Tumor-specific Drug Delivery Research Articles

Design, purification and assessment of GRP78 binding peptide-linked Subunit A of Subtilase cytotoxic for targeting cancer cells.

BackgroundTargeted therapies for cancer, especially the malignant cancer, are always restricted by the deficiency of tumor-specific drug delivery methods. Subtilase cytotoxic is a virulent cytotoxin, and the subunit A (SubA) of it is able to destroy the structure of glucose-regulated protein 78 (GRP78) to induce cell apoptosis, and to be expected as anti-cancer drugs, however, the ubiquitous receptor of subunit B of Subtilase cytotoxic (SubB) restricts its application on cancer therapy.ResultsThe present study constructed and expressed a fusion protein of GBP-SubA in E. coli Rosetta (DE3) system, in which the subunit B of Subtilase cytotoxic was replaced by GRP78 binding peptide (GBP). The fusion protein was expressed in inclusion body form. Subsequently, the denaturation/renaturation process and Ni-column purification were performed. Our data indicated the purified GBP-SubA could bind GRP78 existed on cancer cell surface specifically, internalize into cells to inactivate intracellular GRP78 and induce apoptosis. Moreover, the apoptosis induction effect of GBP-SubA was enhanced obviously along with the increased cancer cell surface GBP78.ConclusionsIt indicates that the recombinant GBP-SubA possesses the dual functions of GBP and SubA to induce cancer cell apoptosis specifically, revealing that GBP-SubA holds important implications for developing as an anti-cancer peptide drug.Graphical abstract:A schematic representation of the construction and function of GBP-SubA. Electronic supplementary materialThe online version of this article (doi:10.1186/s12896-016-0294-5) contains supplementary material, which is available to authorized users.

PH-Activated Targeting Drug Delivery System Based on the Selective Binding of Phenylboronic Acid.

Phenylboronic acid (PBA) is a tumor-targeting molecule, but its nonspecific interaction with normal cells or other components containing cis-diol residues undoubtedly limits its potential application in tumor-targeting drug delivery. Herein, we developed fructose-coated mixed micelles via PBA-terminated polyethylene glycol monostearate (PBA-PEG-C18) and Pluronic P123 (PEG20-PPG70-PEG20) to solve this problem, as the stability of borate formed by PBA and fructose was dramatically dependent on pH. The fluorescence spectroscopic results indicated that the borate formed by PBA and fructose decomposed at a decreased pH, and better binding between PBA and sialic acid (SA) was observed at a low pH. These results implied that the fructose groups decorated on the surface of the micelles could be out-competed by SA at a low pH. In vitro uptake and cytotoxicity studies demonstrated that the fructose coating on the mixed micelles improved the endocytosis and enhanced the cytotoxicity of drug-loaded mixed micelles in HepG2 cells but reduced the cytotoxicity in normal cells. These results demonstrate that a simple decorating strategy may facilitate PBA-targeted nanoparticles for tumor-specific drug delivery.

