A polypeptide based podophyllotoxin conjugate for the treatment of multi drug resistant breast cancer with enhanced efficiency and minimal toxicity.

Podophyllotoxin (PPT) is a chemotherapeutic agent which has shown significant activity against P-glycoprotein (P-gp) mediated multi drug resistant cancer cells. However, because of the poor aqueous solubility and high toxicity, PPT cannot be used in clinical cancer therapy. In order to enhance the efficiency and reduce side effect of PPT, a polypeptide based PPT conjugate PLG-g-mPEG-PPT was developed and used for the treatment of multi drug resistant breast cancer. The PLG-g-mPEG-PPT was prepared by conjugating PPT to poly(l-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-mPEG) via ester bonds. The PPT conjugates self-assembled into nanoparticles with average sizes about 100 nm in aqueous solution. Western blotting assay showed that the PLG-g-mPEG-PPT could effectively inhibit the expression of P-gp in the multiple drug resistant MCF-7/ADR cells. In vitro cytotoxicity assay indicated that the resistance index (RI) values of PLG-g-mPEG-PPT on different drug-resistant cancer cell lines exhibited 57-270 folds reduction than of traditional microtubule inhibitor chemotherapeutic drug PTX or DTX. Hemolysis assay demonstrated that the conjugation greatly decreased the hemolytic activity of free PPT. Maximum tolerated dose (MTD) of PLG-g-mPEG-PPT increased greatly (13.3 folds) as compared to that of free PPT. In vivo study showed that the PLG-g-mPEG-PPT conjugate remarkably enhanced the antitumor efficacy against MCF-7/ADR xenograft tumors with a tumor suppression rate (TSR) of 82.5%, displayed significantly improved anticancer efficacy as compared to free PPT (TSR = 37.1%) with minimal toxicity when both of the two formulations were used in MTD. The development of multiple drug resistance (MDR) of cancer cells is the main cause of chemotherapy failure. The over-expression of P-glycoprotein (P-gp) has been recognized to be the most important cause of MDR in cancer. Podophyllotoxin (PPT) is a chemotherapeutic agent which has shown strong activity against P-gp mediated multidrug resistant cancer cells by simultaneously inhibiting the over-expression of P-gp and the growth of cancer cells. However, PPT can not be used in clinical cancer treatment due to its poor aqueous solubility and high toxicity. Herein, we developed a polypeptide based PPT conjugate PLG-g-mPEG-PPT by conjugating PPT to poly(l-glutamic acid)-g-methoxy poly(ethylene glycol). The PLG-g-mPEG-PPT shows significantly decreased hemolytic activity, greatly improved maximum tolerated dose and remarkably enhanced antitumor efficacy against MCF-7/ADR xenograft tumors as compared to free PPT.

Zhou H ，Lv S ，Zhang D ，Deng M ，Zhang X ，Tang Z ，Chen X ... -  《-》

Transferrin receptor-targeted redox/pH-sensitive podophyllotoxin prodrug micelles for multidrug-resistant breast cancer therapy.

Li Y ，Chen M ，Yao B ，Lu X ，Zhang X ，He P ，Vasilatos SN ，Ren X ，Bian W ，Yao C ... -  《-》

A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors.

Podophyllotoxin (PPT) exhibited significant activity against P-glycoprotein mediated multidrug resistant (MDR) tumor cell lines; however, due to its poor solubility and high toxicity, PPT cannot be dosed systemically, preventing its clinical use for MDR cancer. We developed a nanoparticle dosage form of PPT by covalently conjugating PPT and polyethylene glycol (PEG) with acetylated carboxymethyl cellulose (CMC-Ac) using one-pot esterification chemistry. The polymer conjugates self-assembled into nanoparticles (NPs) of variable sizes (20-120 nm) depending on the PPT-to-PEG molar ratio (2-20). The conjugate with a low PPT/PEG molar ratio of 2 yielded NPs with a mean diameter of 20 nm and released PPT at ∼5%/day in serum, while conjugates with increased PPT/PEG ratios (5 and 20) produced bigger particles (30 nm and 120 nm respectively) that displayed slower drug release (∼2.5%/day and ∼1%/day respectively). The 20 nm particles exhibited 2- to 5-fold enhanced cell killing potency and 5- to 20-fold increased tumor delivery compared to the larger NPs. The biodistribution of the 20 nm PPT-NPs was highly selective to the tumor with 8-fold higher accumulation than all other examined tissues, while the larger PPT-NPs (30 and 120 nm) exhibited increased liver uptake. Within the tumor, >90% of the 20 nm PPT-NPs penetrated to the hypovascular core, while the larger particles were largely restricted in the hypervascular periphery. The 20 nm PPT-NPs displayed significantly improved efficacy against MDR tumors in mice compared to the larger PPT-NPs, native PPT and the standard taxane chemotherapies, with minimal toxicity.

Roy A ，Ernsting MJ ，Undzys E ，Li SD ... -  《-》

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 ... -  《-》

Cisplatin Loaded Poly(L-glutamic acid)-g-Methoxy Poly(ethylene glycol) Complex Nanoparticles for Potential Cancer Therapy: Preparation, In Vitro and In Vivo Evaluation.

Yu H ，Tang Z ，Li M ，Song W ，Zhang D ，Zhang Y ，Yang Y ，Sun H ，Deng M ，Chen X ... -  《Journal of Biomedical Nanotechnology》