Paclitaxel-Hyaluronic Nano-Conjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

• Published in: Molecular cancer therapeutics Vol. 12; no. 11; pp. 2389 - 2399
• Main Authors: Mittapalli, Rajendar K., Liu, Xinli, Adkins, Chris E., Nounou, Mohamed I., Bohn, Kaci A., Terrell, Tori B., Qhattal, Hussaini S., Geldenhuys, Werner J., Palmieri, Diane, Steeg, Patricia S., Smith, Quentin R., Lockman, Paul R.
• Format: Journal Article
• Language: English
• Published: 03-09-2013
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-13-0132

Brain (CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in ~90% of CNS lesions. Therefore to improve efficacy, we have developed ultra-small hyaluronic acid (HA) paclitaxel nano-conjugates (~5kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor mediated endocytocis. Utilizing CD44 receptor-mediated endocytosis as an uptake mechanism allowed paclitaxel to bypass p-glycoprotein mediated efflux on the surface of the cancer cells.
In vitro
cytoxicity of the conjugate and free paclitaxel were similar in that they 1) both caused cell cycle arrest in the G
2
/M phase 2) demonstrated similar degrees of apoptosis induction (cleaved caspase) and 3) had similar IC
50
values when compared to paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate
in vivo
efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared to the control, and paclitaxel treated group (p<0.05). This study suggests that the small molecular weight (MW) HA-paclitaxel nano-conjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer.