Abstract
Targeted drug delivery is critical for minimizing off-target toxicity by chemotherapeutic drugs. Amphotericin-B is an effective anti-leishmaniasis agent that induces significant nephrotoxicity. Complexing amphotericin-B with liposomes (AmBisome, LAmB) reduces nephrotoxicity and improves LAmB efficacy in treating leishmaniasis in humans. However, complicated dosing regimens are required to minimize side effects. Given that Leishmania species are obligate parasites in phagocytes, selectively targeting LAmB to infected phagocytes would likely improve efficacy, decrease systemic toxicity, and simplify dosing regimens. To target LAmB to phagocytes, we developed a PADRE-derivatized-dendrimer (PDD)-LAmB nanocarrier platform by functionalizing dendrimers that complex LAmB with a peptide that targets major histocompatibility complex (MHC) class II receptors. MHC class II receptor expression increases on phagocytes during the course of leishmaniasis, further enhancing infected cells as targets for PDD-LAmB. In a murine model for Leishmania major infection, PDD-LAmB efficiently targeted infected phagocytic cells, reducing the LAmB effective dose by 80 %, with improved pharmacokinetics. Moreover, the PDD MHC class II-targeting peptide is a universal helper T-cell epitope, allowing PDD-LAmB complexes to elicit parasite-specific T-cell responses. Thus, PDD-LAmB complex is a promising candidate for further development and human clinical trials, reducing and simplifying LAmB dosing, reducing side effects, and stimulating T-cell responses.