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 ... -  《-》

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 ... -  《-》

Anti-tumor efficacy of polymer-platinum(II) complex micelles fabricated from folate conjugated PEG-graft-α,β-poly [(N-amino acidyl)-aspartamide] and cis-dichlorodiammine platinum(II) in tumor-bearing mice.

To develop a tumor-targeting nano-sized delivery system of cis-dichlorodiammine platinum(II) (CDDP), polymer-metal complex micelles were fabricated from folate-conjugated PEG-graft-α,β-poly [(N-amino acidyl)-aspartamide] (FA-PEG-g-PAAsp) and CDDP. The formation of polymer-metal complex micelles was confirmed by the measurements of critical aggregation concentration (CAC) and particle size, and the morphological observation. It was found that all the micelles showed spherical shapes with clear core-shell structures in narrow size distributions. The typical particle size measured by dynamic laser scattering (DLS) was ca. 105 nm, suggesting their passive targeting to tumor tissue and endocytosis potential. FA-PEG-g-PAAsp-CDDP micelles showed sustained drug release profiles over 40 h, and their accumulative drug release was ranked in the order of FA-PEG-g-PAsp-Ami-CDDP<FA-PEG-g-PAsp-Glu-CDDP<FA-PEG-g-PAsp-Asp-CDDP, depending on the category of used amino acid (Ami: potassium aminomalonate; Glu: glutamic acid; and Asp: aspartic acid). Cellular uptake of FA-PEG-g-PAsp-Ami-CDDP micelles was found to be higher than that of mPEG-g-PAsp-Ami-CDDP micelles because of folate receptor (FR)-mediated endocytosis, which is revealed by the cellular uptake image of Nile red-loaded micelles, and thereby provided higher cytotoxicity against FR-positive KB cells. Although the anti-tumor activity against KB cell-derived tumors was ordered at CDDP>FA-PEG-g-PAAsp-CDDP>mPEG-g-PAAsp-CDDP, the severe toxicity of CDDP in vivo limited its use as ideal anti-tumor drug. Furthermore, FA-PEG-g-PAAsp-CDDP and mPEG-g-PAAsp-CDDP showed rather low toxicity against mice, just similar to that of PBS. It indicated the great potential utilization of the FA-PEG-g-PAAsp-CDDP micelles as the tumor-targeted drug carriers of CDDP with improved anti-tumor efficacy.

Xue Y ，Tang X ，Huang J ，Zhang X ，Yu J ，Zhang Y ，Gui S ... -  《-》

Cisplatin-loaded polymeric nanoparticles: characterization and potential exploitation for the treatment of non-small cell lung carcinoma.

Cisplatin-loaded poly(l-glutamic acid)-g-methoxy poly(ethylene glycol 5K) nanoparticles (CDDP-NPs) were characterized and exploited for the treatment of non-small cell lung carcinoma (NSCLC). In vitro metabolism experiments showed that a glutamic acid 5-mPEG ester [CH3O(CH2CH2O)nGlu] was generated when the poly(l-glutamic acid)-g-methoxy poly(ethylene glycol 5K) (PLG-g-mPEG5K) was incubated with HeLa cells. This suggests that the poly(glutamic acid) backbone of the PLG-g-mPEG5K is biodegradable. Furthermore, the size of the CDDP-NPs in an aqueous solution was affected by varying the pH (5.0-8.0) and their degradation rate was dependent on temperature. The CDDP-NPs could also bind to the model nucleotide 2'-deoxyguanosine 5'-monophosphate, indicating a biological activity similar to cisplatin. The CDDP-NPs showed a significantly lower peak renal platinum concentration after a single systemic administration when compared to free cisplatin. In vivo experiments with a Lewis lung carcinoma (LLC) model showed that the CDDP-NPs suppressed the growth of tumors. In addition, LLC tumor-bearing mice treated with the CDDP-NPs (5mg/kg cisplatin eq.) showed much longer survival rates (median survival time: 51days) as compared with mice treated with free cisplatin (median survival time: 18days), due to the acceptable antitumor efficacy and low systemic toxicity of CDDP-NPs. These results suggest that the CDDP-NPs may be successfully applied to the treatment of NSCLC.

Shi C ，Yu H ，Sun D ，Ma L ，Tang Z ，Xiao Q ，Chen X ... -  《-》