Paclitaxel-hyaluronic nanoconjugates prolong overall survival in a preclinical brain metastases of breast cancer model.

Abstract

Brain (central nervous system; 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 approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate (∼5 kDa) 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. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able 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 (i) both caused cell-cycle arrest in the G2-M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC50 values when compared with 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 with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer.

• Authors: Rajendar K Mittapalli, Xinli Liu, Chris E Adkins, Mohamed I Nounou, Kaci A Bohn, Tori B Terrell, Hussaini S Qhattal, Werner J Geldenhuys, Diane Palmieri, Patricia S Steeg, Quentin R Smith, Paul R Lockman
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 12 Issue 11 Pg. 2389-99 (Nov 2013) ISSN: 1538-8514 [Electronic] United States
• PMID: 24002934 (Publication Type: Journal Article)
• Copyright: ©2013 AACR.

Chemical References

• Antineoplastic Agents, Phytogenic
• Hyaluronan Receptors
• Nanoconjugates
• Hyaluronic Acid
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Brain Neoplasms (drug therapy, pathology, secondary)
• Breast Neoplasms (drug therapy, mortality, pathology)
• Cell Line, Tumor
• Drug Evaluation, Preclinical
• Female
• Humans
• Hyaluronan Receptors (metabolism)
• Hyaluronic Acid (administration & dosage, pharmacokinetics, pharmacology)
• MCF-7 Cells
• Mammary Neoplasms, Experimental
• Mice, Nude
• Nanoconjugates
• Paclitaxel (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)