Stromal Homeostasis-Restoring Nanomedicine Enhances Pancreatic Cancer Chemotherapy

The desmoplastic stroma imposes a fatal physical delivery barrier in pancreatic ductal adenocarcinoma (PDAC) therapy. Deconstructing the stroma components hence predominates in stroma-targeting approaches, but conflicting outcomes have sometimes occurred due to the multifaceted nature of the stroma. Here, we constructed two sub-20-nm nanomedicines based on a so-called "next-wave" antifibrotic halofuginone (HF) and the tumoricidal paclitaxel (PTX) for enhanced PDAC chemotherapy. This was achieved by coassembling methoxy poly(ethylene glycol)-b-poly(caprolactone) with ketal-linked HF- and PTX-derived prodrugs. HF nanomedicine and PTX nanomedicine had excellent prodrug-nanocarrier compatibility and exhibited greatly improved pharmacokinetic profiles and high tumor accumulation. HF nanomedicine pretreatment restored stromal homeostasis and considerably facilitated the distribution of PTX nanomedicine and its penetration into carcinoma cells, leading to positive modulation of the infiltration of cytotoxic T cells and significant regression of tumor growth in two PDAC models. Our nanomedicine-based stromal remodeling strategy appears promising for treating desmoplastic malignancies.