A novel cabazitaxel liposomes modified with ginsenoside Rk1 for cancer targeted therapy

Abstract

Objective: In this study, we aim to enhance the anti-prostate cancer efficacy of cabazitaxel (CTX) and reduce its immunosuppression and systemic toxicity by developing CTX-loaded liposomes modified with ginsenoside Rk1 (Rk1/CTX-Lip).
Methods: Physical and chemical properties of Rk1/CTX-Lip were investigated. We evaluated the biological functions of Rk1/CTX-Lip, both in vitro and in vivo. A subcutaneous prostate cancer (RM-1)-bearing mouse model was established to study the efficacy of Rk1/CTX-Lip inhibition in tumors. Simultaneously, a Candida albicans infection model was established in tumor-bearing mice to study the infection-relieving efficacy of Rk1/CTX-Lip. Finally, biocompatibility and in vivo safety of Rk1/CTX-Lip were evaluated.
Results: We successfully prepared Rk1/CTX-Lip, achieving high CTX encapsulation efficiency (97.24β±β0.75)% and physical stability. Rk1/CTX-Lip demonstrated evasion of macrophage phagocytosis, effective tumor tissue targeting, and a significant reduction (>50%) in average tumor volume compared with Chol/CTX-Lip. Moreover, it relieved the concurrent infection burden and effectively regulated immune organs and cells, demonstrating superior biocompatibility.
Conclusion: Rk1/CTX-Lip presents a promising new therapy for prostate cancer and holds potential for relieving concurrent fungal infections in cancer patients with low immunity.

Keywords

Cabazitaxel / Fungal infection / Ginsenoside Rk1 / Liposome-drug delivery system / Prostate cancer

References

[[1]] Hoang B, Ernsting MJ, Tang WHS, et al.Cabazitaxel-conjugated nanoparticles for docetaxel-resistant and bone metastatic prostate cancer. Cancer Lett 2017;410:169-179.

[[2]] Hongo H, Kosaka T, Oya M.Analysis of cabazitaxel-resistant mechanism in human castration-resistant prostate cancer. Cancer Sci 2018;109(9):2937-2945.

[[3]] Song YZ, Tian QJ, Huang ZJ, et al.Self-assembled micelles of novel amphiphilic copolymer cholesterol-coupled F68 containing cabazitaxel as a drug delivery system. Int J Nanomedicine 2014;9:2307-2317.

[[4]] Martin SK, Pu H, Penticuff JC, et al.Multinucleation and mesenchymal-to-epithelial transition alleviate resistance to combined cabazitaxel and antiandrogen therapy in advanced prostate cancer. Cancer Res 2016;76(4):912-926.

[[5]] Yin XY, Luo LH, Li W, et al.A cabazitaxel liposome for increased solubility, enhanced antitumor effect and reduced systemic toxicity. Asian J Pharm Sci 2019;14(6):658-667.

[[6]] de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010;376(9747):1147-1154.

[[7]] Lombard AP, Liu CF, Armstrong CM, et al.ABCB1 mediates cabazitaxel-docetaxel cross-resistance in advanced prostate cancer. Mol Cancer Ther 2017;16(10):2257-2266.

[[8]] Paller CJ, Antonarakis ES.Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer. Drug Des Devel Ther 2011;5:117-124.

[[9]] Gazendam RP, van de Geer A, van Hamme JL, et al. Impaired killing of Candida albicans by granulocytes mobilized for transfusion purposes: a role for granule components. Haematologica 2016;101(5):587-596.

[[10]] Lehrnbecher T, Frank C, Engels K, et al.Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 2010;61(3):259-265.

[[11]] McNeil MM, Nash SL, Hajjeh RA, et al. Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997. Clin Infect Dis 2001;33(5):641-647.

[[12]] Enoch DA, Ludlam HA, Brown NM.Invasive fungal infections: a review of epidemiology and management options. J Med Microbiol 2006;55(Pt 7):809-818.

[[13]] Alaarg A, Jordan NY, Verhoef JJF, et al.Docosahexaenoic acid liposomes for targeting chronic inflammatory diseases and cancer: an in vitro assessment. Int J Nanomedicine 2016;11:5027-5040.

[[14]] Behzadi S, Serpooshan V, Tao W, et al.Cellular uptake of nanoparticles: journey inside the cell. Chem Soc Rev 2017;46(14):4218-4244.

[[15]] Kim YJ, Kwon HC, Ko H, et al.Anti-tumor activity of the ginsenoside Rk1 in human hepatocellular carcinoma cells through inhibition of telomerase activity and induction of apoptosis. Biol Pharm Bull 2008;31(5):826-830.

