Cancer-Associated Fibroblast-Targeted Delivery of Captopril to Overcome Penetration Obstacles for Enhanced Pancreatic Cancer Therapy

Abstract

Pancreatic cancer is one of the most stroma-abundant solid cancers. Its desmoplastic nature restricts the penetration of drugs in tumor tissues and is considered as a major challenge for efficient chemotherapy. In the present study, we repurposed the use of captopril to deplete the overexpressed extracellular matrix (ECM) in stroma of pancreatic tumor. Precise delivery of captopril to cancer-associated fibroblasts (CAFs) was achieved using CAFs targeting peptide modified liposomes. The targeted delivery of captopril significantly downregulated the deposition of ECM by blocking the TGF-β1-Smad2 related signaling pathway, which improved the penetration of subsequently administrated liposome-encapsulated chemotherapeutic agent gemcitabine. It proved as a promising solution to break the aforementioned stromal barrier in pancreatic cancer therapy.

Advancing Cancer Treatment Through Nanotechnology Driven Immunotherapy for Pancreatic Cancer

“…(B) Schematic illustration of stromal modulation by FH peptide modified captopril encapsulated Liposomes (FH-Lip-Cap) for improving nanodrug diffusion and penetration, and mechanistic study of FH-Lip-Cap regulating ECM. Reprinted with permission from ref . Copyright 2022 American Chemical Society.…”

“…Similarly, Chen X et al engineered a targeted drug delivery system that could overcome the penetration obstacles in pancreatic cancer by targeting CAFs (Figure B) . They chose captopril, an angiotensin-converting enzyme (ACE) inhibitor that has been reported to have various anticancer mechanisms, including inhibition of angiogenesis, tumor growth, and metastasis .…”

“…The liposomes are modified with FH peptides that target activated CAFs in both experimental and animal models by binding to tenascin C. FH-Lip-Cap reduced excessive extracellular matrix deposition in tumor stroma through the TGF-β1-Smad2 related signaling pathway. Further, FH-Lip-Cap pretreatment improved the tumor penetration of subsequently injected gemcitabine-loaded liposomes (Lip-GEM), enhancing the antitumor effect of Lip-GEM . Compared to other methods, this targeted delivery of captopril offers several benefits, including minimal toxicity, ease of preparation, and efficient delivery to tumor tissue through FH peptide modification.…”

“…133 Similarly, Chen X et al engineered a targeted drug delivery system that could overcome the penetration obstacles in pancreatic cancer by targeting CAFs (Figure 6B). 134 They chose captopril, an angiotensin-converting enzyme (ACE) inhibitor that has been reported to have various anticancer mechanisms, including inhibition of angiogenesis, tumor growth, and metastasis. 135 In addition to delivering captopril to CAFs, they developed FH peptide-modified captopril encapsulated liposomes (FH-Lip-Cap) to improve drug penetration by depleting the dense stroma in tumors.…”

“…Further, FH-Lip-Cap pretreatment improved the tumor penetration of subsequently injected gemcitabine-loaded liposomes (Lip-GEM), enhancing the antitumor effect of Lip-GEM. 134 Compared to other methods, this targeted delivery of captopril offers several benefits, including minimal toxicity, ease of preparation, and efficient delivery to tumor tissue through FH peptide modification.…”