An Amphiphilic PEGylated Peptide Dendron-Gemcitabine Prodrug-Based Nanoagent for Cancer Therapy.

An amphiphilic peptide dendrimer conjugated with gemcitabine (GEM), PEGylated dendron-Gly-Phe-Leu-Gly-GEM (PEGylated dendron-GFLG-GEM), is developed as a nano-prodrug for breast cancer therapy. The self-assembled behavior is observed under a transmission electron microscopy and dynamic light scattering. The negatively charged surface and hydrodynamic size of the amphiphilic nanosized prodrug supported that the prodrug can maintain the stability of GEM during circulation and accumulate in the tumor tissue. Drug release assays are conducted to monitor the release of GEM from this nanodrug delivery system in response to the tumor microenvironment, and these assays confirm that GEM released from the nanocarrier is identical to free GEM. The GEM prodrug can prevent proliferation of tumor cells. The therapeutic effect against breast cancer is systematically investigated using an in vivo animal model. Immunohistochemical results are aligned with the significantly enhanced anticancer efficacy of GEM released from the prodrug. This self-assembled amphiphilic drug delivery nanocarrier may broaden the application for GEM and other anticancer agents for breast cancer chemotherapy.

The Potential of Poly[N-(2-hydroxypropyl)methacrylamide] via Reversible Addition-Fragmentation Chain Transfer Polymerization as Safe Nanocarrier.

N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been presented as nanoscale drug/gene delivery systems and imaging probes, and the well-defined HPMA copolymers prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization promote their to clinical trials, as the significant enhanced anticancer efficacy. The biosafety is another issue associated with the carriers. In this study, we prepared the linear and branched HPMA copolymers labeled with Cy5.5 via RAFT polymerization and click chemistry, and their potential biosafety was studied. The linear copolymer was prepared via RAFT polymerization mediated by the ends-functionalized peptide chain transfer agent (peptide2CTA), resulting in well-defined and block linear HPMA copolymer with molecular weight (MW) of 98 kDa. Additionally, the branched HPMA copolymer was also prepared via RAFT polymerization. Followed by Cy5.5 labeling, the two copolymers showed negative zeta potential and their accumulation into tumor was studied by in vivo optical fluorescence imaging in the nude mice with breast tumors. The biosafety studies on in vitro cytotoxicity and hemocompatibility studies, including hemolysis tests, plasma coagulation and thromboelastography assay were carried out well, demonstrating that the linear HPMA copolymer-Cy5.5 with MW around 100 kDa and biodegradable moiety in the main chain might be utilized as safe nanoscale carrier.

Virus-Mimicking Liposomal System Based on Dendritic Lipopeptides for Efficient Prevention Ischemia/Reperfusion Injury in the Mouse Liver.

Hepatic ischemia-reperfusion injury (IRI) is a pathophysiological and huge challenge during liver surgical procedures. Herein, virus-mimicking liposomal system based on dendritic lipopeptides for efficient prevention of IRI is reported. These virus-mimicking liposomes not only have virus-like nanostructures and components, but also possess virus-like infections to liver tissue, liver cells, and organelles. The distinguished features for prevention of IRI of viral mimics are as follows: (i) viral envelope-like structure to help avoid the host immune system; (ii) well-defined nanostructure and surface to improve the accumulated efficiency in liver tissue; (iii) viral capsids mimic to enhance liver cell uptake and achieve mitochondrial targeting. This type of virus-mimicking design makes prevention of IRI by drug-loading greatly exceed the control groups with high biocompatibility and facile manufacturing.

Reduction-sensitive polymeric micelles as amplifying oxidative stress vehicles for enhanced antitumor therapy.