PH-sensitive surface charge-conversion nanomicelle for anti-tumor drug delivery

Event Abstract Back to Event pH-sensitive surface charge-conversion nanomicelle for anti-tumor drug delivery Wei Wu1, 2*, Guixue Wang1* and Jianshu Li2* 1 Chongqing University, Bioengineering College, China 2 Sichuan University, College of Polymer Science and Engineering, China Introduction: During the last decade, tremendous efforts have been attained in the development of stimuli-responsive polymeric nanocarriers for the controlled delivery of various anti-cancerous drugs[1]. Physiological stimuli-responsive nanocarriers provide the feasible platforms for cancer therapy due to their improved anticancer efficiency as well as reduced systematic cytotoxicity via the tumor specific enhanced permeability and retention (EPR) effect[2]. It is interesting to note the pH-sensitive surface charge-conversion strategy, which is potential for enhancing tumor cell internalization efficiency. In this study, we attempt to engineer this smart tumor-acidity activated surface charge-conversion function into a biodegradable amphiphilic block copolymers for anticancer application. Materials and Methods: Poly(D, L-lactide)-block-poly(2-aminoethyl methacrylate) (PLA-b-PAEMA, MW 8900, PDI 1,24) was firstly synthesized through ring-opening polymerization (ROP) and subsequently atom transition radical polymerization method. PLA-b-PAEMA/DMMA was obtained by using 2,3-dimethykmaleic anhydride (DMMA) modified PLA-b-PAEMA. Results and Discussion: The well-defined PLA-b-PAEMA is further modified by DMMA and succinic anhydride (SA) to yield the tumor-acidity activated surface charge-conversional block copolymer (PLA-b-PAEMA/DMMA) and the control sample (PLA-b-PAEMA/SA). In this design, the biodegradable PLA block and the functional PAEMA/DMMA (or PAEMA/SA) block provide the amphiphilic driving force to self-assemble into nanocarriers, which have PLA aggregated hydrophobic inner core and PAEMA/DMMA (or PAEMA/SA) outer corona, in aqueous solution. As compared with the invariable negative surface charge of PAEMA/SA block, PAEMA/DMMA block shows the tumor-acidity activated surface charge-conversion feature, i.e., exhibiting negatively charged surface during the blood circulation time and positively charged surface in response to slight tumor acidic environment through the hydrolysis of DMMA functional agents. Thus, after the loading of positively charged doxorubicin hydrochloride (DOX·HCl) into the negatively charged corona structure through electrostatic attraction, the DOX·HCl-loaded PLA-b-PAEMA/DMMA carrier (PLA-b-PAEMA/DMMA@DOX·HCl) is expected to prolong blood circulation time because its “stealthy” negatively charged surface could effectively decrease the undesired consumption by the reticuloendothelial system (RES) and the protein adsorption in vivo, and promote the anti-cancer therapeutic efficiency though the tumor activated positively charged surface for enhanced tumor cell adhesion and targeted drug release (Scheme 1). Scheme1. Illustration of tumor-acidity activated carriers for enhanced cell uptake and targeted drug release. Conclusions: In summary, we construct a smart nanocarrier based on biodegradable PLA-b-PAEMA/DMMA copolymer, which could convert surface charge from negative to positive in response to the tumor-acidity. It exhibits various superiorities for tumor-specific drug delivery, including long blood circulation time, enhanced tumor-cell adhesion, tumor targeted drug release and additional cytotoxicity for tumor cells after the charge-conversion. Thus, this biodegradable smart carrier integrated high drug delivery efficiency and well-improved biocompatibility provides a feasible platform for the ideal anti-tumor therapy. Financial support from the National Natural Science Foundation of China (51322303); Financial support from the Foundations of Sichuan Province (2012JQ0009)

Biocompatible and biodegradable fibrinogen microspheres for tumor-targeted doxorubicin delivery.

In the development of effective drug delivery carriers, many researchers have focused on the usage of nontoxic and biocompatible materials and surface modification with targeting molecules for tumor-specific drug delivery. Fibrinogen (Fbg), an abundant glycoprotein in plasma, could be a potential candidate for developing drug carriers because of its biocompatibility and tumor-targeting property via arginine–glycine–aspartate (RGD) peptide sequences. Doxorubicin (DOX), a chemotherapeutic agent, was covalently conjugated to Fbg, and the microspheres were prepared. Acid-labile and non-cleavable linkers were used for the conjugation of DOX to Fbg, resulting in an acid-triggered drug release under a mild acidic condition and a slow-controlled drug release, respectively. In vitro cytotoxicity tests confirmed low cytotoxicity in normal cells and high antitumor effect toward cancer cells. In addition, it was discovered that a longer linker could make the binding of cells to Fbg drug carriers easier. Therefore, DOX–linker–Fbg microspheres could be a suitable drug carrier for safer and effective drug delivery.

Preparation of poly(β-L-malic acid)-based charge-conversional nanoconjugates for tumor-specific uptake and cellular delivery.

