Injectable sustained local release doxorubicin depot technology- a promising adjuvant to systemic treatment?

Abstract

Drug depot technologies that release chemotherapeutics locally in cancerous tissues present an intriguing strategy. This study aimed to assess the feasibility, delivery capacity, and therapeutic efficacy of a thin needle injectable doxorubicin-loaded carbohydrate-ester-based (CarboCell) depot technology. CarboCell was evaluated in three experimental setups: (A) In non-tumorous mice, release kinetics were evaluated 24 h and 48 h after a subcutaneous depot injection. (B) In mice with syngeneic CT 26 colorectal cancer, efficacy was evaluated based on tumour growth control and survival. This was done by two intratumoral injections of 50 µl CarboCell containing 1 mg/mL or 4 mg/mL doxorubicin at 5 days intervals. (C) In ten female pigs, local and distant release of doxorubicin from a 2 mg/mL doxorubicin CarboCell (2 or 4 mL) injected into tibial metaphysis was evaluated using microdialysis in nine tissue compartments. (A) Subcutaneous CarboCell depots demonstrated a sustained release of doxorubicin with (mean ± SEM) 36 ± 13% and 48 ± 20% of the loaded dose being released at 24 h and 48 h time points, respectively. (B) Intratumoral injection effectively controlled tumour growth and markedly extended the median survival time compared to the control group. (C) Doxorubicin peak drug concentrations in the metaphysis were > 0.3 µg/mL and could be quantified at least 10 mm from the application site. The systemic spill-over was minimal. Doxorubicin-loaded CarboCell proved easily administrable, maintaining antitumoral activity, good metaphyseal distribution and providing much higher local concentrations in metaphyseal bone providing high local concentrations in metaphyseal bone with a good distribution and limited systemic exposure.