Injectable Thermosensitive Pendent Cycle Ethers Modified PCL And PEG Copolymer Hydrogel For Locoregional Tumor Chemotherapy

Loco-regional chemotherapy of thermosensitive in situ hydrogel composed of PEGand biodegradable polyesters can provide physiological target for anticancer drugs,improve the antitumor efficiency as well as reduce the systemic exposure and tissuedistribution. PCL-PEG-PCL copolymers are biocompatible, however, to prepare ofPCL-PEG-PCL hydrogel, one must dissolve PCL-PEG-PCL in water at a hightemperature and then quench the solution at0oC. And the instability ofPCL-PEG-PCL sol, the too slow degradation and drug release properties ofPCL-PEG-PCL restrict the biomedical applications of PCL-PEG-PCL gel. In thisstudy, pendent cycle ethers were introduced into PCL to obtain PECT to overcometheses disadvantages. The gel transiton, degradation and paclitaxel release, antitumoreffect of paclitaxel loaded PECT hydrogel (PTX/PECTGel) and paclitaxelpharmacokinetics were investigated. The biocompatibility of PECT was also studied.PECT was synthesized by ring-opening copolymerization of ε-caprolactone and1,4,8-trioxa[4.6]spiro-9-undecanone with PEG as the initiator and catalyst.Thermodynamic analysis demonstrated that cycle ethers could weaken thecrystallinity of PCL as well as impart hydrophility to PCL. Thus, PECT or itsfree-dried powders could be quickly dissolvled in water at room temperature, formingstable core-shell structure PECT nanoparticles aqueous solution. At body temperature,PECT nanoparticles aggregated into gel driven by hydrophobic interaction and thecrystallinity of hydrophobic microdomains.The convenient fabrication of drug formulation, satisfactory degradability andwell-controlled drug release profile are crucial factors for injectable hydrogelformulations in clinical applications. By dissolving freeze-dried powders of paclitaxel(PTX)-loaded PECT nanoparticles in water at ambient temperature could providemuch convenience for clinical PTX encapsulated PECT hydrogel formulation(PTX/PECTGel). Furthermore, the paclitaxel distribution in PTX/PECTGelwas moreamorphous and homogeneous. A small amount of pendant cyclic ether groups in PCLcould tune the in vitro and in vivo retention time of PECT gel and the incorporatedpaclitaxel release from a few weeks to months. Significantly, paclitaxel-loaded PECTnanoparticles could dissociate from PTX/PECTGelduring in vitro paclitaxel release. The peritumoral or intratumoral injected PECT gel could cover the entire surface orfill-up the interior space of tumor, respectively. A single peritumoral injection ofcombiantion formulation PTX/PECTGel(10mg/kg) could completely inhibit thegrowth of EAC tumor. The plasma pharmacokinetic study demonstratedPTX/PECTGelcould greatly decrease the systemic exposure of PTX and the PTXconcentration in normal tissues of intratumoral injection of PTX/PECTGelwasapproximate2μg/g, implying fewer off-target side effects.A well biocpmpatibilty of PECT hydrogel reservoir is the prerequisite for cinicalapplications. In vitro cytotoxicity evaluated in L929cell lines indicated no cellcytotoxicity was observed. Mouse marrow micronucleus test and bacterial reversemutation assay demonstrated PECT did not induce a mutagenic effect or any genetictoxicity. The LD50of PECT nanoparticles was approximate2.564g/kg. The in vivointravenous injection of PECT nanoparticles or chronic biocompatibility of PECT gelconfirmed that PECT did not result in any toxic lesions to animals as proven by thefood and water consumption, body weight, biochemical and hematological parameters,and histological analysis.In short, PTX/PECTGelrepresents a promising cancer chemotherapy formulation,which is of convenient reconstruction and facile injection properties, of wellmodulated degradation and drug release behaviors and of effective tumor growthinhibtion efficiency. PTX/PECTGelcould greatly decrease the plasma concentrationand normal tissue distribution of paclitaxel. Therefore, PTX/PECTGelwas quitesuitable for regional chemotherapy.