In this study, a multifunctional poly(β-L-malic acid)-based nanoconjugate with a pH-dependent charge conversional characteristic was developed for tumor-specific drug delivery. The short branched polyethylenimine-modified poly(β-L-malic acid) (PEPM) was first synthesized. Then, the fragment HAb18 F(ab′)2 and 2,3-dimethylmaleic anhydride were covalently attached to the PEPM to form the nanoconjugate, HDPEPM. In this nanoconjugate, the 2,3-dimethylmaleic anhydride, the shielding group, could shield the positive charge of the conjugate at pH 7.4, while it was selectively hydrolyzed in the tumor extracellular space (pH 6.8) to expose the previously-shielded positive charge. To study the anticancer activity, the anticancer drug, doxorubicin, was covalently attached to the nanoconjugate. The doxorubicin-loaded HDPEPM nanoconjugate was able to efficiently undergo a quick charge conversion from −11.62 mV to 9.04 mV in response to the tumor extracellular pH. The electrostatic interaction between the positively charged HDPEPM nanoconjugates and the negatively charged cell membrane significantly enhanced their cellular uptake, resulting in the enhanced anticancer activity. Also, the tumor targetability of the nanoconjugates could be further improved via the fragment HAb18 F(ab′)2 ligand–receptor-mediated tumor cell-specific endocytosis.

Integrinβ6-targeted immunoliposomes mediate tumor-specific drug delivery and enhance therapeutic efficacy in colon carcinoma.

Adjuvant chemotherapy is one of the significant treatments for colon cancer in clinic. However, it does not achieve the desired therapeutic efficacy, largely due to chemotherapeutic resistance. Integrinβ6 (ITGB6) is expressed in malignant colonic epithelia, but not in normal epithelia, and is associated with the progression, metastasis, and chemotherapeutic resistance of colon cancer. Accordingly, it is necessary to design therapeutic approaches for efficient and targeted drug delivery into ITGB6-positive cancer cells to improve chemotherapeutic efficacy in colon cancer. PEGylated liposomes were employed to design ITGB6-targeted immunoliposomes, which have ITGB6 monoclonal antibodies (mAbs) conjugated. We evaluated the ITGB6-targeted immunoliposomes internalization into colon cancer cells and examined 5-fluorouracil (5-FU)-induced cellular apoptosis produced by ITGB6-targeted immunoliposomes+5-FU. In addition, the biodistribution and antitumor efficiency of ITGB6-targeted immunoliposomes were observed in vivo. ITGB6-targeted immunoliposomes enhanced cellular internalization in ITGB6-positive colon cancer cells compared with liposomes. Furthermore, the ITGB6-targeted immunoliposome internalization was dependent on the ITGB6 expression level on cellular surface. ITGB6-targeted immunoliposomes decreased the 5-FU IC50 more than 90% in HT-29 and SW480β6 cells relative to liposomes. Moreover, when loaded with 5-FU, ITGB6-targeted immunoliposomes produced an approximately 1.5-fold higher 5-FU-induced cellular apoptosis rate than liposomes. In vivo, the therapeutic activity of ITGB6-targeted immunoliposomes+5-FU was significantly superior, resulting in 25% to 35% reduction of tumor weight compared with 5-FU or liposomes+5-FU. ITGB6-targeted immunoliposomes provide a highly efficient approach for targeted drug delivery in colon cancer and thus offer the potential of a novel and promising anticancer strategy for clinical therapy.

Biological evaluation of redox-sensitive micelles based on hyaluronic acid-deoxycholic acid conjugates for tumor-specific delivery of paclitaxel

