CD44-tropic polymeric nanocarrier for breast cancer targeted rapamycin chemotherapy

• DOI: 10.1016/j.nano.2014.02.015
• Publication Date: 2014-03-19T07:31:46Z
• Authors: Yunqi Zhao; Ti Zhang; Shaofeng Duan; Neal M. Davies; M. Laird Forrest
• Keywords: Sirolimus; Drug Carriers; Mice, Inbred BALB C; 0303 health sciences; Antibiotics, Antineoplastic; Hyaluronic acid; 610; Breast Neoplasms; Rats; 3. Good health; Rats, Sprague-Dawley; 03 medical and health sciences; Drug Delivery Systems; Hyaluronan Receptors; Cell Line, Tumor; Breast Cancer; Animals; Nanoparticles; Female; Rapamycin; Breast; CD44; Hyaluronic Acid

In contrast with the conventional targeting of nanoparticles to cancer cells with antibody or peptide conjugates, a hyaluronic acid (HA) matrix nanoparticle with intrinsic-CD44-tropism was developed to deliver rapamycin for localized CD44-positive breast cancer treatment. Rapamycin was chemically conjugated to the particle surface via a novel sustained-release linker, 3-amino-4-methoxy-benzoic acid. The release of the drug from the HA nanoparticle was improved by 42-fold compared to HA-temsirolimus in buffered saline. In CD44-positive MDA-MB-468 cells, using HA as drug delivery carrier, the cell viability was significantly decreased compared to free rapamycin and CD44-blocked controls. Rat pharmacokinetics showed that the area under the curve of HA nanoparticle formulation was 2.96-fold greater than that of the free drug, and the concomitant total body clearance was 8.82-fold slower. Moreover, in immunocompetent BALB/c mice bearing CD44-positive 4T1.2neu breast cancer, the rapamycin-loaded HA particles significantly improved animal survival, suppressed tumor growth and reduced the prevalence of lung metastasis.This study demonstrates increased efficiency of rapamycin delivery and consequential treatment effects in a breast cancer model by hyaluronic acid - L-rapamycin conjugates with intrinsic tropism for CD44-positive cells.