Novel aptamer-nanoparticle bioconjugates enhances delivery of anticancer drug to MUC1-positive cancer cells in vitro

MUC1 protein is an attractive target for anticancer drug delivery owing to its overexpression in most adenocarcinomas. In this study, a reported MUC1 protein aptamer is exploited as the targeting agent of a nanoparticle-based drug delivery system. Paclitaxel (PTX) loaded poly (lactic-co-glycolic-acid) (PLGA) nanoparticles were formulated by an emulsion/evaporation method, and MUC1 aptamers (Apt) were conjugated to the particle surface through a DNA spacer. The aptamer conjugated nanoparticles (Apt-NPs) are about 225.3 nm in size with a stable in vitro drug release profile. Using MCF-7 breast cancer cell as a MUC1-overexpressing model, the MUC1 aptamer increased the uptake of nanoparticles into the target cells as measured by flow cytometry. Moreover, the PTX loaded Apt-NPs enhanced in vitro drug delivery and cytotoxicity to MUC1(+) cancer cells, as compared with non-targeted nanoparticles that lack the MUC1 aptamer (P<0.01). The behavior of this novel aptamer-nanoparticle bioconjugates suggests that MUC1 aptamers may have application potential in targeted drug delivery towards MUC1-overexpressing tumors.     

Titanium dioxide particles phosphorylate histone H2AX independent of ROS production

Zinc oxide (ZnO) nanoparticles are finding applications in a wide range of products including cosmetics, food packaging, imaging, etc. This increases the likelihood of human exposure to these nanoparticles through dermal, inhalation and oral routes. Presently, the majority of the studies concerning ZnO nanoparticle toxicity have been conducted using in vitro systems which lack the complex cell-cell, cell-matrix interactions and hormonal effects found in the in vivo scenario. The present in vivo study in mice was aimed at investigating the oral toxicity of ZnO nanoparticles. Our results showed a significant accumulation of nanoparticles in the liver leading to cellular injury after sub-acute oral exposure of ZnO nanoparticles (300 mg/kg) for 14 consecutive days. This was evident by the elevated alanine aminotransferase (ALT) and alkaline phosphatase (ALP) serum levels and pathological lesions in the liver. ZnO nanoparticles were also found to induce oxidative stress indicated by an increase in lipid peroxidation. The DNA damage in the liver and kidney cells of mice was evaluated by the Fpg-modified Comet assay which revealed a significant (p<0.05) increase in the Fpg-specific DNA lesions in liver indicating oxidative stress as the cause of DNA damage. The TUNEL assay revealed an induction of apoptosis in the liver of mice exposed to ZnO nanoparticles compared to the control. Our results conclusively demonstrate that sub-acute oral exposure to ZnO nanoparticles in mice leads to an accumulation of nanoparticles in the liver causing oxidative stress mediated DNA damage and apoptosis. These results also suggest the need for a complete risk assessment of any new engineered nanoparticle before its arrival into the consumer market.     

Antineoplastic drug‐loaded polymer‐modified magnetite nanoparticles: Comparative analysis of EPR‐mediated drug delivery

This study aimed to design and evaluate enhanced permeation and retention (EPR)‐mediated anticancer effect of polymer‐modified and drug‐loaded magnetite nanocomposites. The preformulated bare (10 nm), chitosan‐superparamagnetic iron oxide (SPIO; 69 nm), heparin‐SPIO (42 nm), and (3‐aminopropyl)triethoxysilane‐polyethylene glycol‐SPIO (17 nm) nanocomposites were utilized to evaluate the EPR‐mediated localized cancer targeting and retention of doxorubicin (DOX) and paclitaxel (PTX) in human ovarian cancer cell lines, A2780 and OVCAR‐3 in vitro and in the tumor‐baring Balb/c mice in vivo. Fluorescence microscopy showed that DOX‐ and PTX‐loaded SPIO nanoparticles caused long‐term accumulation and cytoplasmic retention in A2780 and OVCAR‐3 cells, as compared to free drugs in vitro. In vivo antiproliferative effect of present formulations on immunodeficient female Balb/c mice showed a tremendous amount of ovarian tumor shrinkage within 6 weeks. The present nanocomposite systems of targeted drug delivery proved to be efficient drug carrier with sustained drug release and long‐term retention with enhanced cytotoxic properties in vitro and in vivo.     

