Monoclonal Antibody 2C5-Modified Mixed Dendrimer Micelles for Tumor-Targeted Codelivery of Chemotherapeutics and siRNA

Abstract

Targeted delivery of chemotherapeutics to tumors has the potential to reach a high dose at the tumor while minimizing systemic exposure. Incorporation of antibody within a micellar platform represents a drug delivery system for tumor-targeted delivery of antitumor agents. Such modified immunomicelles can result in an increased accumulation of antitumor agents and enhanced cytotoxicity toward cancer cells. Here, mixed dendrimer micelles (MDM) composed of PEG_2k-DOPE-conjugated generation 4 polyamidoamine dendrimer G4-PAMAM-PEG_2k-DOPE and PEG_5k-DOPE were coloaded with doxorubicin and siMDR-1. This formulation was further modified with monoclonal antibodies 2C5 with nucleosome-restricted specificity that effectively recognized cancer cells via the cell-surface-bound nucleosomes. Micelles with attached 2C5 antibodies significantly enhanced cellular association and tumor killing in both monolayer and spheroid tumor models as well as in vivo in experimental animals compared to the nontargeted formulations.

Keywords: chemotherapy; combination delivery; micelle; mixed dendrimer micelles (MDM); monoclonal antibody 2C5; multidrug resistance; polyamidoamine (PAMAM); siRNA delivery.