Qin Yun,Si Song Wang,Shan Xu,Jin Ping Yang,Juan Fan,Ling Lin Yang,Yue Chen,Shao Zhi Fu,Jing Bo Wu
Colorectal peritoneal carcinomatosis (CRPC) is a common systemic metastasis of intra-abdominal cancers. Intraperitoneal chemotherapy against CRPC is at present the preferred treatment. The aim of this study is to develop a novel hydrogel drug delivery system through the combination of 5-fluorouracil (5-FU) loaded polymeric micelles and cisplatin (DDP) in biodegradable thermosensitive chitosan (CS) hydrogel. The prepared CS hydrogel drug is a free-flowing solution at room temperature and forms a stationary gel at body temperature. Therefore, a CRPC mouse model is established to investigate the antitumor activity of CS hydrogel drug system. The results suggest that intraperitoneal administration of CS hydrogel drug can inhibit tumor growth and metastasis, and prolong survival time compared with other groups, thus improving the chemotherapeutic effect. Ki-67 immunohistochemical analysis reveals that tumors in the CS hydrogel drug group has lower cell proliferation in contrast to other groups ( P < 0.001). Furthermore, hematoxylin-eosin staining of liver and lung tissue indicates that the CS hydrogel drug has also a certain inhibitory effect on colorectal cancer metastasis to the liver and lung. Hence, the work highlights the potential clinical applications of the CS hydrogel drug.
Colorectal peritoneal carcinomatosis (CRPC) is a manifestation of colorectal cancer characterized by aggressive tumor growth. Clinically, patients are typically treated with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. However, this strategy is only suitable for a subset of patients and may result in severe side effects. Therefore, we explored a novel approach using green-engineered materials that we developed an injectable hydrogel (CPE) based on polyphenol-borate ester bonds by functionalizing chitosan. These biopolymer composites exhibit excellent biocompatibility, mitigating drug-related toxicities. Our hydrogel delivery system concurrently administers cabazitaxel and imiquimod (R837) for localized chemotherapy and immunotherapy. Cabazitaxel-mediated chemotherapy induces immunogenic cell death (ICD) of tumor cells, releasing tumor-associated antigens (TAAs), that promote dendritic cell maturation and cytotoxic T lymphocyte (CTL) infiltration. The in situ release of the TLR7 agonist R837 further stimulates the immune system, inducing an effective and sustained antitumor immune response tailored to CRPC. In summary, by establishing an in situ drug reservoir, we effectively inhibited tumor invasion and progression and induced a durable immune response, offering a new perspective on localized immunotherapy for the clinical treatment of CRPC.
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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