Wenchuan She

Dendronized heparin-doxorubicin conjugate based nanoparticle as pH-responsive drug delivery system for cancer therapy.

Heparin drug conjugates are currently investigated as excellent candidates for drug delivery vehicles. In this study, we report the preparation and characterization of dendronized heparin-doxorubicin (heparin-DOX) conjugate as pH-sensitive drug delivery vehicle by combination of the features of dendrimer and heparin. Dynamic light scattering (DLS) and transmission electron microscope (TEM) studies demonstrated the dendronized heparin-DOX conjugate self-assembled into compact nanoparticles with negatively charged surface. The nanoparticles with 9.0 wt% (weight percent) of doxorubicin (DOX) showed pH-sensitive property due to the faster drug release rate at pH 5.0 and slow release rate at pH 7.4 aqueous. The nanoparticles were shown to effectively kill cancer cells in vitro. Notablely, the nanoparticles resulted in strong antitumor activity, high antiangiogenesis effects and induced apoptosis on the 4T1 breast tumor model due to the evidences from mice weight shifts, tumor weights, tumor growth curves, immunohistochemical assessment and histological analysis. Its also noteworthy that dendronized heparin and its nanoparticle with drug demonstrated no significant toxicity to healthy organs of both tumor-bearing and healthy mice, which was confirmed by histological analysis compared with free drug DOX. The dendronized heparin-DOX conjugate based nanopatilce with high antitumor activity and low side effects may be therefore a potential nanoscale drug delivery vehicle for breast cancer therapy.

Arginine functionalized peptide dendrimers as potential gene delivery vehicles.

The quest for highly efficient and safe gene delivery systems has become the key factor for successful application of gene therapy. Peptide dendrimers are currently investigated as excellent candidates for non-viral gene delivery vectors. In this study, we report the synthesis and characterization of arginine functionalized peptide dendrimer-based vectors ranging from 5th generation (G5A) to 6th generation (G6A) via click chemistry, and their use for gene transfection in vitro and in vivo. The dendrimers can condense plasmid DNA (pDNA) and protect pDNAs from nuclease digestion. Both atomic force microscopy (AFM) and dynamic light scattering (DLS) revealed that the sizes of dendrimer/DNA particles were within 180-250 nm range. In vitro studies showed that the functionalized peptide dendrimers provided serum independent and high transfection efficiency on all studied cells, as over 2 fold higher than that of branched polyetherimide (PEI) in the presence of serum. Dendrimer G5A with molecular weight of 17 kDa demonstrated 6-fold transfection activity than PEI in breast tumor models, as well as good biosafety proved by in vitro and in vivo toxicity evaluation. However, G6A with molecular weight of 46 kDa showed much higher cytotoxicity. The functionalized dendrimer G5A with optimal generation may be therefore a potential candidate for gene delivery vehicle.

Peptide Dendrimer–Doxorubicin Conjugate‐Based Nanoparticles as an Enzyme‐Responsive Drug Delivery System for Cancer Therapy

Peptide dendrimers have shown promise as an attractive platform for drug delivery. In this study, mPEGylated peptide dendrimer-doxorubicin (dendrimer-DOX) conjugate-based nanoparticle is prepared and characterized as an enzyme-responsive drug delivery vehicle. The drug DOX is conjugated to the periphery of dendrimer via an enzyme-responsive tetra-peptide linker Gly-Phe-Leu-Gly (GFLG). The dendrimer-DOX conjugate can self-assemble into nanoparticle, which is confirmed by dynamic light scattering, scanning electron microscopy, and transmission electron microscopy studies. At equal dose, mPEGylated dendrimer-DOX conjugate-based nanoparticle results in significantly high antitumor activity, and induces apoptosis on the 4T1 breast tumor model due to the evidences from tumor growth curves, an immunohistochemical analysis, and a histological assessment. The in vivo toxicity evaluation demonstrates that nanoparticle substantially avoids DOX-related toxicities and presents good biosafety without obvious side effects to normal organs of both tumor-bearing and healthy mice as measured by body weight shift, blood routine test, and a histological analysis. Thus, the mPEGylated peptide dendrimer-DOX conjugate-based nanoparticle may be a potential nanoscale drug delivery vehicle for the breast cancer therapy.

PEGylated dendritic diaminocyclohexyl-platinum (II) conjugates as pH-responsive drug delivery vehicles with enhanced tumor accumulation and antitumor efficacy.

