Abstract
Purpose
Gold porphyrin (AuP) is a complex that has been shown to be potent against various tumors. A biocompatible interpenetrating network (IPN) system comprised of polyethyleneglycol diacrylate (PEGdA) and chemically-modified gelatin has been shown to be an effective implantable drug depot to deliver AuP locally. Here we designed IPN microparticles complexed with AuP to facilitate intravenous administration and to diminish systemic toxicity.
Methods
We have synthesized and optimized an IPN microparticle formulation complexed with AuP. Tumor cell cytotoxicity, antitumor activity, and survival rate in lung cancer bearing nude mice were analyzed.
Results
IPN microparticles maintained AuP bioactivity against lung cancer cells (NCI-H460). In vivo study showed no observable systemic toxicity in nude mice bearing NCI-H460 xenografts after intravenous injection of 6 mg/kg AuP formulated with IPN microparticles. An anti-tumor activity level comparable to free AuP was maintained. Mice treated with 6 mg/kg AuP in IPN microparticles showed 100% survival rate while the survival rate of mice treated with free AuP was much less. Furthermore, microparticle-formulated AuP significantly reduced the intratumoral microvasculature when compared with the control.
Conclusion
AuP in IPN microparticles can reduce the systemic toxicity of AuP without compromising its antitumor activity. This work highlighted the potential application of AuP in IPN microparticles for anticancer chemotherapy.
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References
World Heath Organization 2018. https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed Aug 2019
Zhong D, Zhang D, **e T, Zhou M. Biodegradable Microalgae-Based Carriers for Targeted Delivery and Imaging-Guided Therapy toward Lung Metastasis of Breast Cancer. Small. 2020;16:e2000819.
Lee P, Zhang R, Li V, Liu X, Sun RW, Che CM, et al. Enhancement of anticancer efficacy using modified lipophilic nanoparticle drug encapsulation. Int J Nanomedicine. 2012;7:731–7.
Khan MM, Madni A, Tahir N, Parveen F, Khan S, Jan N, et al. Co-Delivery of Curcumin and Cisplatin to Enhance Cytotoxicity of Cisplatin Using Lipid-Chitosan Hybrid Nanoparticles. Int J Nanomed. 2020;15:2207–17.
Yan JJ, Sun RW, Wu P, Lin MC, Chan AS, Che CM. Encapsulation of dual cytotoxic and anti-angiogenic gold(III) complexes by gelatin-acacia microcapsules: in vitro and in vivo studies. Dalton Trans. 2010;39(33):7700–5.
To YF, Sun RW, Chen Y, Chan VS, Yu WY, Tam PK, et al. Gold(III) porphyrin complex is more potent than cisplatin in inhibiting growth of nasopharyngeal carcinoma in vitro and in vivo. Int J Cancer. 2009;124(8):1971–9.
Che CM, Sun RWY, Yu WY, Ko CB, Zhu NY, Sun HZ. Gold(III) porphyrins as a new class of anticancer drugs: cytotoxicity, DNA binding and induction of apoptosis in human cervix epitheloid cancer cells. Chem Commun. 2003;14:1718–9.
Chow KH, Liu J, Sun RW, Vanhoutte PM, Xu A, Chen J, et al. The gold (III) porphyrin complex, gold-2a, suppresses WNT1 expression in breast cancer cells by enhancing the promoter association of YY1. Am J Transl Res. 2011;3(5):479–91.
Lum CT, Huo L, Sun RW, Li M, Kung HF, Che CM, et al. Gold(III) porphyrin 1a prolongs the survival of melanoma-bearing mice and inhibits angiogenesis. Acta Oncol. 2011;50(5):719–26.
Lum CT, Liu X, Sun RW, Li XP, Peng Y, He ML, et al. Gold(III) porphyrin 1a inhibited nasopharyngeal carcinoma metastasis in vivo and inhibited cell migration and invasion in vitro. Cancer Lett. 2010;294(2):159–66.
Tu S, Wai-Yin Sun R, Lin MC, Tao Cui J, Zou B, Gu Q, et al. Gold (III) porphyrin complexes induce apoptosis and cell cycle arrest and inhibit tumor growth in colon cancer. Cancer. 2009;115(19):4459–69.
