Thermosensitive Liposomal Codelivery of HSA–Paclitaxel and HSA–Ellagic Acid Complexes for Enhanced Drug Perfusion and Efficacy Against Pancreatic Cancer

Fibrotic stroma and tumor-promoting pancreatic stellate cells (PSCs), critical characters in the pancreatic ductal adenocarcinoma (PDA) microenvironment, promote a tumor-facilitating environment that simultaneously prevents drug penetration into tumor foci and stimulates tumor growth. Nab-PTX, a human serum albumin (HSA) nanoparticle of paclitaxel (PTX), indicates enhanced matrix penetration in PDA probably due to its small size in vivo and high affinity of HSA with secreted protein acidic and rich in cysteine (SPARC), overexpressed in the PDA stroma. However, this HSA nanoparticle shows poor drug blood retention because of its weak colloidal stability in vivo, thus resulting in insufficient drug accumulation within tumor. Encapsulating HSA nanoparticles into the internal aqueous phase of ordinary liposomes improves their blood retention and the following tumor accumulation, but the large 200 nm size and shielding of HSA in the interior might make it difficult for this hybrid nanomedicine to penetrate the fibrotic PDA matrix and promote bioavailability of the payload. In our current work, we prepared ∼9 nm HSA complexes with an antitumor drug (PTX) and an anti-PSC drug (ellagic acid, EA), and these two HSA–drug complexes were further coencapsulated into thermosensitive liposomes (TSLs). This nanomedicine was named TSL/HSA-PE. The use of TSL/HSA-PE could improve drug blood retention, and upon reaching locally heated tumors, these TSLs can rapidly release their payloads (HSA–drug complexes) to facilitate their further tumor accumulation and matrix penetration. With superior tumor accumulation, impressive matrix penetration, and simultaneous action upon tumor cells and PSCs to disrupt PSCs–PDA interaction, TSL/HSA-PE treatment combined with heat exhibited strong tumor growth inhibition and apoptosis in vivo.