanotechnol. 12, 523 (2017 ).

    Not in our library10.1038/nnano.2017.67

  184. 184.

    P. Evers, Nanotechnology in Medical Applications: The Global Market. BCC Research ( Business Communications Company (BCC) Inc, Wellesley, MA, USA, 2017 ).

    Not in our library

  185. 185.

    R. A. Petros and J. M. Desimone, “ Strategies in the design of nanoparticles for therapeutic applications,” Nat. Rev. Drug Discovery 9(8), 615 (2010 ).

    Not in our library10.1038/nrd2591

  186. 186.

    D. Bobo, K. J. Robinson, J. Islam et al., “ Nanoparticle-based medicines: A review of FDA-approved materials and clinical trials to date,” Pharm. Res. 33(10), 2373 (2016 ).

    Not in our library10.1007/s11095-016-1958-5

  187. 187.

    J. I. Hare, T. Lammers, M. B. Ashford et al., “ Challenges and strategies in anti-cancer nanomedicine development: An industry perspective,” Adv. Drug Delivery Rev. 108, 25 (2017 ).

    Not in our library10.1016/j.addr.2016.04.025

  188. 188.

    Y. Barenholz, “ Doxil®—The first FDA-approved nano-drug: Lessons learned,” J. Controlled Release 160(2), 117 (2012 ).

    Not in our library10.1016/j.jconrel.2012.03.020

  189. 189.

    A. N. Gordon, J. T. Fleagle, D. Guthrie et al., “ Recurrent epithelial ovarian carcinoma: A randomized phase III study of pegylated liposomal doxorubicin versus topotecan,” J. Clin. Oncol. 19(14), 3312 (2001 ).

    Not in our library10.1200/jco.2001.19.14.3312

  190. 190.

    J. P. May and S.-D. Li, “ Hyperthermia-induced drug targeting,” Expert Opin. Drug Delivery 10(4), 511 (2013 ).

    Not in our library10.1517/17425247.2013.758631

  191. 191.

    B. Thiesen and A. Jordan, “ Clinical applications of magnetic nanoparticles for hyperthermia,” Int. J. Hyperthermia 24(6), 467 (2008 ).

    Not in our library10.1080/02656730802104757

  192. 192.
    The use of theranostic gadolinium-based nanoprobes to improve radiotherapy efficacy · 2014
    No notice
  193. 193.

    L. Maggiorella, G. Barouch, C. Devaux et al., “ Nanoscale radiotherapy with hafnium oxide nanoparticles,” Future Oncol. 8(9), 1167 (2012 ).

    Not in our library10.2217/fon.12.96

  194. 194.

    J. Hrkach, D. Von Hoff, M. M. Ali et al., “ Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile,” Sci. Transl. Med. 4(128), 128ra39 (2012 ).

    Not in our library10.1126/scitranslmed.3003651

  195. 195.

    C. Mamot, R. Ritschard, A. Wicki et al., “ Tolerability, safety, pharmacokinetics, and efficacy of doxorubicin-loaded anti-EGFR immunoliposomes in advanced solid tumours: A phase 1 dose-escalation study,” Lancet Oncol. 13(12), 1234 (2012 ).

    Not in our library10.1016/s1470-2045(12)70476-x

  196. 196.

    FDA website, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020416 for Approval document for Feridex I.V.

    Not in our library

  197. 197.

    FDA website, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020410 for Approval document for GastroMARK™.

    Not in our library

  198. 198.

    FDA website, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103411 for Approval document for Oncaspar®.

    Not in our library

  199. 199.

    FDA website, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=050718 for Approval document for Doxil (Liposomal).

    Not in our library

  200. 200.

    FDA website, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=050704 for Approval document for DaunoXome.

    Not in our library

  201. 201.

    FDA website, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=103767 for Approval document for Ontak.

    Not in our library

  202. 202.

    EMA website, https://www.ema.europa.eu/medicines/human/EPAR/myocet for Approval document for Myocet.

    Not in our library

  203. 203.

    FDA website, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/021343Orig1s030,021379Orig1s030,021488Orig1s027,021731Orig1s027ltr.pdf for Approval document for Eligard®.

    Not in our library

  204. 204.

    FDA website, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125031 for Approval document for Neulasta®.

    Not in our library

  205. 205.

    FDA website, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21660_AbraxaneTOC.cfm for Approval document for Abraxane.

    Not in our library

  206. 206.

    EMA website, https://www.ema.europa.eu/en/medicines/human/EPAR/mepact for Approval document for Mepact®.

    Not in our library

  207. 207.

    FDA website, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202497_marqibo_toc.cfm for Approval document for Marqibo®.

    Not in our library

  208. 208.

    FDA website, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207793Orig1s000Approv.pdf for Approval document for Onivyde®.

    Not in our library

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