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Oral In-Situ Nanoplatform with Balanced Hydrophobic-Hydrophilic Property for Transport Across Gastrointestinal Mucosa

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Abstract

Transport of oral nanocarriers across the GI epithelium necessitates transport across hydrophilic mucus layer and the hydrophobic epithelium. Based on hydrophobic-hydrophilic balance, Curcumin-Lipomer (lipid-polymer hybrid nanoparticles) comprising hydrophobic stearic acid and hydrophilic Gantrez™ AN 119 (Gantrez) were developed, by a radical in-situ approach, to successfully traverse both barriers. A monophasic preconcentrate (Cur-Pre) comprising Cur (Curcumin), stearic acid, Gantrez and stabilizers, prepared by simple solution, was added to an aqueous phase to instantaneously generate Curcumin-Lipomer (Cur-Lipo) of nanosize and high entrapment efficiency (EE). Cur-Lipo size and EE was optimized by Box-Behnken Design. Cur-Lipomers of varying hydrophobic-hydrophilic property obtained by varying the stearic acid: Gantrez ratio exhibited size in the range 200–400 nm, EE > 95% and spherical morphology as seen in the TEM. A decrease in contact angle and in mucus interaction, evident with increase in Gantrez concentration, indicated an inverse corelation with hydrophilicity, while a linear corelation was observed for mucopenetration and hydrophilicity. Cur-SLN (solid lipid nanoparticles) which served as the hydrophobic reference revealed contact angle > 90°, maximum interaction with mucus and minimal mucopenetration. The ex-vivo permeation study through chicken ileum, revealed maximum permeation with Cur-Lipo1 and comparable and significantly lower permeation of Cur-Lipo1-D and Cur-SLN proposing the importance of balancing the hydrophobic-hydrophilic property of the nanoparticles. A 1.78-fold enhancement in flux of hydrophobic Cur-SLN, with no significant change in permeation of the hydrophilic Cur-Lipomers (p > 0.05) following stripping off the mucosal layer was observed. This reiterated the significance of hydrophobic-hydrophilic balance as a promising strategy to design nanoformulations with superior permeation across the GI barrier.

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References

  1. Ejazi SA, Louisthelmy R, Maisel K. Mechanisms of nanoparticle transport across intestinal tissue: an oral delivery perspective. ACS Nano. 2023;17(14):13044–61. https://doi.org/10.1021/acsnano.3c02403.

    Article  CAS  PubMed  Google Scholar 

  2. Mittal R, Patel AP, Jhaveri VM, Kay S-IS, Debs LH, Parrish JM, et al. Recent advancements in nanoparticle based drug delivery for gastrointestinal disorders. Expert Opin Drug Deliv. 2018;15(3):301–18. https://doi.org/10.1080/17425247.2018.1420055.

    Article  CAS  PubMed  Google Scholar 

  3. Bachhav SS, Dighe VD, Kotak D, Devarajan PV. Rifampicin Lipid-Polymer hybrid nanoparticles (LIPOMER) for enhanced Peyer’s patch uptake. Int J Pharm. 2017;532(1):612–22. https://doi.org/10.1016/j.ijpharm.2017.09.040.

    Article  CAS  PubMed  Google Scholar 

  4. Roger E, Lagarce F, Garcion E, Benoit J-P. Biopharmaceutical parameters to consider in order to alter the fate of nanocarriers after oral delivery. Nanomedicine. 2010;5(2):287–306. https://doi.org/10.2217/nnm.09.110.

    Article  CAS  PubMed  Google Scholar 

  5. Shahbazi M-A, Santos HA. Improving oral absorption via drug-loaded nanocarriers: absorption mechanisms, intestinal models and rational fabrication. Curr Drug Metab. 2013;14(1):28–56. https://doi.org/10.2174/138920013804545133.

    Article  CAS  PubMed  Google Scholar 

  6. Mo R, Jiang T, Di J, Tai W, Gu Z. Emerging micro-and nanotechnology based synthetic approaches for insulin delivery. Chem Soc Rev. 2014;43(10):3595–629. https://doi.org/10.1039/C3CS60436E.

    Article  CAS  PubMed  Google Scholar 

  7. Shan W, Zhu X, Tao W, Cui Y, Liu M, Wu L, et al. Enhanced oral delivery of protein drugs using zwitterion-functionalized nanoparticles to overcome both the diffusion and absorption barriers. ACS Appl Mater Interfaces. 2016;8(38):25444–53. https://doi.org/10.1021/acsami.6b08183.