Thermoresponsive nanocomposite gel for local drug delivery to suppress the growth of glioma by inducing autophagy

Although the treatments of malignant glioma include surgery, radiotherapy and chemotherapy by oral drug administration, the prognosis of patients with glioma remains very poor. We developed a polyethylene glycol-dipalmitoylphosphatidyle- thanoiamine (mPEG-DPPE) calcium phosphate nanoparticles (NPs) injectable thermoresponsive hydrogel (nanocomposite gel) that could provide a sustained and local delivery of paclitaxel (PTX) and temozolomide (TMZ). In addition, the proportion of PTX and TMZ for the optimal synergistic antiglioma effect on C6 cells was determined to be 1:100 (w/w) by the Chou and Talalay method. Our results clearly indicated that the autophagy induced by PTX:TMZ NPs plays an important role in regulating tumor cell death, while autophagy inhibition dramatically reverses the antitumor effect of PTX:TMZ NPs, suggesting that antiproliferative autophagy occurs in response to PTX:TMZ NPs treatment. The antitumor efficacy of the PTX:TMZ NP-loaded gel was evaluated in situ using C6 tumor-bearing rats, and the PTX:TMZ NP-loaded gel exhibited superior antitumor performance. The antitumor effects of the nanocomposite gel in vivo were shown to correlate with autophagic cell death in this study. The in vivo results further confirmed the advantages of such a strategy. The present study may provide evidence supporting the development of nanomedicine for potential clinical application.     

Modulating pharmacokinetics, tumor uptake and biodistribution by engineered nanoparticles

BACKGROUND: Inorganic nanoparticles provide promising tools for biomedical applications including detection, diagnosis and therapy. While surface properties such as charge are expected to play an important role in their in vivo behavior, very little is known how the surface chemistry of nanoparticles influences their pharmacokinetics, tumor uptake, and biodistribution. METHOD/PRINCIPAL FINDINGS: Using a family of structurally homologous nanoparticles we have investigated how pharmacological properties including tumor uptake and biodistribution are influenced by surface charge using neutral (TEGOH), zwitterionic (Tzwit), negative (TCOOH) and positive (TTMA) nanoparticles. Nanoparticles were injected into mice (normal and athymic) either in the tail vein or into the peritoneum. CONCLUSION: Neutral and zwitterionic nanoparticles demonstrated longer circulation time via both i.p. and i.v. administration, whereas negatively and positively charged nanoparticles possessed relatively short half-lives. These pharmacological characteristics were reflected on the tumor uptake and biodistribution of the respective nanoparticles, with enhanced tumor uptake by neutral and zwitterionic nanoparticles via passive targeting.     

Enhancement of oral bioavailability of pentoxifylline by solid lipid nanoparticles

Pentoxifylline (PTX) is a highly water-soluble, hemorheologic drug that undergoes first-pass effect with 20% bioavailability. The solid lipid nanoparticles (SLNs) of PTX were prepared to enhance its oral bioavailability by homogenization, followed by the sonification method. Seven different variables, each at two levels, were studied: lipid type, surfactant type and concentration, speed of homogenizer, acetone:dichloromethane (DCM) ratio, lecithin:lipid ratio, and sonication time. The mean particle size and size distribution, drug entrapment efficiency (EE%), zeta potential, and drug release of the SLNs were investigated. A pharmacokinetic study was conducted in male Wistar rats after oral administration of 10?mg kg^?1 PTX in the form of free drug or SLNs. The z-average particle size, zeta potential, and EE% of the SLNs were at least 250?nm, ?30.2 mV, and 70%, respectively. Among the studied factors, the lipid type, surfactant type, and percentage had a significant effect on the particle size. Zeta potential was more affected by lipid type, acetone:DCM ratio, and sonication time. Speed of homogenizer and acetone:DCM ratio had a significant effect on the EE%. The optimized SLN was prepared by 80?mg of cetyl alcohol, 10?mg of lecithin, acetone:DCM ratio (1:2), 30-second sonication, 3% Tween 20, and a mixing rate of 800?rpm. In vitro drug release lasted for about 5 hours. It was found that the relative bioavailability of PTX in SLNs was significantly increased, compared to that of the PTX solution. SLNs offer a promising approach to improve the oral bioavailability of PTX that is affected by a high first-pass effect.     

