For in situ thermosensitive hydrogels, it is a big challenge to achieve high drug loading, long-term local retention, and effective drug release simultaneously. To address these issues, we combined the strategy of drug nanocrystals (NCs) and thermosensitive hydrogels with higher gel strength. In particular, we developed paclitaxel NC-based hydrogels using PECT, a thermosensitive polymer synthesized by us (PTX-NC-PECT), and a nanoparticle-based system was used as the control (PTX-NP-PECT). First, high levels of PTX could be loaded in both PECT hydrogels. Moreover, in vivo near infrared fluorescence (NIRF) imaging showed that both hydrogel systems were able to maintain the payloads of 1,1-dioctadecyltetramethyl indotricarbocyanine iodide (DiR) at a peri-tumoural site for at least 21 days, much longer than that achieved with the control hydrogel of Pluronic® F127. Furthermore, we observed that PTX-NCs released free PTX more effectively and homogeneously than PTX-NPs in vitro. It was further verified in vivo that the release of DiR from DiR-NC-PECT was more complete than that from DiR-NP-PECT. Finally, PTX-NC-PECT gel demonstrated the strongest anti-tumour efficacy on MCF-7 breast cancer. In conclusion, PTX-NC-PECT hydrogel might be a high-performance thermosensitive hydrogel for local cancer therapy.
Intraperitoneal (IP) chemotherapy is a preferable treatment option for peritoneal carcinomatosis of malignancies by delivering chemotherapeutic drugs into the abdominal cavity. A persistent major challenge in IP chemotherapy is the need to provide effective drug concentration in the peritoneal cavity for an extended period of time. In the present work, the thermosensitive hydrogel system (PTX/PECT gel ) assembled by PTX (paclitaxel)-loaded amphiphilic copolymer (PECT, poly (ε-caprolactone-co-1,4,8-trioxa [4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly (ε-caprolactone-co-1,4,8-trioxa [4.6]spiro-9-undecanone)) nanoparticles was developed for sustained IP chemotherapy of peritoneal carcinomatosis model. Cytotoxicity assay indicated that PECT hydrogel was biocompatible with very low cytotoxicity and PTX/PECT gel had enhanced cytotoxicity than free PTX. In vivo toxicity study demonstrated the biocompatibility and biosafety of PECT hydrogel as an IP chemotherapy carrier. The fluorescence imaging method was employed to monitor the intraperitoneal degradation of PECT hydrogel by labeling PECT with rhodamine B. PECT hydrogel with the dose of 200 μL showed about 8 days’ retention time and most of the injected hydrogel was located in the intestine. The anti-tumor efficacy study was carried out in mice bearing CT26 intraperitoneal ascites fluid as colorectal peritoneal carcinomatosis model. The result showed that intraperitoneal administration of PTX/PECT gel could effectively suppress growth and metastasis of CT26 peritoneal carcinomatosis in vivo , compared with Taxol® group. The pharmacokinetic studies demonstrated that PTX/PECT gel could improve the bioavailability of PTX by being formulated in PECT hydrogel. Overall, sustained drug concentration at peritoneal levels in combination with drug in the form of nanoparticle contributes to the enhanced anti-tumor efficacy. Thus, our results suggested that PTX/PECT gel may have great potential applications in IP chemotherapy.
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