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Tuning the Emulsion Properties Influences the Size of Poly(Caprolactone) Particles for Drug Delivery Applications

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  • Recent Advances in Drug Delivery
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Abstract

Advances in drug delivery have been accelerated with the addition of polymeric drug carriers. Direct delivery to a target site is a promising step in developing effective drug and gene therapies to treat disease. The efficacy of these drug carriers heavily relies on cell uptake without compromising critical cellular processes that promote cell viability. Drug release from biodegradable polymers is mediated largely by polymer degradation, and therefore the rate of polymer degradation dictates the feasibility of drug delivery applications. Traditionally, poly(caprolactone) (PCL) has only been used in long-term biomedical applications because the degradation time is much slower than other polymers. However, the biocompatibility of this polymer and the potential for longer delivery windows renders it a promising polymer candidate for drug delivery. In this work, we outline sixteen emulsion solvent evaporation preparation methods for PCL nanoparticles and microparticles to develop particles between 300 nm and 1.7 μm and with zeta potentials of -1.8 mV. We further investigated particles in a size range suitable for systemic tumor delivery and inhaled aerosol delivery to determine cell biocompatibility with the polymer in lung adenocarcinoma, endometrial adenocarcinoma, and human embryonic kidney cells. We determined these particles aren’t detrimental to cell viability below particle monolayer coverage atop cells and therefore these formulations hold promise for the next stage of development as sustained-release drug delivery carriers.

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Data Availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Rathna GVN, Bhagyashri S, Gadgil T, Killi N. Polyhydroxyalkanoates: The Application of Eco-Friendly Materials. Polymers as Drug Delivery Systems. New Jersey: John Wiley & Sons; 2016. p. 2-33.

  2. Jahangirian H, Lemraski EG, Webster TJ, Rafiee-Moghaddam R, Abdollahi Y. A review of drug delivery systems based on nanotechnology and green chemistry: green nanomedicine. Int J Nanomedicine. 2017;12:2957–78. https://doi.org/10.2147/IJN.S127683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Xu Y, Liu H, Song L. Novel drug delivery systems targeting oxidative stress in chronic obstructive pulmonary disease: a review. J Nanobiotechnology. 2020;18(1):145. https://doi.org/10.1186/s12951-020-00703-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ulucan-Karnak F, Kuru Cİ. Chapter 13 - Advantages of nanodrug targeting than conventional dosage system. In: Pratap Singh R, Rb Singh K, Singh J, Adetunji CO, editors. Nanotechnology for Drug Delivery and Pharmaceuticals. Academic Press; 2023. p. 295–310.

    Chapter  Google Scholar 

  5. Chang SH, Lee HJ, Park S, Kim Y, Jeong B. Fast Degradable Polycaprolactone for Drug Delivery. Biomacromol. 2018;19(6):2302–7. https://doi.org/10.1021/acs.biomac.8b00266.

    Article  CAS  Google Scholar 

  6. Li L, Gatto GJ, Brand RM, Krovi SA, Cottrell ML, Norton C, et al. Long-acting biodegradable implant for sustained delivery of antiretrovirals (ARVs) and hormones. J Control Release. 2021;340:188–99. https://doi.org/10.1016/j.jconrel.2021.10.021.

    Article  CAS  PubMed  Google Scholar 

  7. Acosta MF, Abrahamson MD, Encinas-Basurto D, Fineman JR, Black SM, Mansour HM. Inhalable Nanoparticles/Microparticles of an AMPK and Nrf2 Activator for Targeted Pulmonary Drug Delivery as Dry Powder Inhalers. AAPS J. 2020;23(1):2. https://doi.org/10.1208/s12248-020-00531-3.

    Article  CAS  PubMed  Google Scholar 

  8. Wiwatchaitawee K, Mekkawy AI, Quarterman JC, Naguib YW, Ebeid K, Geary SM, et al. The MEK 1/2 inhibitor PD98059 exhibits synergistic anti-endometrial cancer activity with paclitaxel in vitro and enhanced tissue distribution in vivo when formulated into PAMAM-coated PLGA-PEG nanoparticles. Drug Deliv Transl Res. 2022;12(7):1684–96. https://doi.org/10.1007/s13346-021-01065-7.

    Article  CAS  PubMed  Google Scholar 

  9. Naguib YW, Givens BE, Ho G, Yu Y, Wei SG, Weiss RM, et al. An injectable microparticle formulation for the sustained release of the specific MEK inhibitor PD98059: in vitro evaluation and pharmacokinetics. Drug Deliv Transl Res. 2021;11(1):182–91. https://doi.org/10.1007/s13346-020-00758-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Terry TL, Givens BE, Rodgers VGJ, Salem AK. Tunable Properties of Poly-DL-Lactide-Monomethoxypolyethylene Glycol Porous Microparticles for Sustained Release of Polyethylenimine-DNA Polyplexes. AAPS PharmSciTech. 2019;20(1):23. https://doi.org/10.1208/s12249-018-1215-9.

