Prodrug-Engineered PI3K/mTOR Nanoblockers Enable Coordinated Tumor Control and Allograft Protection after Transplantation
Year: 2026
Type: preprint
Abstract: Organ transplant recipients with malignancies require therapeutic strategies that control tumor progression without compromising allograft protection. Although mTOR inhibition provides a clinically validated strategy for balancing immunosuppression and tumor control after transplantation, compensatory PI3K/Akt activation limits durable efficacy. Dual PI3K/mTOR blockade represents a rational solution, yet its therapeutic potential is restricted by suboptimal pharmacological properties, including insufficient tissue exposure and dose-limiting toxicity, which compromise sustained target engagement. Here, we developed a prodrug-enabled nanoliposomal platform (PMIProsome) for sustained dual PI3K/mTOR inhibition by converting PF-04691502, a representative dual PI3K/mTOR inhibitor, into a disulfide-linked cholesterol prodrug. PMIProsome optimized systemic drug exposure by enhancing tumor accumulation and reducing systemic toxicity, enabling sustained PI3K/Akt/mTOR pathway inhibition and durable tumor control in an orthotopic hepatocellular carcinoma model. Beyond tumor suppression, PMIProsome retained immunomodulatory activity by attenuating cytotoxic T-cell activation and inflammatory responses, thereby promoting allograft survival. In a concomitant tumor-allograft model, PMIProsome achieved simultaneous tumor control and allograft protection, overcoming the therapeutic conflict between antitumor efficacy and immunosuppression after transplantation. Collectively, these findings establish prodrug-engineered PI3K/mTOR nanoblockers as a therapeutic strategy for coordinating tumor control and allograft protection after transplantation.
Source: Research Square
Institution: First Affiliated Hospital Zhejiang University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225619170