Stroma-targeted nanoparticles that remodel stromal alignment to enhance drug delivery and improve the antitumor efficacy of Nab-paclitaxel in pancreatic ductal adenocarcinoma models

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. A dense desmoplastic and specifically aligned stroma plays integral roles in the progression of PDAC, and inhibits drug penetration to impede treatment. However, direct depletion of stromal components for PDAC therapy interferes with the stromal balance, possibly accelerating tumor progression. Specific fiber alignment of the extracellular matrix, the most significant type of stroma topology in PDAC, is an important feature of PDAC and often overlooked. Here, we found that the alignment of collagen fibers, as determined by second harmonic generation (SHG) imaging, negatively correlated with pancreatic cancer prognosis. We report an integrated, two-step strategy for PDAC treatment, utilizing pretreatment with polymer-lipid-peptide nanoparticles that deliver inhibitors of lysyl oxidase like 2 (LOXL2) and discoidin domain receptor 1 (DDR1), followed by treatment with albumin-bound-paclitaxel (Nab-paclitaxel). The LOXL2 and DDR1 inhibitors intervene with collagen crosslinking and matrix metallopeptidase 1 (MMP1) expression to remodel stromal alignment without decreasing the collagen content, thus facilitating the transport of Nab-paclitaxel through the stromal barrier to enhance drug penetration and accumulation in the PDAC tumor tissue. Through this mechanism, the combined strategy resulted in significant antitumor efficacy in PDAC orthotopic xenograft mice. The current work highlights the key role of stromal alignment in therapeutics transport through stromal barriers. The strategy of remodeling stromal alignment may represent a promising approach for improving drug delivery in other stroma-rich tumors and fibrosis-related diseases.