    Article  CAS  PubMed  Google Scholar 

  11. El-Sherbiny IM, El-Baz NM, Yacoub MH. Inhaled nano- and microparticles for drug delivery. Glob Cardiol Sci Pract. 2015;2015:2. https://doi.org/10.5339/gcsp.2015.2.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Patra JK, Das G, Fraceto LF, Campos EVR, Rodriguez-Torres MDP, Acosta-Torres LS, et al. Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnology. 2018;16(1):71. https://doi.org/10.1186/s12951-018-0392-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ferrari R, Sponchioni M, Morbidelli M, Moscatelli D. Polymer nanoparticles for the intravenous delivery of anticancer drugs: the checkpoints on the road from the synthesis to clinical translation. Nanoscale. 2018;10(48):22701–19. https://doi.org/10.1039/c8nr05933k.

    Article  CAS  PubMed  Google Scholar 

  14. Choi CH, Zuckerman JE, Webster P, Davis ME. Targeting kidney mesangium by nanoparticles of defined size. Proc Natl Acad Sci U S A. 2011;108(16):6656–61. https://doi.org/10.1073/pnas.1103573108.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kalyane D, Raval N, Maheshwari R, Tambe V, Kalia K, Tekade RK. Employment of enhanced permeability and retention effect (EPR): Nanoparticle-based precision tools for targeting of therapeutic and diagnostic agent in cancer. Mater Sci Eng C Mater Biol Appl. 2019;98:1252–76. https://doi.org/10.1016/j.msec.2019.01.066.

    Article  CAS  PubMed  Google Scholar 

  16. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000;65(1–2):271–84. https://doi.org/10.1016/s0168-3659(99)00248-5.

    Article  CAS  PubMed  Google Scholar 

  17. Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE. Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release. 2001;70(1–2):1–20. https://doi.org/10.1016/s0168-3659(00)00339-4.

    Article  CAS  PubMed  Google Scholar 

  18. Owens DE 3rd, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307(1):93–102. https://doi.org/10.1016/j.ijpharm.2005.10.010.

    Article  CAS  PubMed  Google Scholar 

  19. Terry TL, Givens BE, Adamcakova-Dodd A, Thorne PS, Rodgers VGJ, Salem AK. Encapsulating Polyethyleneimine-DNA Nanoplexes into PEGylated Biodegradable Microparticles Increases Transgene Expression In Vitro and Reduces Inflammatory Responses In Vivo. AAPS PharmSciTech. 2021;22(2):69. https://doi.org/10.1208/s12249-021-01932-z.

    Article  CAS  PubMed  Google Scholar 

  20. Manoukian OS, Arul MR, Sardashti N, Stedman T, James R, Rudraiah S, et al. Biodegradable polymeric injectable implants for long-term delivery of contraceptive drugs. J Appl Polym Sci. 2018;135(14). https://doi.org/10.1002/app.46068.

  21. Chandra R, Rustgi R. Biodegradable polymers. Prog Polym Sci. 1998;23(7):1273–335.

    Article  CAS  Google Scholar 

  22. Okada M. Chemical syntheses of biodegradable polymers. Prog Polym Sci. 2002;27(1):87–133. https://doi.org/10.1016/s0079-6700(01)00039-9.

    Article  CAS  Google Scholar 

  23. Woodring RN, Gurysh EG, Bachelder EM, Ainslie KM. Drug Delivery Systems for Localized Cancer Combination Therapy. ACS Appl Bio Mater. 2023;6(3):934–50. https://doi.org/10.1021/acsabm.2c00973.

    Article  CAS  PubMed  Google Scholar 

  24. Woodruff MA, Hutmacher DW. The return of a forgotten polymer—Polycaprolactone in the 21st century. Prog Polym Sci. 2010;35(10):1217–56. https://doi.org/10.1016/j.progpolymsci.2010.04.002.

    Article  CAS  Google Scholar 

  25. Sun H, Mei L, Song C, Cui X, Wang P. The in vivo degradation, absorption and excretion of PCL-based implant. Biomaterials. 2006;27(9):1735–40. https://doi.org/10.1016/j.biomaterials.2005.09.019.

    Article  CAS  PubMed  Google Scholar 

  26. Abramoff MD, Magalhaes PJ, Ram SJ. Image processing with ImageJ. Biophotonics Int. 2004;11(7):36–42.

    Google Scholar 

  27. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676–82. https://doi.org/10.1038/nmeth.2019.

