Abstract 1334: Lipid-based nanoparticulate hydroxychloroquine (HCQ) formulations for use in combination with autophagy inducing drugs for treatment of breast cancer
2016
Many targeted and broad spectrum anticancer drugs used to treat breast cancer trigger survival responses exemplified by the induction of cytoprotective macroautophagy (autophagy). Previously, we and others have shown that the anti-malarial agent hydroxychloroquine (HCQ) can improve the effects of anticancer drugs by inhibiting autophagy when used in high concentrations (1-20 μM). These levels are difficult to attain in vivo, thus, we developed novel liposomal formulations of HCQ (L-HCQ) designed to maintain therapeutic concentrations in plasma and tumor sites over extended periods of time. Liposomes (1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (CHOL) (55:45 molar ratio)) were prepared by extrusion to exhibit a mean particle size of 100 ± 20 nm. Copper HCQ complexation or ammnonium sulphate methods were used for loading HCQ into liposomes achieving >99% encapsulation efficiency (HCQ to lipid ratio: 0.22 ± 0.02 (mol:mol)). In vitro stability studies indicated that more than 80% of the liposomal associated HCQ was retained in the formulation for at least 24 h at 37 °C. In vivo pharmacokinetic studies, demonstrated that free HCQ was eliminated from the plasma compartment within 30 minutes following i.v. injection while the L-HCQ formulations maintained significantly higher plasma HCQ levels (>100 μM) over 24 h regardless of the loading method. Tolerability studies in non-tumor bearing CD1 mice showed no signs of toxicity following single and multiple doses (3 x week, i.v., 75 mg/kg). Inhibition of autophagy in vivo was examined in liver, heart and pancreas tissues of C57B1/6 mice 6 h after dosing with L-HCQ or free HCQ in combination with the autophagy inducing drug rapamycin. The results show that L-HCQ inhibited rapamycin-induced autophagy more effectively than free HCQ, as evident by a significant increase in LC3-II levels in all the examined tissue. Finally, the efficacy of L-HCQ alone (3 x week, i.v., 60 mg/kg) or in combination with the autophagy promoting drug gefitinib, an EGFR tyrosine kinase inhibitor (5 x week, oral gavage, 100 mg/kg), was tested in the JIMT-1 breast cancer xenograft model (s.c.) established in Rag2M mice. After four weeks of treatment, there were no significant differences in tumor volume between untreated and L-HCQ or gefitinib alone treated animals (p>0.05). In contrast, the gefitinib and L-HCQ combination engendered a significant inhibition of tumor growth compared to untreated controls (p In summary, this study established that L-HCQ was able to inhibit autophagy and improved sensitivity in an in vivo model of breast cancer treated with gefitinib. Citation Format: Jagbir Singh, Wieslawa H. Dragowska, Malathi Anantha, Ashleen S. Prasad, Jenna S. Rawji, Norman S. Chow, Marcel B. Bally. Lipid-based nanoparticulate hydroxychloroquine (HCQ) formulations for use in combination with autophagy inducing drugs for treatment of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1334.
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