Wang Y, He QY, Che CM, Tsao SW, Sun RW, Chiu JF. Modulation of gold(III) porphyrin 1a-induced apoptosis by mitogen-activated protein kinase signaling pathways. Biochem Pharmacol. 2008;75(6):1282–91.
Che CM, Sun RWY. Therapeutic applications of gold complexes: lipophilic gold(III) cations and gold(I) complexes for anti-cancer treatment. Chem Commun. 2011;47(34):9554–60.
Aggarwal P, Hall JB, McLeland CB, Dobrovolskaia MA, McNeil SE. Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv Drug Deliver Rev. 2009;61(6):428–37.
Dykman LA, Khlebtsov NG. Immunological properties of gold nanoparticles. Chem Sci. 2017;8(3):1719–35.
Kim CH, Sung SW, Lee ES, Kang TH, Yoon HY, Goo YT, et al. Sterically Stabilized RIPL Peptide-Conjugated Nanostructured Lipid Carriers: Characterization, Cellular Uptake, Cytotoxicity, and Biodistribution. Pharmaceutics. 2018;10:199–220.
Kim CH, Sa CK, Goh MS, Lee ES, Kang TH, Yoon HY, et al. pH-sensitive PEGylation of RIPL peptide-conjugated nanostructured lipid carriers: design and in vitro evaluation. Int J Nanomedicine. 2018;13:6661–75.
Li HW, Li YJ, Ao H, Bi DD, Han MH, Guo YF, et al. Folate-targeting annonaceous acetogenins nanosuspensions: significantly enhanced antitumor efficacy in HeLa tumor-bearing mice. Drug Deliv. 2018;25(1):880–7.
Tang GP, Zeng JM, Gao SJ, Ma YX, Shi L, Li Y, et al. Polyethylene glycol modified polyethylenimine for improved CNS gene transfer: effects of PEGylation extent. Biomaterials. 2003;24(13):2351–62.
Peracchia MT, Fattal E, Desmaele D, Besnard M, Noel JP, Gomis JM, et al. Stealth PEGylated polycyanoacrylate nanoparticles for intravenous administration and splenic targeting. J Control Release. 1999;60(1):121–8.
Kojima C, Turkbey B, Ogawa M, Bernardo M, Regino CA, Bryant LH Jr, et al. Dendrimer-based MRI contrast agents: the effects of PEGylation on relaxivity and pharmacokinetics. Nanomedicine. 2011;7(6):1001–8.
Kooijmans SAA, Fliervoet LAL, van der Meel R, Fens M, Heijnen HFG, van Bergen En Henegouwen PMP, et al. PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. J Control Release. 2016;224:77–85.
Patsula V, Horak D, Kucka J, Mackova H, Lobaz V, Francova P, et al. Synthesis and modification of uniform PEG-neridronate-modified magnetic nanoparticles determines prolonged blood circulation and biodistribution in a mouse preclinical model. Sci Rep. 2019;9(1):10765.
Nie S. Understanding and overcoming major barriers in cancer nanomedicine. Nanomedicine (Lond). 2010;5(4):523–8.
Vonarbourg A, Passirani C, Saulnier P, Benoit JP. Parameters influencing the stealthiness of colloidal drug delivery systems. Biomaterials. 2006;27(24):4356–73.
Chung CYS, Fung SK, Tong KC, Wan PK, Lok CN, Huang Y, et al. A multi-functional PEGylated gold(III) compound: potent anti-cancer properties and self-assembly into nanostructures for drug co-delivery. Chemical Science. 2017;8(3):1942–53.
Lee P, Lok CN, Che CM, Kao WJ. A Multifunctional Hydrogel Delivers Gold Compound and Inhibits Human Lung Cancer Xenograft. Pharm Res. 2019;36(4):61.
Nakajima N, Hashimoto S, Sato H, Takahashi K, Nagoya T, Kamimura K, et al. Efficacy of gelatin hydrogels incorporating triamcinolone acetonide for prevention of fibrosis in a mouse model. Regen Ther. 2019;11:41–6.
Tan H, Sun GQ, Lin W, Mu CD, Ngai T. Gelatin Particle-Stabilized High Internal Phase Emulsions as Nutraceutical Containers. Acs Appl Mater Inter. 2014;6(16):13977–84.
Guerra AD, Yeung OWH, Qi X, Kao WJ, Man K. The Anti-Tumor Effects of M1 Macrophage-Loaded Poly (ethylene glycol) and Gelatin-Based Hydrogels on Hepatocellular Carcinoma. Theranostics. 2017;7(15):3732–44.
