A reconstituted thermosensitive hydrogel system based on paclitaxel-loaded amphiphilic copolymer nanoparticles and antitumor efficacy

Abstract

Combination delivery systems composed of injectable hydrogels and drug-incorporated nanoparticles are urgently in regional cancer chemotherapy to facilitate efficient delivery of chemotherapeutic agents, enhance antitumor efficiency, and decrease side effects. Here, we developed a novel thermosensitive amphiphilic triblock copolymer consisting of methoxy poly(ethylene glycol), poly(octadecanedioic anhydride), and d,l-lactic acid oligomer (PEOALA), built a combination system of thermosensitive injectable hydrogel PTX/PEOALA^Gel based on paclitaxel (PTX)-loaded PEOALA nanoparticles (NPs). PTX/PEOALA^Gel could be stored as freeze-dried powders of paclitaxel-loaded PEOALA NPs, which could be easily redispersed into the water at ambient temperature, and form a hydrogel at the injected site in vivo. The in vitro cytotoxicity of PTX/PEOALA^Gel showed no obvious cytotoxicity in comparison with Taxol® against MCF-7 and HeLa cells. However, the in vivo antitumor activity showed that a single intratumoral injection of the PTX/PEOALA^Gel formulation was more effective than four intravenous (i.v.) injections of Taxol^® at a total dosage of 20 mg/kg in inhibiting the growth of MCF-7 tumor-bearing Balb/c mice, and the inhibition could be sustained for more than 17 d. The pharmacokinetic study demonstrated that the intratumoral injection of PTX/PEOALA^Gel could greatly decrease the systemic exposure of PTX, as confirmed by the rather low plasma concentration, and prolonged circulation time and enhanced tumor PTX accumulation, implying fewer off-target side effects. In summary, the PTX/PEOALA^Gel combination local delivery system could enhance tumor inhibition effect and tumor accumulation of PTX, and lower the systemic exposure. So, the reconstituted PTX/PEOALA^Gel system could potentially be a useful vehicle for regional cancer chemotherapy.

Keywords:

• Reconstituted thermosensitive hydrogel
• paclitaxel
• amphiphilic copolymer
• nanoparticles
• local chemotherapy

Disclosure statement

The authors report no declarations of interest.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (No. 81503000, 81371667), the China Postdoctoral Science Foundation (the 59 batch of grant) and the Specialized Research Fund for the Doctoral Program of Higher Education (20120032110013).