Collagenase Nanoparticles Enhance the Penetration of Drugs into Pancreatic Tumors

Abstract

Overexpressed extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDAC) limits drug penetration into the tumor and is associated with poor prognosis. Here, we demonstrate that a pretreatment based on a proteolytic-enzyme nanoparticle system disassembles the dense PDAC collagen stroma and increases drug penetration into the pancreatic tumor. More specifically, the collagozome, a 100 nm liposome encapsulating collagenase, was rationally designed to protect the collagenase from premature deactivation and prolonged its release rate at the target site. Collagen is the main component of the PDAC stroma, reaching 12.8 ± 2.3% vol in diseased mice pancreases, compared to 1.4 ± 0.4% in healthy mice. Upon intravenous injection of the collagozome, ∼1% of the injected dose reached the pancreas over 8 h, reducing the level of fibrotic tissue to 5.6 ± 0.8%. The collagozome pretreatment allowed increased drug penetration into the pancreas and improved PDAC treatment. PDAC tumors, pretreated with the collagozome followed by paclitaxel micelles, were 87% smaller than tumors pretreated with empty liposomes followed by paclitaxel micelles. Interestingly, degrading the ECM did not increase the number of circulating tumor cells or metastasis. This strategy holds promise for degrading the extracellular stroma in other diseases as well, such as liver fibrosis, enhancing tissue permeability before drug administration.

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“…Furthermore, ECM degradation has been proposed to alleviate solid stress and enhance NCs intratumoral accumulation. Notably, the use of collagenases, relaxin, and hyaluronidases have been explored for this purpose, and their association with chemotherapeutics is already under clinical trials [106][107][108]. Although efficient in promoting the tumor accumulation, the clinical application of such strategies is hampered by safety concerns, high costs, and the intrinsic instability of biologic drugs.…”

Grafted semiconducting polymer amphiphiles for multimodal optical imaging and combination phototherapy

“…Numerous studies have been conducted to overcome such a problem. 111 As collagen is the most abundant tumor ECM protein, the digestion of collagen around tumor is a feasible way to enhance the penetration of nanomedicines. 112 Thus, a bromelain (Bro)-conjugated SPA, SPA24-Bro, was synthesized by an amidation reaction between carboxyl group-graed SPA24 and Bro (Fig.…”

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“…Recently, Zinger et al proposed to utilize collagenase-loaded liposomes with slow release characteristics as a pretreatment to reduce the fibrotic character of pancreatic tumors and improve the delivery of secondary therapeutics (Zinger et al, 2019). They showed higher tumor weight reductions with the pretreatment and micellar paclitaxel, compared to micellar paclitaxel alone.…”