Cisplatin loaded methoxy poly (ethylene glycol)-block-Poly (L-glutamic acid-co-L-Phenylalanine) nanoparticles against human breast cancer cell.

Cisplatin (cis-diaminodichloroplatinum, CDDP) loaded methoxy poly (ethylene glycol)-block-poly (glutamic acid-co-phenyl alanine) [mPEG-b-P (Glu10 -co-Phe10 ) (PGlu10 ) and mPEG-b-P (Glu20 -co-Phe10 ) (PGlu20 )] nanoparticles with two different formulations (CDDP/PGlu10 and CDDP/PGlu20 ) are successfully developed in uniformly sizes. In 190 h, the CDDP/PGlu10 shows 30% release at physiological pH and 39% at lysosomal pH. Similarly, the CDDP/PGlu20 shows 60% release at physiological pH and 90% release at lysosomal pH. The sustained and controlled release of both formulations evidences the in vitro longevity of the nanoparticles. The cell proliferation inhibition of nanoparticles against human breast cancer cell line ZR-75-30 is dose and time dependent. Both CDDP/PGlu10 and CDDP/PGlu20 show excellent hemo compatibility as evaluated by hemolysis experiments. The in vivo fate of CDDP and CDDP loaded nanoparticles are evaluated by pharmacokinetics studies. Free CDDP underwgoes instant platinum concentration decrease after intravenous administration with 1.0 wt% left in 24 h while the CDDP loaded nanoparticles show prolonged blood circulation time with 5 wt% (CDDP/PGlu20 ) to 14 wt% (CDDP/PGlu10 ) left in 24 h. This prolonged blood circulation of CDDP loaded nanoparticles makes them as promising nanocarriers for tumor targeting delivery.

Ahmad Z ，Tang Z ，Shah A ，Lv S ，Zhang D ，Zhang Y ，Chen X ... -  《-》

Pharmacokinetics, biodistribution and in vivo efficacy of cisplatin loaded poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) complex nanoparticles for tumor therapy.

Platinum-based polymeric nano-drugs, especially cisplatin-loaded polymeric nanoparticles (CDDP-NPs), have been extensively exploited for the treatment of solid tumors. However, it is still unclear what role the processing procedure and the properties of the polymeric carrier materials may play in influencing the plasma pharmacokinetics, biodistribution and in vivo efficacy of CDDP-NPs. In this study, a series of poly(l-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-mPEG) copolymers were synthesized for the preparation of CDDP-loaded PLG-g-mPEG (CDDP/PLG-g-mPEG) nanoparticles. All of the parameters, including PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length, ultrafiltration purification and cisplatin loading content, were found to have a significant influence on the plasma pharmacokinetics of the CDDP/PLG-g-mPEG nanoparticles. The blood circulation time of the nanoparticles was prolonged with increases in PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length and CDDP loading content. The use of ultrafiltration purification could prolong the blood circulation time of the nanoparticles as well. Experiments to measure the pharmacokinetics and biodistribution demonstrated that the selected CDDP/PLG-g-mPEG nanoparticles, NP10, had a long blood circulation time and could achieve selective and significant accumulation in Lewis lung carcinoma (LLC) tumors. The platinum plasma concentrations in the LLC tumor-bearing mice receiving NP10 remained up to 46-fold higher than that of mice receiving equivalent doses of free CDDP. In addition, the plasma area under the concentration time curve (AUC) of NP10 was 31-fold higher than that of free CDDP in 48h. The platinum concentration ratio of NP10 to free CDDP in tumors reached as high as 9.4. The tumor AUC ratio of NP10 to CDDP was 6. Using a mouse C26 tumor model, here we demonstrate that NP10 improves the safety and tolerance in vivo when compared to CDDP and effectively inhibits the growth of C26 tumors. Furthermore, increasing the dosage of NP10 by 2 or 3-fold of free CCDP improved its anticancer efficacy to comparable or higher levels. These results indicate that CDDP/PLG-g-mPEG nanoparticles have greater potential for the treatment of solid tumors in clinical application.

Yu H ，Tang Z ，Zhang D ，Song W ，Zhang Y ，Yang Y ，Ahmad Z ，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》

Methoxypoly(ethylene glycol)-block-poly(L-glutamic acid)-loaded cisplatin and a combination with iRGD for the treatment of non-small-cell lung cancers.

CDDP is loaded into methoxypoly(ethylene glycol)-block-poly(L-glutamic acid) (mPEG-b-PLG), and a combination with iRGD is applied for NSCLC chemotherapy. The CDDP-loaded micelles show sustained cisplatin release in PBS, dose- and time-dependent inhibition to HeLa and A549 cell proliferation, and no apparent hemolysis activities. In in vivo studies using subcutaneous NSCLC xenograft models (A549), both free CDDP and CDDP-loaded micelles show an evident anti-tumor effect. However, the toxicity of CDDP is significantly reduced in the cases of CDDP-loaded micelles and co-administration with iRGD, and the survival time is prolonged by over 30%. Therefore, mPEG-b-PLG-loaded cisplatin and the combination with iRGD provides a promising new therapy for NSCLC.

Song W ，Li M ，Tang Z ，Li Q ，Yang Y ，Liu H ，Duan T ，Hong H ，Chen X ... -  《-》

Polypeptide-based combination of paclitaxel and cisplatin for enhanced chemotherapy efficacy and reduced side-effects.

A novel methoxy poly(ethylene glycol)-b-poly(l-glutamic acid)-b-poly(l-phenylalanine) (mPEG-b-P(Glu)-b-P(Phe)) triblock copolymer was prepared and explored as a micelle carrier for the co-delivery of paclitaxel (PTX) and cisplatin (cis-diamminedichlo-platinum, CDDP). PTX and CDDP were loaded inside the hydrophobic P(Phe) inner core and chelated to the middle P(Glu) shell, respectively, while mPEG provided the outer corona for prolonged circulation. An in vitro release profile of the PTX+CDDP-loaded micelles showed that the CDDP chelation cross-link prevented an initial burst release of PTX. The PTX+CDDP-loaded micelles exhibited a high synergism effect in the inhibition of A549 human lung cancer cell line proliferation over 72 h incubation. For the in vivo treatment of xenograft human lung tumor, the PTX+CDDP-loaded micelles displayed an obvious tumor inhibiting effect with a 83.1% tumor suppression rate (TSR%), which was significantly higher than that of a free drug combination or micelles with a single drug. In addition, more importantly, the enhanced anti-tumor efficacy of the PTX+CDDP-loaded micelles came with reduced side-effects. No obvious body weight loss occurred during the treatment of A549 tumor-bearing mice with the PTX+CDDP-loaded micelles. Thus, the polypeptide-based combination of PTX and CDDP may provide useful guidance for effective and safe cancer chemotherapy.

Song W ，Tang Z ，Li M ，Lv S ，Sun H ，Deng M ，Liu H ，Chen X ... -  《-》