    Article  CAS  PubMed  Google Scholar 

  8. Ensign LM, Cone R, Hanes J. Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers. Adv Drug Deliv Rev. 2012;64(6):557–70. https://doi.org/10.1016/j.addr.2011.12.009.

    Article  CAS  PubMed  Google Scholar 

  9. Huckaby JT, Lai SK. PEGylation for enhancing nanoparticle diffusion in mucus. Adv Drug Deliv Rev. 2018;124:125–39. https://doi.org/10.1016/j.addr.2017.08.010.

    Article  CAS  PubMed  Google Scholar 

  10. Yu M, Xu L, Tian F, Su Q, Zheng N, Yang Y, et al. Rapid transport of deformation-tuned nanoparticles across biological hydrogels and cellular barriers. Nat Commun. 2018;9(1):2607. https://doi.org/10.1038/s41467-018-05061-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Menzel C, Bernkop-Schnürch A. Enzyme decorated drug carriers: targeted swords to cleave and overcome the mucus barrier. Adv Drug Deliv Rev. 2018;124:164–74. https://doi.org/10.1016/j.addr.2017.10.004.

    Article  CAS  PubMed  Google Scholar 

  12. Leal J, Smyth HD, Ghosh D. Physicochemical properties of mucus and their impact on transmucosal drug delivery. Int J Pharm. 2017;532(1):555–72. https://doi.org/10.1016/j.ijpharm.2017.09.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kirch J. The role of fluid dynamics, microstructure and mucociliary clearance in the micro-and macroscopic barrier properties of pulmonary mucus. 2012. https://doi.org/10.22028/D291-22833.

  14. Hagesaether E, Adamczak MI, Hiorth M, Tho I. Characterization of Bioadhesion, Mucin‐interactions and Mucosal Permeability of Pharmaceutical Nano‐and Microsystems. Charact Pharm Nano Microsyst. 2021:171–205. https://doi.org/10.1002/9781119414018.ch5.

  15. Anselmo AC, Gokarn Y, Mitragotri S. Non-invasive delivery strategies for biologics. Nat Rev Drug Discovery. 2019;18(1):19–40. https://doi.org/10.1038/nrd.2018.183.

    Article  CAS  PubMed  Google Scholar 

  16. Macedo AS, Castro PM, Roque L, Thomé NG, Reis CP, Pintado ME, et al. Novel and revisited approaches in nanoparticle systems for buccal drug delivery. J Control Release. 2020;320:125–41. https://doi.org/10.1016/j.jconrel.2020.01.006.

    Article  CAS  PubMed  Google Scholar 

  17. Liu C, Jiang X, Gan Y, Yu M. Engineering nanoparticles to overcome the mucus barrier for drug delivery: Design, evaluation and state-of-the-art. Medicine in Drug Discovery. 2021;12:100110. https://doi.org/10.1016/j.medidd.2021.100110.

    Article  CAS  Google Scholar 

  18. Yang M, Lai SK, Wang Y-Y, Zhong W, Happe C, Zhang M, et al. Biodegradable nanoparticles composed entirely of safe materials that rapidly penetrate human mucus. Angewandte Chemie (International ed in English). 2011;50(11):2597. https://doi.org/10.1002/anie.201006849.

  19. Ensign LM, Schneider C, Suk JS, Cone R, Hanes J. Mucus penetrating nanoparticles: biophysical tool and method of drug and gene delivery. Adv Mater. 2012;24(28):3887–94. https://doi.org/10.1002/adma.201201800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gao Y, He Y, Zhang H, Zhang Y, Gao T, Wang J-H, et al. Zwitterion-functionalized mesoporous silica nanoparticles for enhancing oral delivery of protein drugs by overcoming multiple gastrointestinal barriers. J Colloid Interface Sci. 2021;582:364–75. https://doi.org/10.1016/j.jcis.2020.08.010.

    Article  CAS  PubMed  Google Scholar 

  21. Khutoryanskiy VV. Beyond PEGylation: alternative surface-modification of nanoparticles with mucus-inert biomaterials. Adv Drug Deliv Rev. 2018;124:140–9. https://doi.org/10.1016/j.addr.2017.07.015.