Xu K, Fu Y, Chung W, Zheng X, Cui Y, Hsu IC, et al. Thiol-ene-based biological/synthetic hybrid biomatrix for 3-D living cell culture. Acta Biomater. 2012;8(7):2504–16.
Kim SH, Haimovich-Caspi L, Omer L, Talmon Y, Franses EI. Effect of sonication and freezing-thawing on the aggregate size and dynamic surface tension of aqueous DPPC dispersions. J Colloid Interface Sci. 2007;311(1):217–27.
Almalik A, Alradwan I, Kalam MA, Alshamsan A. Effect of cryoprotection on particle size stability and preservation of chitosan nanoparticles with and without hyaluronate or alginate coating. Saudi Pharm J. 2017;25(6):861–7.
Sameti M, Bohr G, Ravi Kumar MN, Kneuer C, Bakowsky U, Nacken M, et al. Stabilisation by freeze-drying of cationically modified silica nanoparticles for gene delivery. Int J Pharm. 2003;266(1–2):51–60.
Emami F, Vatanara A, Park EJ, Na DH. Drying Technologies for the Stability and Bioavailability of Biopharmaceuticals. Pharmaceutics. 2018;10:131–53.
Gil S, Jimenez-Borja C, Martin-Campo J, Romero A, Valverde JL, Sanchez-Silva L. Stabilizer effects on the synthesis of gold-containing microparticles. Application to the liquid phase oxidation of glycerol. J Colloid Interface Sci. 2014;431:105–11.
Ahsan SM, Rao CM. The role of surface charge in the desolvation process of gelatin: implications in nanoparticle synthesis and modulation of drug release. Int J Nanomedicine. 2017;12:795–808.
Tan F, Liu J, Liu MD, Wang JW. Charge density is more important than charge polarity in enhancing osteoblast-like cell attachment on poly(ethylene glycol)-diacrylate hydrogel. Mat Sci Eng C-Mater. 2017;76:330–9.
Lum CT, Yang ZF, Li HY, Sun RWY, Fan ST, Poon RTP, et al. Gold(III) compound is a novel chemocytotoxic agent for hepatocellular carcinoma. Int J Cancer. 2006;118(6):1527–38.
Shibuya M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol. 2006;39(5):469–78.
Kim JH, Kim MS, Lee BH, Kim JK, Ahn EK, Ko HJ, et al. Marmesin-mediated suppression of VEGF/VEGFR and integrin beta1 expression: Its implication in non-small cell lung cancer cell responses and tumor angiogenesis. Oncol Rep. 2017;37(1):91–7.
Pu D, Liu JW, Li ZX, Zhu J, Hou M. Fibroblast Growth Factor Receptor 1 (FGFR1), Partly Related to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and Microvessel Density, is an Independent Prognostic Factor for Non-Small Cell Lung Cancer. Med Sci Monitor. 2017;23:247–57.
Gu Y, Korbel C, Scheuer C, Nenicu A, Menger MD, Laschke MW. Tubeimoside-1 suppresses tumor angiogenesis by stimulation of proteasomal VEGFR2 and Tie2 degradation in a non-small cell lung cancer xenograft model. Oncotarget. 2016;7(5):5258–72.
Gacche RN. Compensatory angiogenesis and tumor refractoriness Oncogenesis. 2015;4:e153.
Lum CT, Wong AST, Lin MCM, Che CM, Sun RWY. A gold(III) porphyrin complex as an anti-cancer candidate to inhibit growth of cancer-stem cells. Chem Commun. 2013;49(39):4364–6.
Acknowledgements and Disclosures
The authors thank Dr. Regina Lo of Department of Pathology for histological analysis. The authors also thank Zhifeng Zhang for the synthesis of IPN and Ka Chung Tong for the preparation of gold porphyrin. This research was supported by Innovation and Technology Fund (ITS/130/14FP) and HKU Faculty Grant (WJK).
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Lee, P.Y., Lok, CN., Che, CM. et al. Multifunctional Microparticles Incorporating Gold Compound Inhibit Human Lung Cancer Xenograft. Pharm Res 37, 220 (2020). https://doi.org/10.1007/s11095-020-02931-8
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DOI: https://doi.org/10.1007/s11095-020-02931-8