Tumor-targeted drug delivery and microenvironment-responsive drug release are attractive strategies in cancer treatment. Our previous study demonstrated that redox-sensitive micelles based on hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates exhibited excellent drug-loading capacities (34.1%) for paclitaxel (PTX) and rapid drug release in response to reducing agent, glutathione. In the present study, the physicochemical and biological properties of PTX-loaded HA-ss-DOCA (PTX-HA-ss-DOCA) micelles were investigated further. The micelles have an average size of about 120nm and a zeta potential of about −36mV. Transmission electron microscopy and wide-angle X-ray diffraction analysis demonstrated redox-sensitive degradation of micelles in the presence of glutathione. Moreover, the encapsulated payload was effectively released from HA-ss-DOCA micelles into cytoplasm and then rapidly transported into nuclei. In vitro cytotoxicity and cell apoptosis assay further revealed that HA significantly improved the tumor-specific drug delivery of HA-ss-DOCA micelles via receptor-mediated endocytosis, while efficient intracellular drug release and transportation lead to marked inhibition of tumor cell growth, as compared to Taxol® and insensitive micelles. More importantly, PTX-HA-ss-DOCA micelles demonstrated superior in vivo antitumor activity compared with Taxol® and insensitive control, and decreased systemic toxicity. Herein we present data which provide valuable insight into the design and development of tumor-specific drug delivery systems.

Selective in vivo imaging of syngeneic, spontaneous, and xenograft tumors using a novel tumor cell-specific hsp70 peptide-based probe.

Although in vivo targeting of tumors using fluorescently labeled probes has greatly gained in importance over the last few years, most of the clinically applied reagents lack tumor cell specificity. Our novel tumor cell-penetrating peptide-based probe (TPP) recognizes an epitope of Hsp70 that is exclusively present on the cell surface of a broad variety of human and mouse tumors and metastases, but not on normal tissues. Because of the rapid turnover rate of membrane Hsp70, fluorescently labeled TPP is continuously internalized into syngeneic, spontaneous, chemically/genetically induced and xenograft tumors following intravenous administration, thereby enabling site-specific labeling of primary tumors and metastases. In contrast with the commercially available nonpeptide small molecule αvβ3-integrin antagonist IntegriSense, TPP exhibits a significantly higher tumor-to-background contrast and stronger tumor-specific signal intensity in all tested tumor models. Moreover, in contrast with IntegriSense, TPP reliably differentiates between tumor cells and cells of the tumor microenvironment, such as tumor-associated macrophages and fibroblasts, which were found to be membrane-Hsp70 negative. Therefore, TPP provides a useful tool for multimodal imaging of tumors and metastases that might help to improve our understanding of tumorigenesis and allow the establishment of improved diagnostic procedures and more accurate therapeutic monitoring. TPP might also be a promising platform for tumor-specific drug delivery and other Hsp70-based targeted therapies.

Abstract LB-102: A tumor-specific tissue penetrating peptide inhibits metastasis

Abstract Neuropilin-binding tumor-penetrating peptides increase vascular and tissue permeability in tumors, allowing drugs conjugated to the peptide and even free drugs co-injected with the peptide to widely distribute within the tumor tissue (Sugahara KN et al, Cancer Cell 16:510, 2009; Science 328:1031, 2010). Thus, the peptides provide an elegant way to enhance therapeutic index of anti-cancer drugs. However, the ability of the peptides to increase vascular permeability has raised concerns that the peptides might enhance metastasis by promoting cell seeding from the primary tumor. Here, we show a recent unexpected finding that a prototypic tumor-penetrating peptide, iRGD (amino acid sequence: CRGDK/RGPD/EC), is a potent metastasis inhibitor. iRGD did not cause systemic tumor cell dissemination or metastasis in mice bearing breast tumors with low metastatic potential. iRGD treatment of mice bearing aggressive orthotopic pancreatic tumors resulted in significant decrease in spontaneous metastasis formation. Primary tumor growth was not affected by the treatment. Another tumor-penetrating peptide, iNGR, also inhibited metastasis, while conventional RGD peptides or a scrambled iRGD peptide that lack neuropilin affinity failed to do. These results indicate that the anti-metastatic effect of iRGD was dependent on its neuropilin-binding peptide motif. In vitro migration assays demonstrated that iRGD potently inhibits tumor cell migration and serves as a chemorepellent of tumor cells in a neuropilin-dependent manner. Chemorepulsion assays based on live cell imaging confirmed the findings, and further demonstrated that iRGD dramatically collapses tumor cell protrusions leading to an instantaneous retraction of tumor cells from iRGD-bound surfaces. Our finding refutes the hypothesis that iRGD may cause enhanced metastasis. The mechanism of the anti-metastatic effect may involve neuropilin-mediated chemorepulsion of tumor cells. Collectively, iRGD may simultaneously achieve tumor-specific drug delivery and metastasis inhibition when utilized for cancer treatment. Citation Format: Kazuki N. Sugahara, Gary B. Braun, Tatiana H. de Mendoza, Venkata R. Kotamraju, Tambet Teesalu, Erkki Ruoslahti, Randall P. French, Andrew M. Lowy. A tumor-specific tissue penetrating peptide inhibits metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-102. doi:10.1158/1538-7445.AM2014-LB-102

