A Green Approach to Producing Polymer Microparticles for Local Sustained Release of Flavopiridol

Abstract

Poly(lactic-co-glycolic acid)(PLGA) microparticles represent an important class of materials used for drug delivery. Current synthesis frequently uses conventional emulsion, where dichloromethane(DCM) is used as the organic phase solvent. Due to the health and environmental toxicity of DCM and its slow degradation, this work replaces DCM with a greener solvent, dimethyl carbonate(DMC). To attain narrow distribution of PLGA particle size, microfluidic flow focusing was chosen over conventional emulsion. This new approach successfully produced PLGA microparticles encapsulated with flavopiridol, a kinase inhibitor. These particles exhibit sustained release profile more desirable than the conventional counterparts. The cytotoxicity and activity tests have demonstrated high biocompatibility and efficacy of these PLGA particles. The high sustainability is also evaluated using simple E-Factor(sEF) and complete E-Factor(cEF). The lower health and environmental toxicities of DMC than DCM are evidenced by approximately one order of magnitude higher in lethal dose, i. e., 50%(LD₅₀) values in rat, 5-fold faster degradation rate, and 30% higher GlaxoSmithKline(GSK) combined greenness value. The approach reported in this work shall provide a new and green means for drug delivery in general. The products enable local sustained delivery of flavopiridol for prevention of post-traumatic osteoarthritis, and anti-cancer therapy.

Keywords

Flavopiridol / Microfluidics / Poly(lactic-co-glycolic acid) microparticle / Green solvent / Local sustained release

References

[1] Panyam J, Labhasetwar V. Adv. Drug Deliv. Rev., 2003, 55: 329.

[2] Kumari A, Yadav S K, Yadav S C. Colloids Surf. B. Biointerfaces, 2010, 75: 1.

[3] Makadia H K, Siegel S J. Polymers(Basel), 2011, 3: 1377.

[4] Liu G, Li Y, Yang S, Zhao Y A, Lu T, Jia W, Ji X, Luo Y. Chem. Res. Chinese Universities, 2019, 35(3): 514.

[5] Cai Q, Qiao C, Ning J, Ding X, Wang H, Zhou Y. Chem. Res. Chinese Universities, 2019, 35(5): 908.

[6] Kim T, See C W, Li X, Zhu D. Eng. Regen., 2020, 1: 6.

[7] Bolandparvaz A, Yik J H, Lewis J, Haudenschild D R. Osteoarthr. Cartil., 2018, 26: S303.

[8] Ren H, Han M, Zhou J, Zheng Z-F, Lu P, Wang J-J, Wang J-Q, Mao Q-J, Gao J-Q, Ouyang H W. Biomaterials, 2014, 35: 6585.

[9] Xu Q, Hashimoto M, Dang T T, Hoare T, Kohane D S, Whitesides G M, Langer R, Anderson D G. Small, 2009, 5: 1575.

[10] Vasiliauskas R, Liu D, Cito S, Zhang H, Shahbazi M-A, Sikanen T, Mazutis L, Santos H A. ACS Appl. Mater. Interfaces, 2015, 7: 14822.

[11] Hung L-H, Teh S-Y, Jester J, Lee A P. Lab. Chip., 2010, 10: 1820.

[12] Zhao Y, Shum H C, Chen H, Adams L L A, Gu Z, Weitz D A. J. Am. Chem. Soc., 2011, 133: 8790.

[13] Wang H, Liu Y, Chen Z, Sun L, Zhao Y. Sci. Adv., 2020, 6: eaay1438.

[14] Chen H, Bian F, Sun L, Zhang D, Shang L, Zhao Y. Adv. Mater., 2020, 32: 2005394.

[15] Zhang H, Chen G, Yu Y, Guo J, Tan Q, Zhao Y. Adv. Sci., 2020, 7: 2000789.

[16] Liu D, Zhang H, Fontana F, Hirvonen J T, Santos H A. Lab Chip, 2017, 17: 1856.

[17] Xu J, Zhang S, Machado A, Lecommandoux S, Sandre O, Gu F, Colin A. Sci. Rep., 2017, 7: 4794.

[18] Kim H-G, Kim K-M, Kim Y H, Lee S H, Kim G M. J. Biobased Mater. Bioenergy, 2013, 7: 108.

[19] Schlosser P M, Bale A S, Gibbons C F, Wilkins A, Cooper G S. Environ Health Perspect, 2015, 123: 114.

[20] Kim H, Kim S, Sah H. J. Biomater. Sci. Polym. Ed., 2018, 29: 35.

[21] Environmental Protection Agency Federal Register, 2019, 84: 11420.

[22] Grassian V H. Environmental Science & Technology, 2007, 41: 4840.

