Phosphatidylcholine Chain-Length of Bioinspired Lipoprotein Modulates Interactions with Collagen for Intratumor Delivery in Pancreatic Cancer

Pancreatic cancer, one of the most lethal malignant tumors, is greatly challenged by poor drug delivery efficiency because of the dense and intricate desmoplastic stroma. Given the abnormal expression of scavenger receptor B type 1 (SR-B1) and the dense collagen I (COL1)-enriched extracellular matrix (ECM) barrier in pancreatic tumors, we developed four BLPs with regular chain-length of phosphatidylcholine (PC) (BLP-M, BLP-S, BLP-P, and BLP-H) to enhance their intratumoral delivery for chemotherapy. With the increase of PC chain-length in BLPs, these BLPs exhibited regular tendency of increased affinity to COL1, reduced diffusion capacity in COL1 hydrogel, lessened tumor accumulation and intratumor distribution, and declined efficacy of prolonging survival in the orthotopic pancreatic cancer model. Particularly, the DMPC-based BLP-M system showed the lowest affinity to COL1 and the highest diffusion capacity in the COL1-based ECM barrier, thereby causing the best efficacy of specific tumor accumulation, intratumor delivery, and survival prolongation in an orthotopic pancreatic tumor model. Thereby, this study provided substantial insights into the targeting and intratumor delivery in pancreatic cancer, and DMPC-based BLPs represented an encouraging delivery platform for effective cancer chemotherapy.