Thermosensitive liposomes with higher phase transition temperature for targeted drug delivery to tumor

Thermosensitive liposomes (TSL) in combination with local hyperthermia (HT) represent a promising tool for tumor specific drug delivery. The objective of the study was to investigate the influence of phase transition temperature (Tm) on the properties of TSL. High temperature triggered TSL (HTSL), low temperature triggered TSL (LTSL) and non-TSL (NTSL) were prepared and temperature sensitive release properties were extensively compared in different media. Mouse plasma was determined to have similar effect on the release profiles compared to human plasma, in which complete release were obtained at 38°C and 40°C for LTSL and HTSL, respectively. The temperature at which complete release achieved was found to be obviously lower than Tm. Brucine, an antitumor alkaloid, was encapsulated into different TSLs. After HT treatment, the viabilities of SMMC 7721 cells were determined to be 21.3±3.8% and 16.8±3.3% for 127μM brucine LTSL and HTSL, respectively. Treating the tumor-bearing mice with LTSL, HTSL and NTSL led to significantly increased brucine uptake in the heated tumor site compared to the brucine solution group by 2.30, 3.80 and 2.26-fold, respectively. The results of this study suggested that Tm of TSL should be increased to obtain improved drug delivery efficiency to tumor.

Near-Infrared Emitting Fluorescent BODIPY Nanovesicles for in Vivo Molecular Imaging and Drug Delivery

Near-infrared fluorescent nanovesicles were prepared by self-assembly of block copolymer hydrophilic poly(ethylene glycol) boron-dipyrromethenes in aqueous solution. The fluorescence enhancement induced by dissociation of nanovesicles could be used as a smart imaging and diagnostic tool. This nanovesicle could encapsulate the antitumor drug, and provide a powerful platform for imaging-guided tumor-specific drug delivery and therapy.

Targeted and heat-triggered doxorubicin delivery to tumors by dual targeted cationic thermosensitive liposomes

Liposomal nanoparticles can circumvent toxicity of encapsulated chemotherapeutic drugs, but fall short in tumor-specific and efficient intracellular drug delivery. To overcome these shortcomings, we designed a multifunctional dual targeted, heat-responsive nanocarrier encapsulating doxorubicin (Dox) as a chemotherapeutic content. Dox-loaded cationic thermosensitive liposomes (Dox-CTSL) carry targeting functions addressing tumor cells and tumor vasculature and have a heat-responsive lipid bilayer. Targeted Dox-CTSL demonstrated superior uptake by and toxicity to different tumor cell lines and endothelial cells compared to non-targeted TSL. Heat triggered intracellular Dox release in acidic cell compartments was visualized as fluorescent Dox nanobursts by live cell confocal microscopy. In vivo, using high resolution intravital microscopy, we demonstrated that Dox-CTSL upon an external heat-trigger delivered 3-fold higher Dox quantity to tumors than TSL. Dox-CTSL bound specifically to tumor vasculature, which in combination with the heat-triggered drug release caused significant tumor vessel damage, which was not observed when non-targeted TSL were administered. Therefore, Dox-CTSL have strong potency to increase drug efficacy due to targeted delivery and heat-triggered drug release in tumors.

Selective targeting of liver cancer with the endothelial marker CD146.