Chemotherapy-photodynamic therapy (PDT)-based combination therapy is a currently frequently used means in cancer treatment that photosensitizer was able to generate reactive oxygen species (ROS) for improving chemotherapy, owing to the high oxidative stress of the tumor microenvironment (TME). Whereas, cancer cells were accustomed to oxidative stress by overexpression of antioxidant such as glutathione (GSH), which would consume the damage of ROS, as well as it could result in ineffective treatment. Herein, amplification of oxidative stress preferentially in tumor cells by consuming GSH or generating ROS is a reasonable treatment strategy to develop anticancer drugs. To achieve excellent therapeutic effects, we designed a GSH-scavenging and ROS-generating polymeric micelle mPEG-S-S-PCL-Por (MSLP) for amplifying oxidative stress and enhanced anticancer therapy. The amphiphilic polymer of methoxy poly(ethylene glycol) (mPEG)-S-S-poly(ε-caprolactone) (PCL)-Protoporphyrin (Por) was self-assembled into polymeric micelles with the anticancer drug doxorubicin (DOX) for treatment and tracking via FRET. Spherical DOX/MSLP micelles with the average size of 88.76 ±â€¯3.52 nm was procured with negatively charged surface, reduction sensitivity and high drug loading content (17.47 ±â€¯1.53 %). The intracellular ROS detection showed that the MSLP could deplete glutathione and regenerate additional ROS. The cellular uptake of DOX/MSLP micelles was grabbed real-time monitoring by the Fluorescence resonance energy transfer (FRET) effect between DOX and MSLP. The reduction-sensitive polymeric micelles MSLP as amplifying oxidative stress vehicles combined chemotherapy and PDT exhibited significant antitumor activity both in vitro (IC50 = 0.041 µg/mL) and much better antitumor efficacy than that of mPEG-PCL-Por (MLP) micelles in vivo.

Hydrogen Peroxide-Activatable Nanoparticles for Luminescence Imaging and In Situ Triggerable Photodynamic Therapy of Cancer.

Abnormally increased reactive oxygen species (ROS) are intimately related to the development and metastasis of cancer. Since hydrogen peroxide (H2O2) is a major component of ROS, molecular imaging and selective treatment in response to high H2O2 are intriguing for the management of cancers. Herein, we report novel self-assembly luminescent nanoparticles, which can be activated by H2O2, thereby serving as an effective nanotheranostics for luminescence imaging and in situ photodynamic therapy (PDT) of tumors with high H2O2. This functional nanomedicine was assembled from an amphiphilic conjugate (defined as CLP) based on chlorin e6 (Ce6) simultaneously conjugated with luminol and poly(ethylene glycol), exhibiting a well-defined core-shell nanostructure. Upon triggering by pathologically relevant levels of H2O2, CLP nanoparticles produced luminescence due to the luminol unit and simultaneous excitation of Ce6 by chemiluminescence resonance energy transfer, enabling in vitro and in vivo imaging of tumors with highly expressed H2O2. In addition, excited Ce6 can produce singlet oxygen (1O2) for in situ PDT of H2O2-high tumors and inhibiting lung metastasis, which was demonstrated by in vitro and in vivo experiments. Furthermore, preliminary studies revealed the biosafety of CLP nanoparticles. Consequently, the self-illuminating nanoparticles are promising for noninvasive imaging and therapy of tumors with high expression of H2O2.

[Genetic analysis of 32 microsatellite loci in 13 families of Wuzhishan pig by multiplex PCR and gene scanning technique].

Wuzhishan pig is one of the rare and endangered breeds in china. They have the following characteristics such as :light body weight and small size, early sexually maturity, high meat quality and genetic identification with 6 approximately 8 pares litter size,body weight of born 0.3 approximately 0.4 kg, 15 approximately 16 kg at 6 month old, 35 kg at 2 years old, and so on. They may be used for laboratory utilization, comparative studies on human medical model, embryonic engineering, nutrition metabolism, sensitivity test on virus and bacteria, skin brut and tranfer, removing lipid, teeth and mouth cavity diseases, studies on cardiovascular model and evaluation of new medicine products. The polymorphisms of 32 microsatellites in 13 families of Wuzhishan pig in Hainan were Analysed. Number of alleles in each family was counted, mean heterozygosity and polymorphism Information content(PIC) were calculated. The results showed that number of alleles was 13.66, mean heterozygosity was 0.559 while polymorphism information content was 0.731. This revealed that genetic diversity is abundant in Wuzhishan pig in Hainan. These results have instructional significance for preserving breeds, selection and breeding, development and utilization of Wuzhishan pig in Hainan.

[The synthesis and spectral study of multicomponent heteropoly compounds with Keggin structure. II].

The multicomponent heteropoly compounds [Me4N]4 + x[SiVxMoyW12 - x - yO40].n H2O with Keggin structure have been synthesized and characterized by FTIR. The vibrational frequencies of containing-oxygen bonds (Si-Oa,M=Od, M-Ob-M and M-Oc-M) in these heteropoly compounds have been studied. The vibrational frequencies nu as(M=Od) and nu as(M-Ob-M) are demonstrated to explain why the acidity of the heteropoly compounds becomes weaker and the oxidative ability becomes stronger when W atoms are substituted by V atoms. The rule of the change is similar with [PVxMoyW12 - x - yO40](3 + x)-. In addition, the acidity of P series is stronger than the acidity of the corresponding Si series.

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.

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.