Novel Self-assembly Endows Human Serum Albumin Nanoparticles with an Enhanced Antitumor Efficacy

Protein-based nanomedicine plays an important role in tumor chemotherapy due to their merits in bioavailability, biocompatibility, biodegradability, and low toxicity. In this study, we developed a novel method of preparing human serum albumin (HSA) nanoparticles for targeted delivery of paclitaxel (PTX) to tumors. HSA-PTX nanoparticles (NPs-PTX) were fabricated via unfolding of HSA in appropriate solution to expose more hydrophobic domains and consequent self-assembling into nanoparticles with added PTX. Via this self-assembly method, a desirable particle size (around 120 nm), a high drug loading (>20%), and a high encapsulation efficiency (near 100%) were obtained. PTX dispersed as an amorphous state in NPs-PTX and the secondary structures of HSA were maintained. In a cytotoxicity study, NPs-PTX displayed an enhanced cytotoxicity in MCF-7 and A549 cells. Confocal microscopy and flow cytometry revealed that the uptake of NPs-PTX was mediated by secreted protein acidic and rich in cysteine and “caveolar” transport. In H22 tumor-bearing mice, NPs-PTX displayed an increasing and everlasting tumor distribution, leading to slower tumor growth and longer mice survival than PTX. Therefore, this novel self-assembly method offers a much easier method to prepare PTX nanoparticles, provides better antitumor efficacy in vitro and in vivo, and more importantly, sets up a delivery platform for other hydrophobic drugs to improve their effectiveness in cancer therapy.     

5-Fluorouracil Nanoparticles Inhibit Hepatocellular Carcinoma via Activation of the p53 Pathway in the Orthotopic Transplant Mouse Model

Biodegradable polymer nanoparticle drug delivery systems provide targeted drug delivery, improved pharmacokinetic and biodistribution, enhanced drug stability and fewer side effects. These drug delivery systems are widely used for delivering cytotoxic agents. In the present study, we synthesized GC/5-FU nanoparticles by combining galactosylated chitosan (GC) material with 5-FU, and tested its effect on liver cancer in vitro and in vivo. The in vitro anti-cancer effects of this sustained release system were both dose- and time-dependent, and demonstrated higher cytotoxicity against hepatic cancer cells than against other cell types. The distribution of GC/5-FU in vivo revealed the greatest accumulation in hepatic cancer tissues. GC/5-FU significantly inhibited tumor growth in an orthotropic liver cancer mouse model, resulting in a significant reduction in tumor weight and increased survival time in comparison to 5-FU alone. Flow cytometry and TUNEL assays in hepatic cancer cells showed that GC/5-FU was associated with higher rates of G0–G1 arrest and apoptosis than 5-FU. Analysis of apoptosis pathways indicated that GC/5-FU upregulates p53 expression at both protein and mRNA levels. This in turn lowers Bcl-2/Bax expression resulting in mitochondrial release of cytochrome C into the cytosol with subsequent caspase-3 activation. Upregulation of caspase-3 expression decreased poly ADP-ribose polymerase 1 (PARP-1) at mRNA and protein levels, further promoting apoptosis. These findings indicate that sustained release of GC/5-FU nanoparticles are more effective at targeting hepatic cancer cells than 5-FU monotherapy in the mouse orthotropic liver cancer mouse model.     

