Sustained degradation of hyaluronic acid using an in situ forming implant

Kelsey Hopkins; Kevin Buno; Natalie Romick; Antonio Carlos Freitas Dos Santos; Samantha Tinsley; Elizabeth Wakelin; Jacqueline Kennedy; Michael Ladisch; Brittany L Allen-Petersen; Luis Solorio

doi:10.1093/pnasnexus/pgac193

Sustained degradation of hyaluronic acid using an in situ forming implant

PNAS Nexus. 2022 Sep 17;1(4):pgac193. doi: 10.1093/pnasnexus/pgac193. eCollection 2022 Sep.

Authors

Affiliations

¹ Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
² Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA.
³ Laboratory of Renewable Resources Engineering, Purdue University, West Lafayette, IN 47907, USA.
⁴ Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
⁵ Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.

Abstract

In pancreatic cancer, excessive hyaluronic acid (HA) in the tumor microenvironment creates a viscous stroma, which reduces systemic drug transport into the tumor and correlates with poor patient prognosis. HA can be degraded through both enzymatic and nonenzymatic methods to improve mass transport properties. Here, we use an in situ forming implant to provide sustained degradation of HA directly at a local, targeted site. We formulated and characterized an implant capable of sustained release of hyaluronidase (HAase) using 15 kDa poly(lactic-co-glycolic) acid and bovine testicular HAase. The implant releases bioactive HAase to degrade the HA through enzymatic hydrolysis at early timepoints. In the first 24 h, 17.9% of the HAase is released, which can reduce the viscosity of a 10 mg/mL HA solution by 94.1% and deplete the HA content within primary human pancreatic tumor samples and ex vivo murine tumors. At later timepoints, as lower quantities of HAase are released (51.4% released in total over 21 d), the degradation of HA is supplemented by the acidic by-products that accumulate as a result of implant degradation. Acidic conditions degrade HA through nonenzymatic methods. This formulation has potential as an intratumoral injection to allow sustained degradation of HA at the pancreatic tumor site.

Keywords: bioactivity; hyaluronidase; long acting injectable; pancreatic cancer; protein/peptide.