Local Sustained Delivery of Temozolomide via an Injectable Poly(Anhydride-Ester) Depot for Glioblastoma Therapy.

Background/Objectives: Glioblastoma (GBM) remains one of the most aggressive primary brain malignancies, with limited therapeutic progress over the past two decades. Systemic administration of temozolomide (TMZ) is a pillar of clinical management but is constrained by poor brain penetration, short half-life, and systemic toxicity. Localized drug delivery systems represent a compelling approach to address these limitations. We report the development and evaluation of an injectable poly(sebacic acid-ricinoleic acid) poly(anhydride-ester) (pSARA) gel for sustained intratumoral delivery of TMZ. Methods: The pSARA gel was synthesized using a one-pot melt polycondensation technique, and its in vitro release dynamics were assessed using spectrophotometry. In vivo efficacy of the TMZ-loaded pSARA gel was evaluated as a monotherapy and as an adjuvant to radiation or surgical resection using an orthotopic 9L gliosarcoma rat model. Results: The formulation exhibits shear-thinning behavior, enabling syringe-based administration, and undergoes surface erosion in aqueous environments to achieve controlled drug release. In vivo, the TMZ-loaded pSARA significantly prolonged survival compared to controls and outperformed paclitaxel-loaded formulations. Furthermore, combination therapy with radiation or surgical resection demonstrated combined survival benefits, including long-term survivors. Conclusions: These findings highlight the translational potential of pSARA-based local delivery systems as an adjunct or alternative to systemic chemotherapy in GBM treatment.