Preparation and evaluation of warfarin-β-cyclodextrin loaded chitosan nanoparticles for transdermal delivery

The main objective of the present work was to prepare warfarin-β-cyclodextrin (WAF-β-CD) loaded chitosan (CS) nanoparticles for transdermal delivery. CS is a hydrophilic carrier therefore, to overcome the hydrophobic nature of WAF and allow its incorporation into CS nanoparticles, WAF was first complexed with β-cyclodextrin (β-CD). CS nanoparticles were prepared by ionotropic pre-gelation using tripolyphosphate (TPP). Morphology, size and structure characterization of nanoparticles were carried out using SEM, TEM and FTIR, respectively. Nanoparticles prepared with 3:1 CS:TPP weight ratio and 2mg/ml final CS concentration were found optimum. They possessed spherical particles (35±12nm diameter) with narrow size distribution (PDI=0.364) and 94% entrapment efficiency. The in vitro release as well as the ex vivo permeation profiles of WAF-β-CD from the selected nanoparticle formulation were studied at different time intervals up to 8h. In vitro release of WAF-β-CD from CS nanoparticles followed a Higuchi release profile whereas its ex vivo permeation (at pH 7.4) followed a zero order permeation profile. Results suggested that the developed WAF-β-CD loaded CS carrier could offer a controlled and constant delivery of WAF transdermally.     

Visualization of superparamagnetic nanoparticles in vascular tissue using XμCT and histology

In order to increase the dose of antineoplastic agents in the tumor area, the concept of magnetic drug targeting (MDT) has been developed. Magnetic nanoparticles consisting of iron oxide and a biocompatible cover layer suspended in an aqueous solution (ferrofluid) serve as carriers for chemotherapeutics being enriched by an external magnetic field after intra-arterial application in desired body compartments (i.e., tumor). We established an ex vivo model to simulate in vivo conditions in a circulating system consisting of magnetic iron oxide nanoparticles passing an intact bovine artery and being focused by an external magnetic field to study their distribution in the vessel. Micro-computed X-ray tomography (XμCT) and histology can elucidate the arrangement of these particles after application. XμCT-analysis has been performed on arterial sections after MDT in order to determine the distribution of the nanoparticles. These measurements have been carried out with a cone X-ray source and corresponding histological sections were stained with Prussian blue. It could be shown that combining XμCT and histology offers the opportunity for a better understanding of the mechanisms of nanoparticle deposition in the vascular system after MDT.     

抗人精子蛋白17磁性纳米探针靶向的卵巢癌体内外磁共振成像

用MRI(magnetic resonance imaging)技术探索连接抗人精子蛋白17单克隆抗体(anti-Sp17 mAb)的磁性纳米探针对体外培养及动物体内Sp17+卵巢癌的靶向性。将anti-Sp17mAb连接到表面包覆壳聚糖的超顺磁性氧化铁纳米颗粒上,制成磁性纳米探针anti-Sp17-MNP,用作MRI阴性对比剂。将磁性纳米探针与Sp17+和Sp17-培养的肿瘤细胞共育,进行一系列体外磁共振成像实验。荷瘤小鼠尾静脉注射磁性纳米颗粒,用7T磁共振仪在体成像,观察肿瘤部位的信号变化,并用普鲁士蓝染色肿瘤组织切片,观察有无铁粒子聚集。体外MRI数据显示,anti-Sp17-MNP与细胞靶向结合,并与细胞共育2 h后,Sp17+HO-8910的T2*信号强度比Sp17-HepG2低2倍;anti-Sp17-MNP对肿瘤细胞的靶向作用可被重组人Sp17阻断。7T磁共振仪对动物在体肿瘤成像结果显示,感兴趣区因磁性纳米探针靶向聚集而导致信号降低,并经组织切片普鲁士蓝染色证实。本研究结果表明,用anti-Sp17抗体和新的合成路线制备的纳米探针具有用作MR对比剂进行分子成像的潜能。     