    Article  CAS  PubMed  Google Scholar 

  22. Schneider CS, Xu Q, Boylan NJ, Chisholm J, Tang BC, Schuster BS, et al. Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation. Sci Adv. 2017;3(4):e1601556. https://doi.org/10.1126/sciadv.1601556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wu L, Shan W, Zhang Z, Huang Y. Engineering nanomaterials to overcome the mucosal barrier by modulating surface properties. Adv Drug Deliv Rev. 2018;124:150–63. https://doi.org/10.1016/j.addr.2017.10.001.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang X, Cheng H, Dong W, Zhang M, Liu Q, Wang X, et al. Design and intestinal mucus penetration mechanism of core-shell nanocomplex. J Control Release. 2018;272:29–38. https://doi.org/10.1016/j.jconrel.2017.12.034.

    Article  CAS  PubMed  Google Scholar 

  25. Fang L, Wang L, Yao Y, Zhang J, Wu X, Li X, et al. Micro-and nano-carrier systems: The non-invasive and painless local administration strategies for disease therapy in mucosal tissues. Nanomedicine. 2017;13(1):153–71. https://doi.org/10.1016/j.nano.2016.08.025.

    Article  CAS  PubMed  Google Scholar 

  26. Forier K, Messiaen A-S, Raemdonck K, Deschout H, Rejman J, De Baets F, et al. Transport of nanoparticles in cystic fibrosis sputum and bacterial biofilms by single-particle tracking microscopy. Nanomedicine. 2013;8(6):935–49. https://doi.org/10.2217/nnm.12.129.

    Article  CAS  PubMed  Google Scholar 

  27. Valamla B, Thakor P, Phuse R, Dalvi M, Kharat P, Kumar A, et al. Engineering drug delivery systems to overcome the vaginal mucosal barrier: Current understanding and research agenda of mucoadhesive formulations of vaginal delivery. J Drug Deliv Sci Technol. 2022;70:103162. https://doi.org/10.1016/j.jddst.2022.103162.

    Article  CAS  Google Scholar 

  28. Hu S, Yang Z, Wang S, Wang L, He Q, Tang H, et al. Zwitterionic polydopamine modified nanoparticles as an efficient nanoplatform to overcome both the mucus and epithelial barriers. Chem Eng J. 2022;428:132107. https://doi.org/10.1016/j.cej.2021.132107.

    Article  CAS  Google Scholar 

  29. Jahagirdar PS, Gupta PK, Kulkarni SP, Devarajan PV. Polymeric curcumin nanoparticles by a facile in situ method for macrophage targeted delivery. Bioeng Transl Med. 2019;4(1):141–51. https://doi.org/10.1002/btm2.10112.

    Article  CAS  PubMed  Google Scholar 

  30. Joshi HA, Patwardhan RS, Sharma D, Sandur SK, Devarajan PV. Pre-clinical evaluation of an innovative oral nano-formulation of baicalein for modulation of radiation responses. Int J Pharm. 2021;595:120181. https://doi.org/10.1016/j.ijpharm.2020.120181.

    Article  CAS  PubMed  Google Scholar 

  31. Poinard B, Kamaluddin S, Tan AQQ, Neoh KG, Kah JCY. Polydopamine coating enhances mucopenetration and cell uptake of nanoparticles. ACS Appl Mater Interfaces. 2019;11(5):4777–89. https://doi.org/10.1021/acsami.8b18107.

    Article  CAS  PubMed  Google Scholar 

  32. Grießinger J, Dünnhaupt S, Cattoz B, Griffiths P, Oh S, Igómez SB, et al. Methods to determine the interactions of micro-and nanoparticles with mucus. Eur J Pharm Biopharm. 2015;96:464–76. https://doi.org/10.1016/j.ejpb.2015.01.005.

    Article  CAS  PubMed  Google Scholar 

  33. Hu S, Pei X, Duan L, Zhu Z, Liu Y, Chen J, et al. A mussel-inspired film for adhesion to wet buccal tissue and efficient buccal drug delivery. Nat Commun. 2021;12(1):1689. https://doi.org/10.1038/s41467-021-21989-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Westerhout J, Bellmann S, van Ee R, Havenaar R, Leeman W, Steeg E, et al. Prediction of oral absorption of nanoparticles from biorelevant matrices using a combination of physiologically relevant in vitro and ex vivo models. J Food Chem Nanotechnol. 2017;3(4):111–9. https://doi.org/10.17756/jfcn.2017-046.

