Remote triggered release of doxorubicin in tumors by synergistic application of thermosensitive liposomes and gold nanorods.

ABSTRACT

Delivery of chemotherapeutic agents after encapsulation in nanocarriers such as liposomes diminishes side-effects, as PEGylated nanocarrier pharmacokinetics decrease dosing to healthy tissues and accumulate in tumors due to the enhanced permeability and retention effect. Once in the tumor, however, dosing of the chemotherapeutic to tumor cells is limited potentially by the rate of release from the carriers and the size-constrained, poor diffusivity of nanocarriers in tumor interstitium. Here, we report the design and fabrication of a thermosensitive liposomal nanocarrier that maintains its encapsulation stability with a high concentration of doxorubicin payload, thereby minimizing "leak" and attendant toxicity. When used synergistically with PEGylated gold nanorods and near-infrared stimulation, remote triggered release of doxorubicin from thermosensitive liposomes was achieved in a mouse tumor model of human glioblastoma (U87), resulting in a significant increase in efficacy when compared to nontriggered or nonthermosensitive PEGylated liposomes. This enhancement in efficacy is attributed to increase in tumor-site apoptosis, as was evident from noninvasive apoptosis imaging using Annexin-Vivo 750 probe. This strategy affords remotely triggered control of tumor dosing of nanocarrier-encapsulated doxorubicin without sacrificing the ability to differentially dose drugs to tumors via the enhanced permeation and retention effect.