Model-Driven Optimization of Subcutaneous Polymer Prodrugs Achieves Cancer Remission in Mice.

Abstract

The limitations of chemotherapy (e.g., toxicities, limited efficacy) have led to the development of nanocarriers for drug delivery to improve pharmacokinetics (PK) and therapeutic outcomes. However, optimizing dosing regimens remains challenging. Moreover, since chemotherapy is mainly administered intravenously (IV), this results in patient discomfort and high treatment costs. To address these issues, we used PK/pharmacodynamics (PD) modeling and applied it to subcutaneously (SC) injectable water-soluble polymer prodrug based on paclitaxel (Ptx) and polyacrylamide (PAAm), synthesized by "drug-initiated" controlled radical polymerization. PK/PD studies were performed on MCF-7 tumor-bearing mice. The PK model was developed on IV Ptx and SC Ptx-PAAm data. The PD model was developed on control, IV Ptx, and SC Ptx-PAAm groups (15 mg/kg), and validated on an independent group (SC Ptx-PAAm at 60 mg/kg). A series of optimal dosing regimens identified in silico were then validated in vivo with excellent agreement. Among them, a dosing regimen combining a loading dose and daily injections achieved a 60% complete response rate without added toxicity, outperforming prior results. To our knowledge, this is the first validated PK/PD model for nanocarriers, offering a framework for more effective, cost-efficient, and ethically refined drug development.