Environmentally responsive peptide dendrimers loaded with drugs are suitable candidates for cancer therapy. In this study, we report the preparation and characterization of mPEGylated peptide dendrimer-linked diaminocyclohexyl platinum (II) (dendrimer-DACHPt) conjugates as pH-responsive drug delivery vehicles for tumor suppression in mice. The DACHPt has a molecular structure, is and activity closely related to oxaliplatin and was linked to dendrimer via N,O-chelate coordination. The products were pH-responsive and released drug significantly faster in acidic environments (pH 5.0) than pH 7.4. Consequently, the conjugates suppressed tumor growth better than clinical oxaliplatin(®) without inducing toxicity in an SKOV-3 human ovarian cancer xenograft. Through the systemic delivery of conjugates, 25-fold higher tumor platinum uptake at 36 h post-injection was seen observed due to the enhanced permeability and retention (EPR) effect thereby remarkably enhancing the therapeutic indexes of this small-molecule drug. Thus, the mPEGylated peptide dendrimer-linked DACH-platinum conjugates are novel potential drug delivery systems with implications in future ovarian cancer therapy.

Functional L-Lysine Dendritic Macromolecules as Liver-Imaging Probes

Liver-imaging probes are prepared through the conjugation of Gd chelates and galactosyl moieties to peptide dendrimers. The dendritic probes possessing highly controlled structures and a single molecular weight have a two-fold increase in T(1) relaxivity to 9.1 x 10(3) (Gd M)(-1) s(-1) compared to Gd-DTPA. No obvious cytotoxicity of this multifunctional dendritic agent is discovered in vitro. The dendrimer bearing galactosyl moieties leads to a much-higher hepatocyte-cell uptake in vitro and provides good signal-intensity enhancement (35%) of mouse liver in vivo especially at 60 min after intravenous injection. In comparison, non-targeting Gd dendrimers provide only an 11% enhancement of imaging contrast at the same time point. Overall, the dendrimers bearing galactosyl moieties may be used as liver-imaging probes.

A dendronized heparin–gadolinium polymer self-assembled into a nanoscale system as a potential magnetic resonance imaging contrast agent

We reported the preparation and characterization of a dendronized heparin–gadolinium polymer (Dendronized-heparin–Gd) based nanoscale system as a potential MRI contrast agent, which combined the advantages of heparin and the peptide dendron. The dendronized polymer self-assembled into a compact nanoscale system, which was confirmed by dynamic light scattering (DLS) and scanning electron microscopy (SEM) results, and a negative charge was observed. The content of gadolinium (Gd(III)) was 6% as a weight percentage, determined by inductively coupled plasma mass spectrometry (ICP-MS) analysis. The in vitro and in vivo toxicity studies demonstrated that the Dendronized-heparin–Gd polymeric nanoscale system exhibited good biocompatibility – no obvious side effects to normal cells and organs of healthy mice were observed by a cytotoxicity assay, body weight shift and histological analysis. The polymeric nanoscale system showed a 7-fold increase in the T1 relaxivity compared to the clinical agent Magnevist (Gd-DTPA). In vivo MR imaging studies on the mice bearing 4T1 breast tumors showed that the nanoscale system had a much higher contrast enhancement in the tumor than Gd-DTPA. The distribution of Gd(III) in the tissues at different times after administration indicated a higher Gd(III) accumulation in the tumor for the nanoscale system compared to Gd-DTPA. Overall, the dendronized heparin polymer based nanoscale system with a high contrast enhancement in tumors and low side effects may be used as a MRI contrast agent for disease diagnosis.

Environment-responsive Polymeric Nanoparticles as Drug Delivery Systems for Cancer Therapy

Environment-responsive polymeric nanoparticles as antitumor drug delivery systems could response to tiny environmental stimulus, change their structure and release the antitumor drug. They have been widely applied in biomedical area due to their considerable advantages of prolonging survival time with lower toxicity, controllability and high drug loading in cancer therapy. Here, we present an overview of the recent work on environment-responsive polymeric nanoparticles as drug delivery systems for cancer therapy, including pH sensitive, temperature sensitive, redox sensitive and enzyme sensitive, based on the domestic and international research progress. In addition, recent advances and future directions in the development of environmentresponsive polymeric nanoparticles as antitumor drug delivery systems are also included.