Ratiometric co-encapsulation and co-delivery of doxorubicin and paclitaxel by tumor-targeted lipodisks for combination therapy of breast cancer.

Combination therapy is a promising treatment for certain advanced drug-resistant cancers. Although effective inhibition of various tumor cells was reported in vitro, combination treatment requires improvement in vivo due to uncontrolled ratiometric delivery. In this study, a tumor-targeting lipodisk nanoparticle formulation was developed for ratiometric loading and the transportation of two hydrophobic model drugs, doxorubicin (DOX) and paclitaxel (PTX), in one single platform. Furthermore, a slightly acidic pH-sensitive peptide (SAPSP) incorporated into lipodisks effectively enhanced the tumor-targeting and cell internalization. The obtained co-loaded lipodisks were approximately 30 nm with a pH-sensitive property. The ratiometric co-delivery of two drugs via lipodisks was confirmed in both the drug-resistant MCF-7/ADR cell line and its parental MCF-7 cell line in vitro, as well as in a tumor-bearing mouse model in vivo compared with a cocktail solution of free drugs. Co-loaded lipodisks exerted improved cytotoxicity to tumor cells in culture, particularly to drug-resistant tumor cells at synergistic drug ratios. In an in vivo xenograft mouse model, the anti-tumor ability of co-loaded lipodisks was evidenced by the remarkable inhibitory effect on tumor growth of either MCF-7 or MCF-7/ADR tumors, which may be attributed to the increased and ratiometric accumulation of both drugs in the tumor tissues. Therefore, tumor-specific lipodisks were crucial for the combination treatment of DOX and PTX to completely exert a synergistic anti-cancer effect. It is concluded that for co-loaded lipodisks, cytotoxicity data in vitro could be used to predict their inhibitory activity in vivo, potentially enhancing the clinical outcome of synergistic therapy.

Feng C ，Zhang H ，Chen J ，Wang S ，Xin Y ，Qu Y ，Zhang Q ，Ji W ，Yamashita F ，Rui M ，Xu X ... -  《-》

A co-delivery system based on paclitaxel grafted mPEG-b-PLG loaded with doxorubicin: preparation, in vitro and in vivo evaluation.

Herein, we develop a co-delivery system of paclitaxel (PTX) and doxorubicin hydrochloride (DOX·HCl) based on methoxypoly(ethylene glycol)-block-poly(L-glutamic acid) (mPEG-b-PLG) for cancer treatment. PTX was grafted to the mPEG-b-PLG by esterification to give mPEG-b-PLG-g-PTX. DOX·HCl was encapsulated via electrostatic interaction and hydrophobic stack between the DOX·HCl and mPEG-b-PLG-g-PTX in aqueous solution. The release rate of DOX·HCl from the drug-loaded nanoparticles (mPEG-b-PLG-g-PTX-DOX) was slow at blood pH (pH 7.4), but obviously increased at endosome pH (pH 5.4). The mPEG-b-PLG-g-PTX-DOX exhibited slight synergistic effect in inhibition of proliferation of A549 and MCF-7 human cancer cells. For in vivo treatment of xenograft human breast tumor (MCF-7), the mPEG-b-PLG-g-PTX-DOX nanoparticles exhibited remarkable tumor inhibition effect with a 95.5% tumor-suppression-rate which was significantly higher than those of related single anticancer agents such as free DOX·HCl and mPEG-b-PLG-g-PTX. These results indicated that the mPEG-b-PLG-g-PTX-DOX would have great potential in cancer therapy.

Li Q ，Lv S ，Tang Z ，Liu M ，Zhang D ，Yang Y ，Chen X ... -  《-》

Targeted Biomimetic Nanoparticles for Synergistic Combination Chemotherapy of Paclitaxel and Doxorubicin.

Rui M ，Xin Y ，Li R ，Ge Y ，Feng C ，Xu X ... -  《-》

Folate-targeted polymersomes loaded with both paclitaxel and doxorubicin for the combination chemotherapy of hepatocellular carcinoma.

Combination chemotherapy is a promising method of improving cancer treatment, but the distinct pharmacokinetics of combined drugs and non-specific drug distribution slow down the development in the clinic. In this study, folate (FA) receptor-targeted polymersomes with apparent bilayered lamellar structure were successfully developed to co-encapsulate a hydrophobic-hydrophilic chemotherapeutic drug pair (PTX and DOX) in a single vesicle for enhancing the combination chemotherapeutic effect. Hydrophobic PTX was loaded into the thick hydrophobic lamellar membrane by the self-assembly of triblock copolymer PCL8000-PEG8000-PCL8000, while hydrophilic DOX was encapsulated into the hydrophilic reservoir using a trans-membrane ammonium sulfate gradient method. In vitro release study indicated that the drugs were released from the polymersomes in a controlled and sustained manner. Cellular uptake study indicated that FA-targeted Co-PS had higher internalization efficiency in FA receptor-overexpressing BEL-7404 cells than non-targeted Co-PS. In vitro cytotoxicity assay demonstrated that FA-targeted Co-PS exhibited less cytotoxic effect than free drug cocktail, but suppressed the growth of tumor cells more efficiently than non-targeted Co-PS. Ex vivo imaging biodistribution studies revealed that FA-targeted Co-PS led to highly efficient targeting and accumulation in the BEL-7404 xenograft tumor. Furthermore, the in vivo antitumor study showed that the combination chemotherapy of polymersomes to BEL-7404 tumor via intravenous injection was superior to free drug cocktail treatment, and the FA-targeted Co-PS exhibited significantly higher tumor growth inhibition than non-targeted Co-PS group. Therefore, the newly developed FA-targeted co-delivery polymersomes hold great promise for simultaneous delivery of multiple chemotherapeutics and would have great potential in tumor-targeting and combination chemotherapy. Combination chemotherapy is a promising method of improving cancer treatment, but the distinct pharmacokinetics of combined drugs and non-specific drug distribution slow down the development in the clinic. In our study, novel folate-targeted co-delivery polymersomes (Co-PS) were successfully developed to encapsulate a hydrophobic-hydrophilic chemotherapeutic drug pair (paclitaxel and doxorubicin) into the different compartments of the vesicle. In vivo studies revealed that the combination chemotherapy of polymersomes to BEL-7404 xenograft tumor via intravenous injection was superior to free drug cocktail treatment, and the FA-targeted Co-PS exhibited significantly higher tumor growth inhibition than non-targeted Co-PS group. Therefore, the newly developed FA-targeted co-delivery polymersomes hold great promise for simultaneous delivery of multiple chemotherapeutics and would have great potential in tumor-targeting and combination chemotherapy.

Zhu D ，Wu S ，Hu C ，Chen Z ，Wang H ，Fan F ，Qin Y ，Wang C ，Sun H ，Leng X ，Kong D ，Zhang L ... -  《-》

Macrophage-Derived Extracellular Vesicles as Drug Delivery Systems for Triple Negative Breast Cancer (TNBC) Therapy.

Haney MJ ，Zhao Y ，Jin YS ，Li SM ，Bago JR ，Klyachko NL ，Kabanov AV ，Batrakova EV ... -  《-》