壳聚糖-有机累托石/海藻酸钠复合纳米粒的制备

目的:以BSA作为模型药物,制备壳聚糖季铵盐-OREC复合物纳米微粒,建立一种安全有效的药物控释传递系统。方法:超声条件下,制备不同质量比的具有壳聚糖硅酸盐插层结构的复合物纳米微粒,观察其形态学特征、进行红外光谱分析。同时,测定OREC对BSA包封率和载药量的影响。结果:成功制备了不同质量比的OREC-HTCC纳米粒子。电镜结果显示纳米粒呈圆球形,均匀,平均粒径约为30nm。红外图谱分析证实,HTCC插入了OREC插层中,BSA成功地包裹入HTCC-ALG/OREC混合材料制备的纳米微粒。加入OREC后,纳米粒子的包封率及载药量均明显提高,但随着加入量的增加,包封率及载药量逐渐减少。结论:OREC-HTCC纳米粒子是良好的蛋白药物载体,具有粒径小、包封率高、缓释效果好等优点,为CS-OREC作为潜在的药物给药系统的进一步应用提供科学依据。     

Mechanisms of enhanced antiglioma efficacy of polysorbate 80‐modified paclitaxel‐loaded PLGA nanoparticles by focused ultrasound

The presence of blood‐brain barrier (BBB) greatly limits the availability of drugs and their efficacy against glioma. Focused ultrasound (FUS) can induce transient and local BBB opening for enhanced drug delivery. Here, we developed polysorbate 80‐modified paclitaxel‐loaded PLGA nanoparticles (PS‐80‐PTX‐NPs, PPNP) and examined the enhanced local delivery into the brain for glioma treatment by combining with FUS. Our result showed PPNP had good stability, fast drug release rate and significant toxicity to glioma cells. Combined with FUS, PPNP showed a stronger BBB permeation efficiency both in the in vitro and in vivo BBB models. Mechanism studies revealed the disrupted tight junction, reduced P‐glycoprotein expression and ApoE‐dependent PS‐80 permeation collectively contribute to the enhanced drug delivery, resulting in significantly stronger antitumour efficacy and longer survival time in the tumour‐bearing mice. Our study provided a new strategy to efficiently and locally deliver drugs into the brain to treat glioma.     

Polyelectrolyte nanoparticles based on water-soluble chitosan-poly(l-aspartic acid)-polyethylene glycol for controlled protein release

Water-soluble chitosan (WSC)-poly(l-aspartic acid) (PASP)-polyethylene glycol (PEG) nanoparticles (CPP nanoparticles) were prepared spontaneously under quite mild conditions by polyelectrolyte complexation. These nanoparticles were well dispersed and stable in aqueous solution, and their physicochemical properties were characterized by turbidity, FTIR spectroscopy, dynamic light scattering (DLS), transmission electron microscope (TEM), and zeta potential. PEG was chosen to modify WSC-PASP nanoparticles to make a protein-protective agent. Investigation on the encapsulation efficiency and loading capacity of the bovine serum albumin (BSA)-loaded CPP nanoparticles was also conducted. Encapsulation efficiency was obviously decreased with the increase of initial BSA concentration. Furthermore, its in vitro release characteristics were evaluated at pH 1.2, 2.5, and 7.4. In vitro release showed that these nanoparticles provided an initial burst release, followed by a slowly sustained release for more than 24 h. The BSA released from CPP nanoparticles showed no significant conformational change compared with native BSA, which is superior to the BSA released from nanoparticles without PEG. A cell viability study suggested that the nanoparticles had good biocompatibility. This nanoparticle system was considered promising as an advanced drug delivery system for the peptide and protein drug delivery.     