Hepatocellular carcinomas are well-vascularized tumors; the endothelial cells in these tumors have a specific phenotype. Our aim was to develop a new approach for tumor-specific drug delivery with monoclonal antibody targeting of endothelial ligands. CD146, a molecule expressed on the endothelial surface of hepatocellular carcinoma, was identified as a promising candidate for targeting. In the present study, endothelial cells immediately captured circulating anti-CD146 (ME-9F1) antibody, while antibody binding in tumors was significantly higher than in hepatic endothelium. Macroscopically, after intravenous injection, there were no differences in the mean accumulation of anti-CD146 antibody in tumor compared to liver tissue , due to a compensating higher blood vessel density in the liver tissue. Additional blockade of nontumoral epitopes and intra-arterial administration, improved selective antibody capture in the tumor microvasculature and largely prevented antibody distribution in the lung and liver. The potential practical use of this approach was demonstrated by imaging of radionuclide-labeled ME-9F1 antibody, which showed excellent tumor-selective uptake. Our results provide a promising principle for the use of endothelial markers for intratumoral drug delivery. Tumor endothelium-based access might offer new opportunities for the imaging and therapy of hepatocellular carcinoma and other liver malignancies.

Novel biocompatible pH-stimuli responsive superparamagnetic hybrid hollow microspheres as tumor-specific drug delivery system

Novel biocompatible pH-stimuli responsive superparamagnetic hybrid hollow microspheres have been designed via the layer-by-layer (LbL) self-assembly technique via the electrostatic interaction between the poly(ethylene glycol) grafted chitosan (CS-g-PEG) as polycation and the citrate modified ferroferric oxide nanoparticles (Fe3O4–CA) as hybrid anion onto the uniform polystyrene sulfonate (PSS) microsphere templates. The well-defined hybrid hollow microspheres ((CS-g-PEG/Fe3O4–CA)4/CS-g-PEG) were obtained after etching the templates by washing with DMF. They possessed superparamagnetic characteristics with a saturation magnetization of 37.23emu/g, and exhibited excellent stability in high ion-strength media and pH dependent DOX release. Their unique structure and outstanding performance make them potential platform for tumor-specific delivery in the tumor diagnostic and therapy.

Tumor Homing Peptides as Molecular Probes for Cancer Therapeutics, Diagnostics and Theranostics

Cancer is one of the leading causes of mortality worldwide, with more than 10 million new cases each year. Despite the presence of several anticancer agents, cancer treatment is still not very effective. Main reasons behind this high mortality rate are the lack of screening tests for early diagnosis, and non-availability of tumor specific drug delivery system. Most of the current anticancer drugs are unable to differentiate between cancerous and normal cells, leading to systemic toxicity, and adverse side effects. In order to tackle this problem, a considerable progress has been made over the years to identify peptides, which specifically bind to the tumor cells, and tumor vasculature (tumor homing peptides). With the advances in phage display technology, and combinatorial libraries like one-bead one-compound library, several hundreds of tumor homing peptides, and their derivatives, which have potential to detect tumor in vivo, and deliver anticancer agents specifically to the tumor site, have been discovered. Currently, many tumor homing peptide-based therapies for cancer treatment and diagnosis are being tested in various phases of clinical trials. In this review, we have discussed the progress made so far in the identification of tumor homing peptides, and their applications in cancer therapeutics, diagnosis, and theranostics. In addition, a brief discussion on tumor homing peptide resource, and in silico designing of tumor homing peptides has also been provided.

