Telomerase Responsive Delivery of Doxorubicin from Mesoporous Silica Nanoparticles in Multiple Malignancies: Therapeutic Efficacies against Experimental Aggressive Murine Lymphoma.

Abstract

Mammalian telomerase maintains the length and integrity of telomeres by adding the telomeric repeats to the chromosome end. This work describes the telomerase responsive delivery of doxorubicin against telomerase positive human and murine cancer cells. Wrapping of doxorubicin loaded mesoporous silica nanoparticles with specific oligonucleotide sequence, containing telomeric repeat complementary sequence and a telomerase substrate primer sequence, resulted in slow and sustained release of doxorubicin, contiguous to the tumor cells. The DNA wrapped nanoprobe significantly inhibits the proliferation and enhanced the cytotoxicity in telomerase positive human and mouse tumor cells, and its function is impeded following exposure to specific telomerase inhibitor, AZT. Entrapping of doxorubicin by telomerase specific oligo manifests enhanced apoptosis and significantly higher uptake of the drug in the tumor cells. Treatment of telomerase positive Dalton's lymphoma bearing mice with a novel and newly designed oligo wrapped nanoprobe, specific for mouse telomerase, significantly enhanced the survival and improved the histopathological parameters. In addition, the treatment also induced significant reduction in the number of tumor foci and restored the normal architecture of the vascularized organs, besides preventing metastasis.