Localized co-delivery of collagenase and trastuzumab by thermosensitive hydrogels for enhanced antitumor efficacy in human breast xenograft

Abstract

Modulation of the collagen-rich extracellular matrix (ECM) in solid tumors by the treatment with collagenase has been proved effective in enhancement of the interstitial transport and antitumor efficacy of antibodies. We, therefore, developed a PLGA-PEG-PLGA polymer-based thermosensitive hydrogel, which incorporated a HER2-targeted monoclonal antibody trastuzumab and collagenase (Col/Tra/Gel) for peritumoral administration. HER2-positvie BT474 tumor-bearing mice were selected as a model. The Col/Tra/Gel showed the continuous and biphasic release of protein drugs for 9 days in vitro. NIR imaging studies demonstrated a long-term retention of Col/Tra/Gel hydrogel in the peritumoral area for over 20 days. Treatment with Col/Tra/Gel reduced the collagen density and enhanced apoptotic cell death in tumor tissue, resulting in superior treatments with increased efficacy and reduced toxicity compared with other control groups. Moreover, a quarter-dose of Col/Tra/Gel exhibited a better antitumor efficacy than that of intravenous injection of clinical trastuzumab formulation. This localized co-delivery system offers a potential strategy for the modulation of dense ECM and enhancement of antibody efficacy.

The role of collagen in cancer: from bench to bedside

“…Combining collagen inhibitors and standard therapeutics, such as chemotherapy and radiotherapy, is a promising anticancer strategy. Collagenase combined with trastuzumab via thermosensitive hydrogels exerted an anticancer effect on animals [212]. Nitric oxide activated endogenous MMP-1 and MMP-2 to deplete collagen, and it significantly improved anticancer efficacy while exerting no overt toxicity in animal models [213].…”

Thermo-Sensitive Nanomaterials: Recent Advance in Synthesis and Biomedical Applications

“…Thermal responsive microgels can carry a drug [ 136 , 137 ] or drug-loaded NPs [ 138 , 139 ]. The combination of various drugs in a single microgel can be achieved by encapsulating them directly in the hydrogel [ 140 ] or by designing hydrogel composites such as the dual drug loaded thermo-sensitive hydrogel composite recently published by Xu and co-workers [ 141 ]. In this study, the anti-tumor effect of the combination of cisplatin-containing thermo-sensitive hydrogel and paclitaxel-loaded polymeric micelles in a single composite (called PDMT) was investigated in an in vivo cervical cancer model.…”

<p>Mechanism Investigation of Hyaluronidase-Combined Multistage Nanoparticles for Solid Tumor Penetration and Antitumor Effect</p>

“…Collagen I is another main component of tumor ECM, and the decrease of collagen I content could also enhance the penetration of NPs in tumors and improve antitumor efficacy. 39 In order to study whether the enhanced penetration of NPs-EPI/HAase in HepG2 tumors was due to the reduction of collagen I content, collagen I of sectioned tumor tissues was stained and examined. As shown in Figure 9A and C, there was no significant difference in collagen I expression among the four groups, indicating that the enhanced penetration of NPs-EPI/HAase was not due to the reduction of collagen I by NPs.…”