Nanoparticles For Tumor-targeted Drug Delivery Research Articles

Hydroxychloroquine loaded hollow apoferritin nanocages for cancer drug repurposing and autophagy inhibition

Hydroxychloroquine sulfate (HCQ) is currently being repurposed for cancer treatment. The antitumor mechanism of HCQ is inhibition of cellular autophagy, but its therapeutic potential is severely limited by poor solubility, lack of tumor targeting and lower cellular uptake. Therefore, utilization of human H-chain apoferritin (HFn) composed only of heavy subunits is an attractive approach for tumor targeting drug delivery. This study focused on pH-triggered encapsulation of HCQ within the inner cavity of HFn to form HFn@HCQ nanoparticles for tumor-targeted drug delivery. Characterization using a range of techniques has been used to confirm the successful establishment of HFn@HCQ. HFn@HCQ exhibited pH-responsive release behavior, with almost no drug release at pH 7.4, but 80% release at pH 5.0. Owing to its intrinsic binding to transferrin receptor 1 (TfR1), HFn@HCQ was significantly internalized through TfR1-mediated endocytosis, with a 4.4-fold difference of internalization amount across cell lines. Additionally, HFn@HCQ enhanced the antitumor effect against four different cancer cell lines when compared against HCQ alone, especially in TfR1 high-expressing cells, where the inhibitory effect was 3-fold higher than free HCQ. The autophagy inhibition of HFn@HCQ has been demonstrated, which is a major pathway to induce cancer cell death. According to current findings, HFn based drug delivery is a promising strategy to target and kill TfR1 overexpressing tumor cells.

Hypoxia-responsive nanoparticles for tumor-targeted drug delivery.

Hypoxia is a negative prognostic indicator of solid tumors. Increasing evidence indicates that the intratumoral hypoxic microenvironment is strongly related to enhanced tumor aggressiveness, decreased therapeutic effect and poor prognosis of chemotherapy, radiotherapy (RT), and photodynamic therapy (PDT). However, due to an unusual gene expression profile and abnormal metabolism, enzymes responsible for reduction reactions or electron donation are highly reactive in hypoxic tumor cells and provide the possibility of exploiting targeted drug delivery systems for cancer therapy. Taking advantage of the specific bioreductive microenvironments in hypoxic tumors, researchers have recently developed several hypoxia-responsive nanoparticles (HR-NPs) for targeted cancer therapy. In this review, the hypoxia-responsive molecular structures that were employed to construct HR-NPs are presented. Furthermore, the strategies to make use of these HR-NPs, and the recent advances in HR-NPs for efficient tumor-targeted drug delivery and cancer therapy are highlighted.

Advances in aggregatable nanoparticles for tumor-targeted drug delivery

Recent days, aggregatable nanoparticles, which can specifically respond to certain stimulus, have shown great potential in tumor-targeted drug delivery with prolonged retention and deeper penetration. In this review, we summarize recent advances in design of aggregatable nanoparticles by different stimuli. Internal (pH and enzyme) and external (light, temperature and ROS) stimuli are introduced for a comprehensive description. Moreover, the aggregated nanoparticles usually exhibit photothermal, photoacoustic, PET and enhanced MRI contrast, which is also described. In the end, we discuss about the potential applications and challenges for the future clinical translation.

Recent insights into the development of nucleic acid-based nanoparticles for tumor-targeted drug delivery.

Cancer is one of the most abundant causes of death in the world due to its characteristic features such as indefinite growth of cells, invasion of healthy tissues, and also metastasis. Conventional treatments of both chemotherapy and radiation have intense side effects and kills cancer cells along with normal healthy cells. Therefore, targeted drug delivery system has become the most suitable way to optimize all the side effects involved in conventional drug delivery systems. Among the various targeted drug delivery systems, nucleic acid-based nanoparticles are providing a constructive treatment option against cancer. The rapid advancement of nucleic acid-based nanomedicine will lead to an effective tumor targeted drug delivery in an optimal manner. Promising features such as potential targeted drug delivery, better biocompatibility, and self-programmability could make nucleic acids as an effective nanocarrier as well as an optimal tool in the treatment of cancer. This review presents the recent insights into the development of nucleic acid-based nanoparticles for tumor-targeted drug delivery and discussed their importance and limitations in successful drug delivery for effective anticancer therapy.