Targeted delivery of paclitaxel using folate-conjugated heparin-poly(β-benzyl-l-aspartate) self-assembled nanoparticles

A self-assembled nanoparticulate system composed of a folate-conjugated heparin-poly(β-benzyl-l-aspartate) (HP) amphiphilic copolymer was proposed for targeted delivery of the antineoplastic drug paclitaxel (PTX). PTX was incorporated into three types of heparin-based nanoparticles, including HP, folate-conjugated HP (FHP), and folate-polyethylene glycol (PEG)-conjugated HP (FPHP), using a simple dialysis method. The PTX-loaded nanoparticles were then characterized according to particle size (140-190 nm) and size distribution, drug-loading content and efficiency, and in vitro release behavior. In the cellular uptake study using KB cells positive for the folate-receptor (FR), FHP and FPHP nanoparticles showed a much higher cellular uptake than did unconjugated HP nanoparticles. Specifically, when the PEG spacer was inserted between the folate ligand and heparin backbone, FPHP nanoparticles had a greater cellular uptake than did FHP nanoparticles. The in vitro cytotoxicity of PTX-loaded HP, FHP, and FPHP nanoparticles was studied in KB cells and FR-negative A549 cells. Compared with the cytotoxicity in A549 cells, PTX-loaded FHP and FPHP nanoparticles exhibited more potent cytotoxicity in KB cells than did PTX-loaded HP nanoparticles and free-PTX, suggesting that the presence of folate enhanced intracellular uptake via FR-mediated endocytosis. In addition, FPHP nanoparticles exhibited much greater cytotoxicity in KB cells than did FHP nanoparticles. These results suggest that PTX-loaded folate-conjugated HP nanoparticles are a potentially useful delivery system for cancer cells positive for the folate-receptor.     

Nobiletin potentiates paclitaxel anticancer efficacy in A549/T xenograft model: Pharmacokinetic and pharmacological study

BackgroundNobiletin (N), a polymethoxylated flavone from citrus fruits, enhanced anti-cancer effects of paclitaxel (PTX) in multi-drug resistance (MDR) cancer cells via inhibiting P-glycoprotein (P-gp) in our previous report. But the in vivo chemo-sensitizing effect of nobiletin is unknown. Moreover, considering the nonlinear pharmacokinetics and narrow therapeutic window of PTX, drug-drug interaction should be explored for using nobiletin with PTX together.PurposeIn this study, we wanted to explore whether nobiletin could affect the pharmacokinetic (PK) behavior of PTX and reverse drug resistance in vivo as well as the corresponding mechanisms.Study Design and MethodsAccurate and sensitive UPLC-MS/MS method was developed for the detection of PTX, and was applied to the pharmacokinetic study in rats. In vivo anti-MDR tumor study was carried out with A549/T xenograft nude mice model. Immunohistochemistry and western blot analysis were used for evaluating the levels of P-gp, Nrf2, and AKT/ERK pathways in MDR tumors.ResultsNobiletin significantly enhanced the therapeutic effects of PTX, and inhibited the MDR tumor sizes in the A549/T xenograft model, while PTX or nobiletin alone did not. We found that nobiletin increased the PTX concentrations in tumor tissues but did not affect the PK behavior of PTX. Notably, Nrf2 and phosphorylation of AKT/ERK expression in MDR tumor tissues were significantly inhibited by giving nobiletin and PTX together. However, nobiletin did not affect the expression of P-gp.ConclusionNobiletin reversed PTX resistance in MDR tumor via increasing the PTX content in the MDR tumor and inhibiting AKT/ERK/Nrf2 pathways, but without affecting the systematic exposure of PTX, indicating that nobiletin may be an effective and safe MDR tumor reversal agent.     

