Development of SMA-RL71 as a nanomedicine for the treatment of triple negative breast cancer
Martey, Orleans Nii Korley
Patients diagnosed with triple negative breast cancer (TNBC) have a poor prognosis, due in part to the lack of targeted treatment options. In the search for novel drugs, a second-generation curcumin derivative, 3,5,-bis(3,4,5-trimethoxybenzylidene)-1 methylpiperidine-4-one (RL71), was identified and exhibits potent in vitro cytotoxicity. The ability of RL71 to decrease tumor growth was improved via encapsulation in styrene maleic acid (SMA) micelles, however, the xenograft tumor continue to grow compared to control. In order to improve drug efficacy, in the present study, an increased treatment duration of SMA-RL71 (eight iv doses, SMA-RL71 10 mg/kg, 2x/week over 24 days) was administered to mice bearing MDA-MB-231 xenografts SMA-RL71 treatment suppressed tumor growth by 67% compared to control. Tumors from SMA-RL71-treated mice also showed a 26% decrease in angiogenesis and 24% increase in apoptosis. The drug treatment also modulated the EGFR, Akt/mTOR/4EBP1, and the SGK3 mediated-INPP4B signaling proteins. Also, SMA-RL71 modulated Wnt/beta-catenin and PP2A and PKC-alpha associated proteins. Other signaling proteins modulated were associated with metastasis (AQP3, EHF, LOLX1, SELL), tumor suppression (CSRNP1, MICB) and cell cycling (CDK2, NEK11). Also GNL1 may be a potential biomarker in TNBC as its expression was decreased 62% in vivo, 55% and 82% in MDA-MB-321 and Hs578T cells, respectively. Through multiple linear regression, drug treatment and 10 tumor protein signatures (pAkt, pAkt/Akt, pEGFR, pEGFR/EGFR, PKC-alpha, Ki67, EGFR, PP2Aa, PP2Bb, and CaD1) were identified and dependently networked to predict SMA-RL71 treatment outcome. Treatment groups were 100% classified as drug-treated or vehicle-treated by linear discriminant analysis and classified via the area under the receiver operating characteristic with 95% specificity and sensitivity following random forest analysis. Signaling protein expressions were then classified via hierarchical clustering by measure of similarity, and associated EGFR, pEGFR/EGFR, Wnt-beta-catenin, PP2A, PKC-alpha and NF-kB signaling proteins with Ki67 (apoptosis), the anti-metastasis protein, CaD1, with Apoptag (apoptosis), and pAKT and pAKT/AKT with CD105 (angiogenesis). Safety evaluation of SMA-RL71 in Swiss Webster mice showed a 3-fold margin of safety relative to the maximum tolerated dose (MTD) (15 mg/kg) and was non-toxic to the liver and kidney as shown by normal levels of plasma ALT and creatinine levels in subchronic toxicity studies following weekly iv dose at 10 mg/kg. Overall, RL71 has clinical potential following encapsulation in SMA micelles. However, the safety margin could be improved by selecting a lower dose relative to kinetically-derived maximum dose instead of MTD. Furthermore, the novel carriers of RL71 such as carbon nano onions could be trialed.
Advisor: Rosengren, Rhonda J.
Degree Name: Doctor of Philosophy
Degree Discipline: Pharmacology and Toxicology
Publisher: University of Otago
Keywords: xenograft model; molecular target; SMA-RL71; nanomedicine; GNL1
Research Type: Thesis