Low-density lipoprotein-decorated and Adriamycin-loaded silica nanoparticles for tumor-targeted chemotherapy of colorectal cancer.

Chemotherapy for colorectal cancer remains an unsatisfactory method of treatment and requires the development of more advanced drug delivery systems (DDSs). Among inorganic materials, silica nanoparticles (SLNs) have been considered a suitable candidate to be developed as versatile carriers for drug delivery and imaging applications. Low-density lipoprotein (LDL) is a widespread material that is responsible for cholesterol transport in plasma. The concept of employing LDL-modified nanoparticles for tumor-targeted drug delivery has been widely adopted. The objective of this study was to develop and test a new DDS for effective chemotherapy of colorectal cancer. We successfully developed an Adriamycin (Adr)-loaded DDS based on LDL-modified SLNs (LDL/SLN/Adr). The tumor-homing property of LDL and the drug-loading capability of SLNs were combined to prepare LDL/SLN/Adr that can specifically deliver Adr to the cancer site to achieve effective chemotherapy of HT-29 colorectal cancer. In vitro analysis showed that LDL/SLN/Adr consisted of nano-sized particles and was capable of targeting the low-density lipoprotein receptors (LDLR) which were overexpressed in many cancer cell lines. As a result, LDL/SLN/Adr exerted better cytotoxicity than unmodified SLNs and free drugs. In vivo imaging and anticancer assays also confirmed the preferable tumor-homing and enhanced anticancer effect of LDL/SLN/Adr. LDL/SLN/Adr might be a promising DDS for effective chemotherapy of colorectal cancer.

The potential of biomimetic nanoparticles for tumor-targeted drug delivery.

In past decades, rapid progress in nanoparticle (NP) synthesis and engineering has provided a broad range of nanoscale agents affording both therapeutic and diagnostic functions. More recently, the emergence of biomimetic NPs as an efficient and promising technology has further expanded this field. The employment of biomemetic NPs offers many distinct advantages, including enhanced stability, the solubilization of hydrophobic payloads, extended blood residence times and the ability to better target a region of interest. In this review, we focus on two main categories of biomimetic NPs, protein/peptide-templated biomimetic NPs and cell membrane-derived biomimetic NPs. The properties, applications and challenges of these biomimetic NPs in tumor diagnosis and treatment are discussed. The pros and cons, and future development, of biomimetic NPs are also considered.

Synthesis and Evaluation of Doxorubicin-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery.

Doxorubicin is an effective and widely used cancer chemotherapeutic agent, but its application is greatly compromised by its cumulative dose-dependent side effect of cardiotoxicity. A gold nanoparticle-based drug delivery system has been designed to overcome this limitation. Five novel thiolated doxorubicin analogs were synthesized and their biological activities evaluated. Two of these analogs and PEG stabilizing ligands were then conjugated to gold nanoparticles, and the resulting Au-Dox constructs were evaluated. The results show that release of native drug can be achieved by the action of reducing agents such as glutathione or under acidic conditions, but reductive drug release gave the cleanest drug release. Gold nanoparticles (Au-Dox) were prepared with different loadings of PEG and doxorubicin, and one formulation was evaluated for mammalian stability and toxicity. Plasma levels of doxorubicin in mice treated with Au-Dox were significantly lower than in mice treated with the same amount of doxorubicin, indicating that the construct is stable under physiological conditions. Treatment of mice with Au-Dox gave no histopathologically observable differences from mice treated with saline, while mice treated with an equivalent dose of doxorubicin showed significant histopathologically observable lesions.

