Objective(s): Patient-derived xenograft (PDX) model becomes a more and more important tool for tumor research. This study aimed to establish a colorectal cancer PDX model and verify its applicability. Materials and Methods: Fresh human colorectal cancer tissue was surgically removed and subcutaneously inoculated into immunodeficient mice to establish the PDX model. Hematoxylin and eosin (HE) staining and immunohistochemical staining were used to evaluate the model. The successful PDX model was selected to study the efficacy of capecitabine in treating colorectal cancer. Results: HE staining showed that the PDX mice model of colorectal cancer could preserve the histological characteristics of the primary tumor. Immunohistochemistry staining showed α-fetoprotein (AFP), carcinoembryonic antigen (CEA), and E-cadherin were strongly positively expressed in primary human and PDX tumor tissues, with a high degree of similarity. Capecitabine significantly inhibited PDX tumor growth and reduced the expression of AFP and CEA proteins in the tumor tissues (all P s <0.05). Conclusion: We successfully established a colorectal cancer PDX model, and the PDX model could retain the histological and biological characteristics of the primary tumor. Using this PDX model, we revealed that capecitabine at a dose of 300–400 mg/kg can effectively treat colorectal cancer, and no significant difference in toxicity was found among different dose groups. The current work provides a feasible framework for establishing and validating the PDX tumor model to better facilitate the evaluation of drug efficacy and safety.
Gemcitabine (GEM), as a first-line chemotherapeutics for pancreatic ductal adenocarcinoma (PDAC) treatment, still faces several clinical challenges, restricted by instability in blood circulations, low tumor selectivity, and acquired nature characteristics of chemo-resistance. To solve these challenges, the rational design of combination therapy with GEM and other therapy modalities is imperative. Herein, a small molecular self-assembly nano-prodrug is developed, which can achieve the co-delivery of GEM, Ferrocene and nutlin-3a on the achievement of GEM-induced apoptosis with ferroptosis. In this nano-prodrug, the disulfide linkage not only acts as a GSH-responsive trigger but also plays an important role in self-assembly behavior of nanoparticle that can load nutlin-3a. Interestingly, nutlin-3a plays an important role in both ferroptosis and apoptosis, one is effectively sensitized cells to ferroptosis by inhibiting cystine uptake, and the other is promoted apoptosis by elevating p53 expression. To further enhance the drug tumor accumulation and maintain stability in systemic circulations, this nano-prodrug is then encapsulated into plectin1 receptor-targeting phospholipid micelles (DSPE-PEG-PTP), which displays high selective tumor inhibition and good biosafety on different mice models, especially in orthotopic and patient-derived xenograft (PDX) models. The findings provide new insights into the combination therapy of GEM with ferroptosis for reduced chemo-resistance on PDAC treatment.
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