    Article  CAS  PubMed  Google Scholar 

  28. Prasad A, Kandasubramanian B. Fused deposition processing polycaprolactone of composites for biomedical applications. Polym-Plast Technol Mater. 2019;58(13):1365–98. https://doi.org/10.1080/25740881.2018.1563117.

    Article  CAS  Google Scholar 

  29. Mason TG, Wilking JN, Meleson K, Chang CB, Graves SM. Nanoemulsions: formation, structure, and physical properties. J Phys: Condens Matter. 2006;18(41):R635–66. https://doi.org/10.1088/0953-8984/18/41/r01.

    Article  CAS  Google Scholar 

  30. Witt S, Scheper T, Walter JG. Production of polycaprolactone nanoparticles with hydrodynamic diameters below 100 nm. Eng Life Sci. 2019;19(10):658–65. https://doi.org/10.1002/elsc.201800214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jiang D, Salem AK. Optimized dextran-polyethylenimine conjugates are efficient non-viral vectors with reduced cytotoxicity when used in serum containing environments. Int J Pharm. 2012;427(1):71–9. https://doi.org/10.1016/j.ijpharm.2011.10.032.

    Article  CAS  PubMed  Google Scholar 

  32. Stark WJ. Nanoparticles in biological systems. Angew Chem Int Ed Engl. 2011;50(6):1242–58. https://doi.org/10.1002/anie.200906684.

    Article  CAS  PubMed  Google Scholar 

  33. Huang K, Hu Y, Yu C, Boerhan R, Jiang G. Charged surface groups of nanoparticles and the adsorbed proteins codetermine the fate of nanoparticles upon interacting with cells. RSC Adv. 2016;6(63):58315–24. https://doi.org/10.1039/c6ra07468e.

    Article  CAS  Google Scholar 

  34. Oh N, Park JH. Endocytosis and exocytosis of nanoparticles in mammalian cells. Int J Nanomed. 2014;9(Suppl 1):51–63. https://doi.org/10.2147/IJN.S26592.

    Article  CAS  Google Scholar 

  35. Foroozandeh P, Aziz AA. Insight into Cellular Uptake and Intracellular Trafficking of Nanoparticles. Nanoscale Res Lett. 2018;13(1):339. https://doi.org/10.1186/s11671-018-2728-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lukasiewicz S, Mikolajczyk A, Blasiak E, Fic E, Dziedzicka-Wasylewska M. Polycaprolactone nanoparticles as promising candidates for nanocarriers in novel nanomedicines. Pharmaceutics 2021;13(2). https://doi.org/10.3390/pharmaceutics13020191.

  37. Bruinsmann FA, Buss JH, Souto GD, Schultze E, de Cristo SoaresAlves A, Seixas FK, et al. Erlotinib-Loaded Poly(epsilon-Caprolactone) Nanocapsules Improve In Vitro Cytotoxicity and Anticlonogenic Effects on Human A549 Lung Cancer Cells. AAPS PharmSciTech. 2020;21(6):229. https://doi.org/10.1208/s12249-020-01723-y.

    Article  CAS  PubMed  Google Scholar 

  38. Yu W, Liu R, Zhou Y, Gao H. Size-Tunable Strategies for a Tumor Targeted Drug Delivery System. ACS Cent Sci. 2020;6(2):100–16. https://doi.org/10.1021/acscentsci.9b01139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang Q, Bao J, Duan T, Hu M, He Y, Wang J, et al. Nanomicelle-microsphere composite as a drug carrier to improve lung-targeting specificity for lung cancer. Pharmaceutics 2022;14(3). https://doi.org/10.3390/pharmaceutics14030510.

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Acknowledgements

The authors acknowledge the Electron Microscopy Center at the University of Kentucky for SEM images, with particular support from Nicholas Briot, PhD.

Funding

This work was supported by the University of Kentucky Clinical and Translational Sciences funded by the NIH National Center for Advancing Translational Sciences through grant number UL1TR001998. This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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A.S. and C.R. contributed equally to concept, experimental design, experimental methods, data analysis, manuscript preparation and editing. H.S. conducted experiments and data analysis. B.G. was responsible for conceptualization, manuscript preparation and editing.

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Correspondence to Brittany E. Givens.

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Communicated by Aliasger Salem.

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Ashbey Manning and Claire Rowlands are co-first authors.

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Manning, A.N., Rowlands, C.E., Saindon, H. et al. Tuning the Emulsion Properties Influences the Size of Poly(Caprolactone) Particles for Drug Delivery Applications. AAPS J 25, 100 (2023). https://doi.org/10.1208/s12248-023-00869-4

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