Cytocompatible chitosan-graft-mPEG-based 5-fluorouracil-loaded polymeric nanoparticles for tumor-targeted drug delivery

Biodegradable materials like chitosan (CH) and methoxy polyethylene glycol (mPEG) are widely being used as drug delivery carriers for various therapeutic applications. In this study, copolymer (CH-g-mPEG) of CH and carboxylic acid terminated mPEG was synthesized by carbodiimide-mediated acid amine reaction. The resultant hydrophilic copolymer was characterized by Fourier transform infrared spectroscopy and 1H NMR studies, revealing its relevant functional bands and proton peaks, respectively. Blank polymeric nanoparticles (B-PNPs) and 5-fluorouracil loaded polymeric nanoparticles (5-FU-PNPs) were formulated by ionic gelation method. Furthermore, folic acid functionalized FA-PNPs and FA-5-FU-PNPs were prepared for folate receptor-targeted drug delivery. FA-5-FU-PNPs were characterized by particle size, zeta potential, and in vitro drug release studies, resulting in 197.7 nm, +29.9 mv, and sustained drug release of 88% in 24 h, respectively. Cytotoxicity studies were performed for FA-PNPs and FA-5-FU-PNPs in MCF-7 cell line, which exhibited a cell viability of 80 and 41%, respectively. In vitro internalization studies were carried out for 5-FU-PNPs and FA-5-FU-PNPs which demonstrated increased cellular uptake of FA-5-FU-PNPs by receptor-mediated transport. Significant (p < .01) reduction (1.5-fold) of reactive oxygen species (ROS) accumulation was observed in lipopolysaccharides-stimulated RAW264.7 macrophages, revealing its potent antioxidant property. From the obtained results, it is concluded that folic acid functionalization of 5-FU-PNPs is an ideal approach for sustained and targeted drug delivery, thereby influencing better therapeutic effect.

α-Amylase- and Redox-Responsive Nanoparticles for Tumor-Targeted Drug Delivery.

Paclitaxel (PTX) is an effective antineoplastic agent and shows potent antitumor activity against a wide spectrum of cancers. Yet, the wide clinical use of PTX is limited by its poor aqueous solubility and the side effects associated with its current therapeutic formulation. To tackle these obstacles, we report, for the first time, α-amylase- and redox-responsive nanoparticles based on hydroxyethyl starch (HES) for the tumor-targeted delivery of PTX. PTX is conjugated onto HES by a redox-sensitive disulfide bond to form HES-SS-PTX, which was confirmed by results from NMR, high-performance liquid chromatography-mass spectrometry, and Fourier transform infrared spectrometry. The HES-SS-PTX conjugates assemble into stable and monodispersed nanoparticles (NPs), as characterized with Dynamic light scattering, transmission electron microscopy, and atomic force microscopy. In blood, α-amylase will degrade the HES shell and thus decrease the size of the HES-SS-PTX NPs, facilitating NP extravasation and penetration into the tumor. A pharmacokinetic study demonstrated that the HES-SS-PTX NPs have a longer half-life than that of the commercial PTX formulation (Taxol). As a consequence, HES-SS-PTX NPs accumulate more in the tumor compared with the extent of Taxol, as shown in an in vivo imaging study. Under reductive conditions, the HES-SS-PTX NPs could disassemble quickly as evidenced by their triggered collapse, burst drug release, and enhanced cytotoxicity against 4T1 tumor cells in the presence of a reducing agent. Collectively, the HES-SS-PTX NPs show improved in vivo antitumor efficacy (63.6 vs 52.4%) and reduced toxicity in 4T1 tumor-bearing mice compared with those of Taxol. These results highlight the advantages of HES-based α-amylase- and redox-responsive NPs, showing their great clinical translation potential for cancer chemotherapy.

