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 G 2 -M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC 50 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.

The 2016 John J. Abel Award Lecture: Targeting the Mechanical Microenvironment in Cancer

“…As mentioned previously, overexpression of HYAL enzymes (which degrade HMW-HA to LMW-HA) led to increased Kakizaki et al, 2004;Lokeshwar et al, 2010 Small oligo HA Binds to HA receptors and blocks larger HA molecules Inhibit tumor growth in breast and lung cancers, osteosarcoma, and melanoma; also has tumor-promoting effects in colorectal cancer Evanko and Vogel, 1990;Benitez et al, 2011;Urakawa et al, 2012a,b;Schmaus et al, 2014a,b Sulfated HA Inhibits HYAL activity Tumor-inhibitory effects in vitro; inhibited tumor growth in preclinical prostate cancer models PEGPH20 Human recombinant PH20 hyaluronidase; degrades HA In preclinical pancreatic cancer models it inhibited tumor growth, lowered IFP, increased penetration of therapeutics, increased survival, and decreased metastasis in combination with chemotherapies; phase 1 trial with gemcitabine had 42% response rate in pancreatic cancer Provenzano et al, 2012;Jacobetz et al, 2013;Mittapalli et al, 2013 BAPN, b-aminopropionitrile; DHB, ethyl 3,4 dihydroxybenzoate; DPEN, diphenylethylenediamine.…”

“…Indeed, in pancreatic cancer preclinical trials, it did just that: PEGPH20 inhibited tumor growth, lowered IFP and increased penetration of therapeutics, and increased survival and decreased metastasis in combination with chemotherapies (Provenzano et al, 2012;Jacobetz et al, 2013). In a phase 1 clinical trial, PEGPH20 in combination with gemcitabine had a 42% response rate in stage IV metastatic pancreatic cancer (Mittapalli et al, 2013). Together, these data suggest that targeting unique ECM proteins could be fruitful in altering the mechanical properties of the tumor microenvironment, thus impinging on tumor development and progression.…”

Biomaterial applications in neural therapy and repair

“…In addition to ECM hydrogels, natural polymers like hyaluronic acid (HA) [70,71], fibrin [72], HAmethylcellulose (HAMC) [73], chitosan [74,75], and collagen [76] have been used extensively to deliver cells or molecules in the CNS. Collagen is a popular material used in biomedical applications since it is the most abundant protein and main component of peripheral ECM in mammalian tissues.…”

Advanced biomaterials for repairing the nervous system: what can hydrogels do for the brain?

“…Naturally derived polymers including fibrin [36][37][38][39], hyaluronan-methylcellulose (HAMC) blend [40][41][42][43][44][45], hyaluronic acid [46][47][48], agarose [49] and chitosan [50] have been used to successfully deliver molecules to the CNS. For example, an injectable hydrogel system developed by the Shoichet group shows promise for intrathecal delivery of growth factors into the injured spinal cord.…”