Abstract

We have constructed Herceptin-conjugated, paclitaxel (PTX) loaded, PCL-PEG worm-like nanocrystal micelles ( [email protected] ) for the combinatorial therapy of HER2-positive breast cancer that exploit the specific targeting of Herceptin to HER2-positive breast cancer cells. Firstly, amphiphilic PCL 2000 -MPEG 2000 and PCL 5000 -PEG 2000 -CHO were selected as the optimized matrix to wrap PTX that self-assembled into worm-like micelles with internal nanocrystal structures ( [email protected] ). Then the aldehydes of PCL 5000 -PEG 2000 -CHO exposed on the outside surface of [email protected] were utilized to react with the primary amines of Herceptin and formed stable, carbon-nitrogen single linkers (–C–N–) between the antibodies and nanoparticles . This study shows [email protected] remained relatively stable in the circulation and in the tumor microenvironment , and rapidly targeted and entered into the HER2-overexpressing tumor cells while sparing normal tissues from the toxic effects. [email protected] shrank the tumors and prolonged survival time in a SKBR-3-tumor-xenograft, nude mice model more effectively than TAXOL®, [email protected] , Herceptin+TAXOL® and [email protected] Mechanistic studies showed that [email protected] entered into the HER2-positive tumor cells through the caveolin-mediated pathway. The conjugated Herceptin greatly enhanced the binding ability of the nanoparticle to the targeted SKBR-3 cells. This novel strategy provides a rational and simple antibody-conjugated-nanoparticle platform for the clinical application of combinatorial anticancer treatment.