Chemosensitizing indomethacin-conjugated chitosan oligosaccharide nanoparticles for tumor-targeted drug delivery.

Chemosensitizing nanoparticles (NPs) based on amphiphilic chitosan oligosaccharide-indomethacin (CSO-IDM; CI) conjugate were developed for tumor-targeted delivery of doxorubicin (DOX). IDM was introduced to the CSO backbone as a hydrophobic residue to synthesize an amphiphilic conjugate and a chemosenstizer of DOX for improving antitumor efficacies. IDM, conjugated to CSO, may inhibit the efflux of cellular uptaken DOX via multidrug resistance-associated protein (MRP) and subsequently augment the anti-proliferation potentials of DOX in A549 cells (MRP-expressed human lung cancer cells). Chemosensitizing properties of developed CI NPs were assessed in cell culture models and the tumor targetability of CI/DOX NPs was demonstrated in A549 tumor-xenografted mouse model by a real-time optical imaging. Developed CI NPs can be used as a multifunctional nanosystem for the therapy of MRP-expressed cancers.

Cell membrane-coated nanoparticles for tumor-targeted drug delivery

Nanoparticles can be enriched at tumor site and improve the therapeutic efficacy of many chemotherapy drugs with the well-known enhanced permeability and retention (EPR) effect. While conventional preparations of materials for nanoscale drug delivery system mainly focused on chemical synthesis, recently the combination of synthetic carrier and natural biomimetic carrier has gained more and more attention. As a new generation of biomimetic nanoparticles, cell membrane-coated nanoparticles combine the complex biological functions of natural membranes and the physicochemical properties of synthetic nanomaterials for a more effective drug delivery. Herein, we briefly review the recent advances on cell membrane-coated nanoparticles for tumor-targeted drug delivery via the prolonging systemic circulation lifetime and the active targeting effect. Since the preferential accumulation of cell membrane-coated nanoparticles in tumor site, they are able to improve the therapeutic efficacy of conventional chemotherapy drugs in antitumor treatment as well as to reduce the systemic toxicity. We also introduce a systematic targeted strategy for the promising application of this platform on brain tumors.

Surface spermidine functionalized PEGylated poly(lactide-co-glycolide) nanoparticles for tumor-targeted drug delivery

SPD functionalized nanoparticles could target the delivery of a drug into tumor cells by binding specifically with PTS.

Synthesis and Evaluation of Paclitaxel-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery.

The synthesis of a series of thiolated paclitaxel analogs is described as part of a novel nanomedicine program aimed at developing formulations of paclitaxel that will bind to gold nanoparticles for tumor targeted drug delivery. Preliminary evaluation of the new nanomedicine composed of 27 nm gold nanoparticles, tumor necrosis factor alpha (TNFα), thiolated polyethylene glycol (PEG-thiol), and one of several thiolated paclitaxel analogs is presented.

Cholesterol-modified poly(lactide-co-glycolide) nanoparticles for tumor-targeted drug delivery

Poly(lactide-co-glycolide)-cholesterol (PLGA-C)-based nanoparticles (NPs) were developed for the tumor-targeted delivery of curcumin (CUR). PLGA-C/CUR NPs with ∼200nm mean diameter, narrow size distribution, and neutral zeta potential were fabricated by a modified emulsification-solvent evaporation method. The existence of cholesterol moiety in PLGA-C copolymer was confirmed by proton nuclear magnetic resonance (1H NMR) analysis. In vitro stability of developed NPs after 24h incubation was confirmed in phosphate buffered saline (PBS) and serum media. Sustained (∼6days) and pH-responsive drug release profiles from PLGA-C NPs were presented. Blank PLGA and PLGA-C NPs exhibited a negligible cytotoxicity in Hep-2 (human laryngeal carcinoma) cells in the tested concentration range. According to the results of flow cytometry and confocal laser scanning microscopy (CLSM) studies, PLGA-C NPs presented an improved cellular accumulation efficiency, compared to PLGA NPs, in Hep-2 cells. Enhanced in vivo tumor targetability of PLGA-C NPs, compared to PLGA NPs, in Hep-2 tumor-xenografted mouse model was also verified by a real-time near-infrared fluorescence (NIRF) imaging study. Developed PLGA-C NPs may be a candidate of efficient and biocompatible nanosystems for tumor-targeted drug delivery and cancer imaging.