Emulsan-based nanoparticles for in vivo drug delivery to tumors

Nanoparticles have been widely used as drug carriers, and finding new materials for them is important for efficient drug delivery. Herein, we developed a new nanoparticle using emulsan and flax seed oil. Emulsan is one of the representative biosurfactants obtained from Acinetobacter calcoaceticus RAG-1. The resulting nanoparticles have an emulsan shell and a hydrophobic oil core, into which pheophorbide a (Pba) was loaded as a model drug. The nanoparticles were about 165.7?nm and were stably dispersed in an aqueous condition for more than one week. They demonstrated fast uptake in SCC7 mouse squamous cell carcinoma cells and killed the tumor cells after laser irradiation due to the photodynamic effect of Pba. After injection into SCC7 tumor-bearing mice via the tail vein, the particles showed longer blood circulation and 3.04-fold higher tumor accumulation in tissue than free Pba. These results demonstrate that emulsan-based nanoparticles have promising potential in drug delivery.     

Gadolinium-rhodamine nanoparticles for cell labeling and tracking via magnetic resonance and optical imaging

A novel dual-labeled nanoparticle for use in labeling and tracking cells in vivo is described. We report the construction and characterization of these gadolinium-rhodamine nanoparticles. These particles are constructed from lipid monomers with diacetylene bonds that are sonicated and photolyzed to form polymerized nanoparticles. Cells are efficiently labeled with these nanoparticles. We have inoculated labeled tumor cells subcutaneouosly into the flanks of C3H mice and have been able to image these labeled tumor cells via MRI and optical imaging. Furthermore, the labeled tumor cells can be visualized via fluorescent microscopy after tissue biopsy. Our results suggest that these nanoparticles could be used to track cells in vivo. This basic platform can be modified with different fluorophores and targeting agents for studying metastisic cell, stem cell, and immune cell trafficking among other applications.     

In vivo tumor cell targeting with "click" nanoparticles

The in vivo fate of nanomaterials strongly determines their biomedical efficacy. Accordingly, much effort has been invested into the development of library screening methods to select targeting ligands for a diversity of sites in vivo. Still, broad application of chemical and biological screens to the in vivo targeting of nanomaterials requires ligand attachment chemistries that are generalizable, efficient, covalent, orthogonal to diverse biochemical libraries, applicable under aqueous conditions, and stable in in vivo environments. To date, the copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition or "click" reaction has shown considerable promise as a method for developing targeted nanomaterials in vitro. Here, we investigate the utility of "click" chemistry for the in vivo targeting of inorganic nanoparticles to tumors. We find that "click" chemistry allows cyclic LyP-1 targeting peptides to be specifically linked to azido-nanoparticles and to direct their binding to p32-expressing tumor cells in vitro. Moreover, "click" nanoparticles are able to stably circulate for hours in vivo following intravenous administration (>5 h circulation time), extravasate into tumors, and penetrate the tumor interstitium to specifically bind p32-expressing cells in tumors. In the future, in vivo use of "click" nanomaterials should expedite the progression from ligand discovery to in vivo evaluation and diversify approaches toward multifunctional nanoparticle development.     

Polymeric micelles with water-insoluble drug as hydrophobic moiety for drug delivery

The hydrophobic block of polymeric micelles formed by amphiphilic copolymers has no direct therapeutical effect, and the metabolites of these hydrophobic segments might lead to some unexpected side effects. Here the hydrophobic core of polymeric micelles is replaced by highly water-insoluble drugs themselves, forming a new micellar drug delivery system. By grafting hydrophobic drugs of paclitaxel (PTX) onto the surface of hydrophilic hyperbranched poly(ether-ester) (HPEE), we constructed an amphiphilic copolymer (HPEE-PTX). HPEE-PTX could self-assemble into micellar nanoparticles in aqueous solution with tunable drug contents from 4.1 to 10.7%. Moreover, the hydrolysis of HPEE-PTX in serum resulted in the cumulative release of PTX. In vivo evaluation indicated that the dosage toleration of PTX in mice had been improved greatly and HPEE-PTX micellar nanoparticles could be used as an efficient prodrug with satisfactory therapeutical effect. We believe that most of the lipophilic drugs could improve their characters through this strategy.