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.
Highlights
Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer-related death among women worldwide (DeSantis et al, 2017)
This rapid release of trastuzumab in the first phase accounts for nearly 60% of cumulative release and could be attributed to large mesh sizes of the hydrogel, which allows for the zero-order release of trastuzumab from the gel matrix
The density of tumor vessels in the PBS group was 9-fold higher than that of the Col/Tra/Gel group. These results proved that the Col/ Tra/Gel treatment induced the degradation of collagen and apoptosis of tumor cells, further confirming the essential of collagenase for the degradation of collagen and the deep penetration of trastuzumab for enhanced antitumor efficacy
Summary
Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer-related death among women worldwide (DeSantis et al, 2017). Trastuzumab (Herceptin), a HER2-targeted monoclonal antibody (mAb), was one of the first monoclonal antibodies approved by FDA in 2011 (Shpilberg & Jackisch, 2013). It inhibits the proliferation and survival of HER2-positive tumors and has achieved great successes in the clinic (Shpilberg & Jackisch, 2013; Moslehi, 2016; von Minckwitz et al, 2017). A Phase III clinical trial has been reported that co-delivery of trastuzumab with recombinant human hyaluronidase (rHuPH20) through subcutaneous (s.c.) administration achieved a comparable outcome to i.v. injection in terms of pharmacokinetic profiles, efficacy, and safety (Frost, 2007; Shpilberg and Jackisch, 2013; Xu et al, 2015). Localized delivery (e.g. s.c. injection) appears to be an alternative strategy for the administration of therapeutic antibodies
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