Bioreducible shell-cross-linked hyaluronic acid nanoparticles for tumor-targeted drug delivery.

The major issues of self-assembled nanoparticles as drug carriers for cancer therapy include biostability and tumor-targetability because the premature drug release from and nonspecific accumulation of the drug-loaded nanoparticles may cause undesirable toxicity to normal organs and lower therapeutic efficacy. In this study, we developed robust and tumor-targeted nanocarriers based on an amphiphilic hyaluronic acid (HA)-polycaprolactone (PCL) block copolymer, in which the HA shell was cross-linked via a bioreducible disulfide linkage. Doxorubicin (DOX), chosen as a model anticancer drug, was effectively encapsulated into the nanoparticles with high drug loading efficiency. The DOX-loaded bioreducible HA nanoparticles (DOX-HA-ss-NPs) greatly retarded the drug release under physiological conditions (pH 7.4), whereas the drug release rate was markedly enhanced in the presence of glutathione, a thiol-containing tripeptide capable of reducing disulfide bonds in the cytoplasm. Furthermore, DOX-HA-ss-NPs could effectively deliver the DOX into the nuclei of SCC7 cells in vitro as well as to tumors in vivo after systemic administration into SCC7 tumor-bearing mice, resulting in improved antitumor efficacy in tumor-bearing mice. Overall, it was demonstrated that bioreducible shell-cross-linked nanoparticles could be used as a potential carrier for cancer therapy.

Synthesis and characterization of Arabic gum capped gold nanoparticles for tumor-targeted drug delivery

In this study, green synthesis of gold nanoparticles (GNPs) was achieved by sunlight-mediated method using the leaves extract of Vitex negundo(V. negundo) as a reducing agent and Arabic gum is used as a capping agent. Epirubicin-loaded Arabic gum-capped gold nanoparticles (E-GNPs) was synthesized and then functionalized with folic acid for tumor-targeted drug delivery. Folic acid-functionalized (Fa-E-GNPs) nanoparticles were characterized by different physicochemical characterization methods such as UV spectra, FESEM, particle size analysis, zeta potential, SAED and HRTEM. In vitro stability of the Fa-E-GNPs was also analyzed. The Fa-E-GNPs showed enhanced cytotoxic effects on lung adenocarcinoma (A549) cell line, suggesting that the folic acid functionalization led to cancer cell targeting and in turn increased the uptake of epirubicin by cancer cells.

Click conjugation of peptide to hydrogel nanoparticles for tumor-targeted drug delivery.

Here we introduce a modified peptide-decorated polymeric nanoparticle (NP) for cancer cell targeting, which can deliver drugs, such as doxorubicin (Dox), to several kinds of cancer cells. Specifically, we employ a nucleolin-targeting NP, with a matrix based on a copolymer of acrylamide (AAm) and 2-carboxyethyl acrylate (CEA). The negatively charged co(CEA-AAm) NP was conjugated with a nucleolin-targeting F3 peptide using a highly efficient and specific copper(I) catalyzed azide-alkyne click reaction. F3 peptide binds to angiogenic tumor vasculatures and other nucleolin overexpressing tumor cells. Attaching F3 peptide onto the NP increases the NP uptake by the nucleolin-expressing glioma cell line 9L and the breast cancer cell line MCF-7. Notably, the F3-conjugated NPs show much higher uptake by the nucleolin-overexpressing glioma cell line 9L than that by the breast cancer cell line MCF-7, the latter having a lower expression of nucleolin on its plasma membrane surface. Moreover, the F3 peptide also dramatically enhances the uptake of co(CEA-AAm) NPs by the drug-resistant cell line NCI/ADR-RES. Also, with this F3-conjugated co(CEA-AAm) NP, a high loading and slow release of doxorubicin were achieved.

