Stromal Homeostasis-Restoring Nanomedicine Enhances Pancreatic Cancer Chemotherapy

Abstract

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.

Stromal and tumor immune microenvironment reprogramming through multifunctional cisplatin-based liposomes boosts the efficacy of anti-PD-1 immunotherapy in pancreatic cancer

“…46 According to Na Yu et al , nanomedicine-based strategies for matrix homeostasis remodelling appear promising for treating pancreatic cancer. 47 The liposomes we used are matrix-targeted and pH-responsive liposomes, which should, most likely, result in the destruction of only the central mesenchyme, while leaving the external mesenchyme unharmed.…”

Nanomedicine and epigenetics: New alliances to increase the odds in pancreatic cancer survival

“…Moreover, ECM degradation did not increase the number of circulating tumor cells, which is often a concern when the ECM is targeted [103]. A promising approach for treating desmoplastic malignancies was recently published by Yu et al [104]. Specifically, they constructed two polymeric methoxy PEG-b-poly(caprolactone) (mPEG-PCL) nanocarriers based on halofuginone (HF) (HKS NPs) and PTX (PKS NPs).…”

Intelligent Biogenic Missile for Two-Photon Fluorescence Imaging-Guided Combined Photodynamic Therapy and Chemotherapy in Tumors

“…2 Surgical intervention remains ineffective against hematological malignancies, and radiotherapy is limited to localized treatment. 3 Chemotherapeutic drugs are commonly administered systemically, exerting their effects not solely on neoplastic cells but also on nonmalignant counterparts. It is noteworthy that all of these modalities entail a greater degree of detriment to normal tissues.…”

“…Conventional strategies for cancer treatment encompass surgical intervention, chemotherapy and radiation therapy . Surgical intervention remains ineffective against hematological malignancies, and radiotherapy is limited to localized treatment . Chemotherapeutic drugs are commonly administered systemically, exerting their effects not solely on neoplastic cells but also on nonmalignant counterparts.…”