title: 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.affiliation: Corresponding Author: Paul R. Lockman, Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1406 S. Coulter Dr., Amarillo, TX, 79106-1712; paul.lockman@ttuhsc.edu.
authors.forename: Rajendar K
authors.initials: RK
authors.lastname: Mittapalli
authors.forename: Xinli
authors.initials: X
authors.lastname: Liu
authors.forename: Chris E
authors.initials: CE
authors.lastname: Adkins
authors.forename: Mohamed I
authors.initials: MI
authors.lastname: Nounou
authors.forename: Kaci A
authors.initials: KA
authors.lastname: Bohn
authors.forename: Tori B
authors.initials: TB
authors.lastname: Terrell
authors.forename: Hussaini S
authors.initials: HS
authors.lastname: Qhattal
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.forename: Diane
authors.initials: D
authors.lastname: Palmieri
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.forename: Quentin R
authors.initials: QR
authors.lastname: Smith
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lockman
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental; D008819:Mice, Nude; D058726:Nanoconjugates; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018960:Hyaluronan Receptors; D058726:Nanoconjugates; D006820:Hyaluronic Acid; D017239:Paclitaxel