Design and analysis of doxorubicin derivativatized gold nanoparticles for tumor-targeted drug delivery

Design and analysis of doxorubicin derivativatized gold nanoparticles for tumor-targeted drug delivery

TLyP-1-conjugated Au-nanorod@SiO(2) core-shell nanoparticles for tumor-targeted drug delivery and photothermal therapy.

Mesoporous silica-coated Au nanorod (AuNR@SiO2) is one of the most important appealing nanomaterials for cancer therapy. The multifunctions of chemotherapy, photothermal therapy, and imaging of AuNR@SiO2 make it very useful for cancer therapy. In this study, AuNR@SiO2 was functionalized to deliver hydrophobic antitumor drug and to heat the targeted tumor with the energy of near-infrared (NIR). To carry out the function of targeting the tumor, tLyP-1, a kind of tumor homing and penetrating peptide, was engrafted to AuNR@SiO2. The fabricated AuNR@SiO2-tLyP-1 which was loaded with camptothecin (CPT) showed a robust, selective targeting and penetrating efficiency to Hela and MCF-7 cells and induced the death of these cells. When the micromasses of these AuNR@SiO2-tLyP-1 internalized cells were irradiated by NIR illumination, all the cells were killed instantaneously owing to the increased temperature caused by the surface plasma resonance (SPR) of the internalized AuNR@SiO2-tLyP-1. Moreover, the systematic toxicity of CPT-loaded AuNR@SiO2-tLyP-1 on human mesenchymal stem cells (hMSCs) was minimized, because the AuNR@SiO2-tLyP-1 selectively targeted and penetrated into the tumor cells, and little hydrophobic CPT was released into the culture medium or blood. This study indicates that the AuNR@SiO2-tLyP-1 drug delivery system (DDS) has great potential application for the chemo-photothermal cancer therapy.

Bioreducible carboxymethyl dextran nanoparticles for tumor-targeted drug delivery.

Bioreducible carboxymethyl dextran (CMD) derivatives are synthesized by the chemical modification of CMD with lithocholic acid (LCA) through a disulfide linkage. The hydrophobic nature of LCA allows the conjugates (CMD-SS-LCAs) to form self-assembled nanoparticles in aqueous conditions. Depending on the degree of LCA substitution, the particle diameters range from 163 to 242 nm. Doxorubicin (DOX), chosen as a model anticancer drug, is effectively encapsulated into the nanoparticles with high loading efficiency (>70%). In vitro optical imaging tests reveal that the fluorescence signal of DOX quenched in the bioreducible nanoparticles is highly recovered in the presence of glutathione (GSH), a tripeptide capable of reducing disulfide bonds in the intracellular compartments. Bioreducible nanoparticles rapidly release DOX when they are incubated with 10 mm GSH, whereas the drug release is greatly retarded in physiological buffer (pH 7.4). DOX-loaded bioreducible nanoparticles exhibit higher toxicity to SCC7 cancer cells than DOX-loaded nanoparticles without the disulfide bond. Confocal laser scanning microscopy observation demonstrate that bioreducible nanoparticles can effectively deliver DOX into the nuclei of SCC7 cells. In vivo biodistribution study indicates that Cy5.5-labeled CMD-SS-LCAs selectively accumulate at tumor sites after systemic administration into tumor-bearing mice. Notably, DOX-loaded bioreducible nanoparticles exhibit higher antitumor efficacy than reduction-insensitive control nanoparticles. Overall, it is evident that bioreducible CMD-SS-LCA nanoparticles are useful as a drug carrier for cancer therapy.