[23] Yang X, Zhao X, Phelps M A, Piao L, Rozewski D M, Liu Q, Lee L J, Marcucci G, Grever M R, Byrd J C, Dalton J T, Lee R J. Int. J. Pharm., 2009, 365: 170.

[24] Chao S-H, Price D H. J. Biol. Chem., 2001, 276: 31793.

[25] Bugai A, Quaresma A J C, Friedel C C, Lenasi T, Düster R, Sibley C R, Fujinaga K, Kukanja P, Hennig T, Blasius M, Geyer M, Ule J, Dölken L, Barborič M. Mol. Cell, 2019, 74: 254.

[26] Morales F, Giordano A. Cell Cycle, 201, 15: 519.

[27] Yik J H N, Hu Z A, Kumari R, Christiansen B A, Haudenschild D R. Arthritis Rheumatol, 2014, 66: 1537.

[28] Hu Z, Yik J H N, Cissell D D, Michelier P V, Athanasiou K A, Haudenschild D R. Eur. Cell Mater., 201, 30: 200.

[29] Fukui T, Yik J H N, Doyran B, Davis J, Haudenschild A K, Adamopoulos I E, Han L, Haudenschild D R. Osteoarthr. Cartil., 2021, 29: 68.

[30] Malachowski T, Hassel A. Eng. Regen., 2020, 1: 35.

[31] Tundo P, Selva M. Acc. Chem. Res., 2002, 35: 706.

[32] McDonald J C, Duffy D C, Anderson J R, Chiu D T, Wu H, Schueller O J A, Whitesides G M. Electrophoresis, 2000, 21: 27.

[33] Trantidou T, Elani Y, Parsons E, Ces O. Microsyst. Nanoeng., 2017, 3: 16091.

[34] Hines D J, Kaplan D L. Crit. Rev. Ther. Drug Carrier Syst., 2013, 30: 257.

[35] Sedlacek H H. Crit. Rev. Oncol. Hematol., 2001, 38: 139.

[36] Sedlacek H H, Czech J, Naik R, Kaur G, Worland P, Losiewicz M, Parker B, Carlson B, Smith A, Senderowicz A, Sausville E. Int. J. Oncol., 199, 9: 1143.

[37] Xiong S, George S, Yu H, Damoiseaux R, France B, Ng K W, Loo J S-C. Arch. Toxicol., 2013, 87: 1075.

[38] Porceddu M, Buron N, Roussel C, Labbe G, Fromenty B, Borgne-Sanchez A. Toxicological Sciences, 2012, 129: 332.

[39] Sanabria-Ríos D J, Rivera-Torres Y, Rosario J, Ríos C, Gutierrez R, Carballeira N M, Vélez C, Zayas B, Álvarez-Colón F, Ortiz-Soto G, Serrano V, Altieri-Rivera J, Ríos-Olivares E, Rodríguez J W. Bioorg. Med. Chem. Lett., 2015, 25: 2174.

[40] Albisa A, Piacentini E, Arruebo M, Sebastian V, Giorno L. ACS Sustain. Chem. Eng., 2018, 6: 6663.

[41] Pinheiro C T, Quina M J, Gando-Ferreira L M. ACS Sustain. Chem. Eng., 2018, 6: 6820.

[42] Alder C M, Hayler J D, Henderson R K, Redman A M, Shukla L, Shuster L E, Sneddon H F. Green Chemistry, 201, 18: 3879.

[43] Han F Y, Thurecht K J, Whittaker A K, Smith M T. Front Pharmacol., 201, 7: 185.

[44] Zhai S, Senderowicz A M, Sausville E A, Figg W D. Ann. Pharmacother., 2002, 36: 905.

[45] Center for Drug Evaluation and Research U. S. Food and Drug Administration, 1997, BP2: 20.

[46] Blewis M E, Lao B J, Jadin K D, McCarty W J, Bugbee W D, Firestein G S, Sah R L. Biotechnol. Bioeng., 2010, 106: 149.

[47] Sheikh Z, Brooks P J, Barzilay O, Fine N, Glogauer M. Materials(Basel), 2015, 8: 5671.

[48] Gustafson H H, Holt-Casper D, Grainger D W, Ghandehari H. Nano Today, 2015, 10: 487.

[49] Conaghan P G, Cohen S B, Berenbaum F, Lufkin J, Johnson J R, Bodick N. Arthritis Rheumatol, 2018, 70: 204.

[50] Kumar A, Bendele A M, Blanks R C, Bodick N. Osteoarthr. Cartil., 2015, 23: 151.

[51] Office of Chemical Safety Environmental Protection Agency, 2018, EPA-740-R1-7016: 33.