Development of a PAMAM Dendrimer for Sustained Release of Temozolomide against Experimental Murine Lymphoma: Assessment of Therapeutic Efficacy.

ABSTRACT

Enhanced drug localization at the tumor sites with minimal toxicity was demonstrated using dendrimer-conjugated temozolomide for treating experimental lymphoma, developed as a solid tumor. Herein, we have constructed a polyamidoamine (PAMAM) dendrimer conjugated with temozolomide to enhance the stability of the active drug metabolites, derived from the prodrug temozolomide. Our results suggest that the active drug (5-(3-methyltriazen-1-yl)imidazole-4-carboxamide) (MTIC) (derived from temozolomide) showed stable and sustained release from the dendrimer-temozolomide conjugate, suggesting the suitability of the construct for therapy. Besides growth inhibition and direct killing, the dendrimer-temozolomide construct induced extensive apoptosis not only in parental Dalton lymphoma tumor cells but also in the doxorubicin-resistant form of the tumor cells. Dendrimer-temozolomide conjugation significantly reduced the solid tumor growth and increased the lifespan with better prognosis, including improved histopathology of the treated mice, while untreated littermates developed extensive metastasis and succumbed to death.