Injectable, Self-Healing Chimeric Catechol-Fe(III) Hydrogel for Localized Combination Cancer Therapy

Abstract

Conventional intravenous or oral administration of a combination of chemotherapeutics displays poor bioavailability and induces undesirable systemic toxicity. Therefore, localized delivery of such chemotherapeutic combinations using polymeric hydrogels is expected to help in enhancing drug efficacy and reducing systemic toxicity. In this manuscript, we have utilized a chitosan-catechol based hydrogel (CAT-Gel) assembled through catechol-Fe­(III) coordinative interactions for localized combination therapy in murine lung and breast cancer models. CAT-Gel offers a unique blend of material properties such as injectability and self-healing along with useful biological attributes like their noncytotoxic and nonhemolytic nature. The amphipathic nature of this hydrogel enabled us to incorporate a recipe of hydrophilic doxorubicin hydrochloride (DOX) and hydrophobic docetaxel (DTX) anticancer drugs. Rheology studies confirmed the self-healing nature of this chimeric hydrogel even after drug loading. CAT-Gel was retained for more than 40 days in mice upon subcutaneous injection. The sequential and sustained release of the entrapped DOX and DTX from the hydrogel resulted in synergistic therapeutic effect with increased median survival against murine lung and breast cancer models. Therefore, CAT-Gel provides a new coordinatively assembled biocompatible scaffold for localized delivery of chemotherapeutic drugs.

Recent advances in shear‐thinning and self‐healing hydrogels for biomedical applications

“…More recently, Yavvari et al . showed that a chitosan‐catechol based shear‐thinning and self‐healing hydrogel assembled through catechol‐Fe(III) coordination with encapsulated chemotherapeutics, allowed sustained delivery over 40 days in murine lung and breast cancer models …”

“…154 More recently, Yavvari et al showed that a chitosan-catechol based shear-thinning and self-healing hydrogel assembled through catechol-Fe(III) coordination with encapsulated chemotherapeutics, allowed sustained delivery over 40 days in murine lung and breast cancer models. 15 With a more theoretical approach, Grindy et al demonstrated that a model system of four-arm PEG crosslinked with multiple, kinetically distinct dynamic metal-ligand complexes allowed control over the mechanical properties under load by tuning the relative concentrations of two types of crosslinkers. 155 In a new theoretical framework, modeling hydrogels with kinetically distinct crosslinks was shown to enable the separation of temporal hierarchy from spatial hierarchy.…”

“…Shear‐thinning and self‐healing properties allow homogenous encapsulation of payloads, injection through needles without clogging, and recovery to their initial state, making them ideal for controlled release of small molecules, proteins, and genes . Local and sustained delivery through hydrogels provides greater concentrations of therapeutics at the desired site of action while minimizing the side effects often associated with systemic delivery.…”

Coordination Bonds and Diels–Alder Bonds Dual Crosslinked Polymer Networks of Self‐healing Polyurethane

“…In recent years, the rapid development of self‐healing materials benefited from the unique ability that they can restore the original properties and functionalities after damage, to improve their durability, safety, and longevity . Hence, the self‐healing materials have been developed for applications in various fields including structural materials, coating, soft robotics and artificial skin, and medicine engineering . As is well known, many people used the dynamic covalent and noncovalent bonds to design the self‐healing materials .…”

“…1 Hence, the self-healing materials have been developed for applications in various fields including structural materials, 2,3 coating, 4-6 soft robotics and artificial skin, [7][8][9][10][11] and medicine engineering. [12][13][14][15] As is well known, many people used the dynamic covalent and noncovalent bonds to design the self-healing materials. [16][17][18][19] So far, the self-healing materials fabricated from the dynamic covalent show high mechanical properties but sacrifice the self-healing efficiency.…”