Preparation, characterization and in vivo evaluation of polyether polyol-platinate conjugate

Polyether Polyol (PEP) has been proposed by our research team as a new bioconjugation material due to its easy synthesis procedure, good water solubility and multiple pendent groups along the main chain. The objectives of this project are to demonstrate the biocompatibility of PEP, and to prepare, characterize and evaluate a new polymer-drug conjugate PEP-platinate. PEP was found to be nontoxic from the results of fibroblast cell viability assay and hemolytic assay. Injection of PEP into nude mice did not cause any body weight loss. Thus PEP satisfied the biocompatibility requirement as a polymeric drug carrier. Next, we showed the usefulness of PEP as a polymeric drug carrier and its advantage over PEG by preparing and characterizing PEP-platinate. The drug loading was 9.1%-12.6% (cisplatin/conjugate w/w), at least 4 times higher than a PEG conjugate of similar molecular weight. The solubility of cisplatin in water was increased by around 10 fold after conjugation, exceeding the improvement by pegylation. A platinum complex was released from the conjugate without an initial burst and in a sustained manner over 2 days in aqueous buffers. The release of active drugs was confirmed by the antitumor activity of PEP-platinate in vitro against HONE-1 (human nasopharyngeal carcinoma) and MCF-7 (human breast cancer), albeit at a potency lower than free cisplatin. In vivo, PEP-platinate improved the therapeutic index of cisplatin after intravenous administration. The conjugate showed similar extent of tumor inhibition as free cisplatin in nude mice bearing human nasopharyngeal carcinoma xenografts, and about 20% growth inhibition at the conclusion of the animal study. Systemic side effects were reduced in the mice receiving PEP-platinate, as evidenced by the significant decrease in weight loss in comparison to the mice receiving cisplatin injection. These findings support the proposal that PEP is a suitable drug carrier and that PEP-platinate has a higher therapeutic index than cisplatin when administrated intravenously in mice model bearing human nasopharyngeal carcinoma xenografts