Targeting Intratibial Osteosarcoma Using Water-Soluble Copolymers Conjugated to Collagen Hybridizing Peptides

Abstract

Osteosarcoma (OS) is the most common form of primary malignant bone cancer in adolescents. Over the years, OS prognosis has greatly improved due to adjuvant and neoadjuvant (preoperative) chemotherapeutic treatment, increasing the chances of successful surgery and reducing the need for limb amputation. However, chemotherapeutic treatment to treat OS is limited by off-target toxicities and requires improved localization at the tumor site. Collagen, the main constituent of bone tissue, is extensively degraded and remodeled in OS, leading to an increased availability of denatured (monomeric) collagen. Collagen hybridizing peptides (CHPs) comprise a class of peptides rationally designed to selectively bind to denatured collagen. In this work, we have conjugated CHPs as targeting moieties to water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers to target OS tumors. We demonstrated increased accumulation of collagen-targeted HPMA copolymer–CHP conjugates compared to nontargeted HPMA copolymers, as well as increased retention compared to both nontargeted copolymers and CHPs, in a murine intratibial OS tumor model. Furthermore, we used microcomputed tomography analysis to evaluate the bone microarchitecture and correlated bone morphometric parameters (porosity, bone volume, and surface area) with maximum accumulation (S max) and accumulation at 168 h postinjection (S 168) of the copolymers at the tumor. Our results provide the foundation for the use of HPMA copolymer–CHP conjugates as targeted drug delivery systems in OS tumors.

Targeting damaged collagen for intra‐articular delivery of therapeutics using collagen hybridizing peptides

“…Since local injection is a better drug delivery route for managing OA, and fast clearance in the joint is a known problem for IA therapeutics used in OA treatment, we investigated CHP binding to joint tissues after IA injection for the first time. Since CHP can be readily conjugated to drug molecules 16 and drug delivery systems for enhanced accumulation in pathological sites with high collagen degradation, 31,32 extended retention of CHPs in the joint tissue could potentially be applied to extending the efficacy of IA OA drugs. CHP retention was tested by in vivo imaging of rat knees after IA injection of NIRF‐labeled CHPs (Figures 1–2).…”

From Collagen Mimetics to Collagen Hybridization and Back

“…We demonstrated that the CHPs can be used to detect bone remodeling activity during development and disease progression, ,− mechanical damage to collagen in tendons, ,− invasive cancer, fibrosis, and other pathologies − (Figure B). Due to their simple chemical structure, the CHPs can even be conjugated to either small molecules or macromolecules for localizing therapeutics to inflamed tissues (Figure B). − These striking properties of CHPs are made possible by two key aspects of the CHPs. First, CHP hybridization relies not on the conventional protein–epitope binding mediated by side chain interactions of folded protein but on the formation of the secondary protein structure of the protein backbone.…”