Magnetic nanoparticles with a pH-sheddable layer for antitumor drug delivery

A dually responsive nanocarrier with a multilayer core–shell architecture was prepared based on Fe3O4@SiO2 nanoparticles successively coated with poly(benzyl L-aspartate) (PBLA) and poly(ethylene glycol) (PEG) for the purpose of tumor specific drug delivery applications. In this system, PEG chains are connected to the surface via pH-sensitive benzoic-imine bonds and serve as a pH-sheddable hydrophilic corona. Meanwhile, the PBLA segments serve as a hydrophobic middle layer used to load the drugs via hydrophobic interactions. The Fe3O4@SiO2 nanoparticle functions as a superparamagnetic core used to direct the drug loaded nanocarrier to the target pathological site. The obtained materials were characterized with FT-IR, 1H NMR, dynamic light scattering, zeta-potential, TEM, TGA, and hysteresis loop analysis. An anticancer drug doxorubicin (DOX) was selected as the model drug loaded into the nanocarrier, which was relatively stable under physiological conditions due to its neutral hydrophilic shell, and could quickly release the drug in response to increased acidity via shedding of the PEG shells through cleavage of the intermediate benzoic-imine bonds. Meanwhile, the neutral shell shedding would reveal a positively charged nanoparticle surface that is readily taken up by tumor cells. These pH- and magnetic-responsive nanoparticles showed significant potential for use in the targeted intracellular delivery of hydrophobic chemotherapeutics in cancer therapy.

Avidity and shear stress-linked anchoring to tumor endothelium: transfer the principles of leukocyte adhesion for tumor-specific drug delivery

Avidity and shear stress-linked anchoring to tumor endothelium: transfer the principles of leukocyte adhesion for tumor-specific drug delivery

Copper-free azide–alkyne cycloaddition of targeting peptides to porous silicon nanoparticles for intracellular drug uptake

Porous silicon (PSi) has been demonstrated as a promising drug delivery vector for poorly water-soluble drugs. Here, a simple and efficient method based on copper-free click chemistry was used to introduce targeting moieties to PSi nanoparticles in order to enhance the intracellular uptake and tumor specific targeting hydrophobic drug delivery. Two RGD derivatives (RGDS and iRGD) with azide-terminated groups were conjugated to bicyclononyne-functionalized PSi nanoparticles via copper-free azide–alkyne cycloaddition. The surface functionalization was performed in aqueous solution at 37 °C for 30 min resulting in conjugation efficiencies of 15.2 and 3.4% (molar ratios) and the nanoparticle size increased from 165.6 nm to 179.6 and 188.8 nm for RGDS and iRGD, respectively. The peptides modification enhanced the cell uptake efficiency of PSi nanoparticles in EA.hy926 cells. PSi-RGDS and PSi-iRGD nanoparticles loaded with sorafenib showed a similar trend for the in vitro antiproliferation activity compared to sorafenib dissolved in dimethyl sulfoxide. Furthermore, sorafenib-loaded PSi-RGDS deliver the drug intracellulary efficiently due to the higher surface conjugation ratio, resulting in enhanced in vitro antiproliferation effect. Our results highlight the surface functionalization methodology for PSi nanoparticles applied here as a universal method to introduce functional moieties onto the surface of PSi nanoparticles and demonstrate their potential active targeting properties for anticancer drug delivery.

LHRH‐PE40 Fusion Protein Tethered Silica Nanorattles for Imaging‐Guided Tumor‐Specific Drug Delivery and Bimodal Therapy

Docyanine green (ICG) and LHRH-PE40 fusion protein are tethered onto drug carriers of silica nanorattles for imaging-guided tumor-specific drug delivery and bimodal therapy. The synergistic therapeutic effect of toxin PE40 and the chemotherapeutic drug docetaxel (Dtxl), specifically directed by LHRH to cancer, improves cancer treatment. Simultaneously, ICG enables real-time monitoring of the silica nanocomposites and therapeutic response.

Targeting Tumors Using Nanoparticle Platforms: A Phase I Study of a Systemically Administered Gene Therapy System

The potential for nonviral gene therapy to treat cancer has been limited by the difficulty of targeting therapeutic genes to tumors. In this issue of Molecular Therapy, Senzer et al.1 show evidence of specific tumor targeting as well as clinical efficacy in a phase I trial of a nonviral vector. This is the first phase I clinical trial to demonstrate tumor specificity and uptake by metastatic tumors of a systemically delivered liposomal nanoparticle. Importantly, the therapeutic nanoparticle elicited minimal side effects and the majority of patients demonstrated stable disease. This phase I trial has shown this delivery system to be a safe, stable, efficient, and tumor-specific drug delivery platform for systemic administration.