[[16]] Ryoo N, Rahman MA, Hwang H, et al.Ginsenoside Rk1 is a novel inhibitor of NMDA receptors in cultured rat hippocampal neurons. J Ginseng Res 2020;44(3):490-495.

[[17]] Hu JN, Xu XY, Li W, et al.Ginsenoside Rk1 ameliorates paracetamol-induced hepatotoxicity in mice through inhibition of inflammation, oxidative stress, nitrative stress and apoptosis. J Ginseng Res 2019;43(1):10-19.

[[18]] Kang S, Min H.Ginseng, the ‘Immunity Boost’: the effects of Panax ginseng on immune system. J Ginseng Res 2012;36(4):354-368.

[[19]] Zheng SW, Zheng HS, Zhang R, et al.Immunomodulatory effect of ginsenoside Rb2 against cyclophosphamide-induced immunosuppression in mice. Front Pharmacol 2022;13:927087.

[[20]] Chen CF, Chiou WF, Zhang JT.Comparison of the pharmacological effects of Panax ginseng and Panax quinquefolium. Acta Pharmacol Sin 2008;29(9):1103-1108.

[[21]] Gallay J, de Kruijff B, Demel RA. Sterol-phospholipid interactions in model membranes. Effect of polar group substitutions in the cholesterol side-chain at C20 and C22. Biochim Biophys Acta 1984;769(1):96-104.

[[22]] Commander R, Wei C, Sharma A, et al.Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion. Nat Commun 2020;11(1):1533.

[[23]] Choi JS, Chun KS, Kundu J, et al.Biochemical basis of cancer chemoprevention and/or chemotherapy with ginsenosides (Review). Int J Mol Med 2013;32(6):1227-1238.

[[24]] Yallapu MM, Othman SF, Curtis ET, et al.Multi-functional magnetic nanoparticles for magnetic resonance imaging and cancer therapy. Biomaterials 2011;32(7):1890-1905.

[[25]] Hong C, Wang D, Liang JM, et al.Novel ginsenoside-based multifunctional liposomal delivery system for combination therapy of gastric cancer. Theranostics 2019;9(15):4437-4449.

[[26]] Patra S, Pradhan B, Nayak R, et al.Chemotherapeutic efficacy of curcumin and resveratrol against cancer: chemoprevention, chemoprotection, drug synergism and clinical pharmacokinetics. Semin Cancer Biol 2021;73:310-320.

[[27]] Lee Y, Park A, Park YJ, et al.Ginsenoside 20(R)-Rg3 enhances natural killer cell activity by increasing activating receptor expression through the MAPK/ERK signaling pathway. Int Immunopharmacol 2022;107:108618.

[[28]] Oh MJ, Choi HD, Ha SK, et al.Immunomodulatory effects of polysaccharide fraction isolated from Fagopyrum esculentum on innate immune system. Biochem Biophys Res Commun 2018;496(4):1210-1216.

[[29]] Liao D, Luo YP, Markowitz D, et al.Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS One 2009;4(11):e7965.

[[30]] Sam QH, Yew WS, Seneviratne CJ, et al.Immunomodulation as therapy for fungal infection: are we closer? Front Microbiol 2018;9:1612.

[[31]] Chen Y, Pan Y, Hu D, et al.Recent progress in nanoformulations of cabazitaxel. Biomed Mater 2021;16(3):032002

[[32]] Sun B, Lovell JF, Zhang Y.Current development of cabazitaxel drug delivery systems. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2023;15(2):e1854.

[[33]] Mirzavi F, Barati M, Soleimani A, et al.A review on liposomebased therapeutic approaches against malignant melanoma. Int J Pharm 2021;599:120413.

[[34]] Kang JH, Jang WY, Ko YT.The effect of surface charges on the cellular uptake of liposomes investigated by live cell imaging. Pharm Res 2017;34(4):704-717.

[[35]] Diehl R, Ferrara F, Müller C, et al.Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches. Cell Mol Immunol 2017;14(2):146-179.

[[36]] Emadi A, Jones RJ, Brodsky RA.Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol 2009;6(11):638-647.

[[37]] Yu GC, Zhao XL, Zhou J, et al.Supramolecular polymer-based nanomedicine: high therapeutic performance and negligible longterm immunotoxicity. J Am Chem Soc 2018;140(25):8005-8019.

[[38]] Angarone M.Fungal infections in cancer patients. Cancer Treat Res 2014;161:129-155.

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