    Article  Google Scholar 

  35. Behrens I, Pena AIV, Alonso MJ, Kissel T. Comparative uptake studies of bioadhesive and non-bioadhesive nanoparticles in human intestinal cell lines and rats: the effect of mucus on particle adsorption and transport. Pharm Res. 2002;19:1185–93. https://doi.org/10.1023/A:1019854327540.

    Article  CAS  PubMed  Google Scholar 

  36. Jindal AB, Devarajan PV. Asymmetric lipid–polymer particles (LIPOMER) by modified nanoprecipitation: role of non-solvent composition. Int J Pharm. 2015;489(1–2):246–51. https://doi.org/10.1016/j.ijpharm.2015.04.073.

    Article  CAS  PubMed  Google Scholar 

  37. Kapse SV, Gaikwad RV, Samad A, Devarajan PV. Self nanoprecipitating preconcentrate of tamoxifen citrate for enhanced bioavailability. Int J Pharm. 2012;429(1–2):104–12. https://doi.org/10.1016/j.ijpharm.2012.02.042.

    Article  CAS  PubMed  Google Scholar 

  38. John R, Dalal B, Shankarkumar A, Devarajan PV. Innovative betulin nanosuspension exhibits enhanced anticancer activity in a triple negative breast cancer cell line and Zebrafish angiogenesis model. Int J Pharm. 2021;600: 120511. https://doi.org/10.1016/j.ijpharm.2021.120511.

    Article  CAS  PubMed  Google Scholar 

  39. Todke PA, Devarajan PV. In-silico approach as a tool for selection of excipients for safer amphotericin B nanoformulations. J Control Release. 2022;349:756–64. https://doi.org/10.1016/j.jconrel.2022.07.030.

    Article  CAS  PubMed  Google Scholar 

  40. D’Souza AA, Devarajan PV. Bioenhanced oral curcumin nanoparticles: role of carbohydrates. Carbohyd Polym. 2016;136:1251–8. https://doi.org/10.1016/j.carbpol.2015.10.021.

    Article  CAS  Google Scholar 

  41. Ferreira SC, Bruns R, Ferreira HS, Matos GD, David J, Brandão G, et al. Box-Behnken design: An alternative for the optimization of analytical methods. Anal Chim Acta. 2007;597(2):179–86. https://doi.org/10.1016/j.aca.2007.07.011.

    Article  CAS  PubMed  Google Scholar 

  42. Homayouni A, Sadeghi F, Varshosaz J, Garekani HA, Nokhodchi A. Promising dissolution enhancement effect of soluplus on crystallized celecoxib obtained through antisolvent precipitation and high pressure homogenization techniques. Colloids Surf B. 2014;122:591–600. https://doi.org/10.1016/j.colsurfb.2014.07.037.

    Article  CAS  Google Scholar 

  43. Crick CR, Parkin IP. Preparation and characterisation of super-hydrophobic surfaces. Chem Eur J. 2010;16(12):3568–88. https://doi.org/10.1002/chem.200903335.

    Article  CAS  PubMed  Google Scholar 

  44. Azioune A, Chehimi MM, Miksa B, Basinska T, Slomkowski S. Hydrophobic protein− polypyrrole interactions: The role of van der Waals and Lewis acid− base forces as determined by contact angle measurements. Langmuir. 2002;18(4):1150–6. https://doi.org/10.1021/la010444o.

    Article  CAS  Google Scholar 

  45. Chater PI, Wilcox MD, Pearson JP. Efficacy and safety concerns over the use of mucus modulating agents for drug delivery using nanoscale systems. Adv Drug Deliv Rev. 2018;124:184–92. https://doi.org/10.1016/j.addr.2017.12.006.

    Article  CAS  PubMed  Google Scholar 

  46. Nordgård CT, Draget KI. Co association of mucus modulating agents and nanoparticles for mucosal drug delivery. Adv Drug Deliv Rev. 2018;124:175–83. https://doi.org/10.1016/j.addr.2018.01.001.

    Article  CAS  PubMed  Google Scholar 

  47. Svensson O, Thuresson K, Arnebrant T. Interactions between drug delivery particles and mucin in solution and at interfaces. Langmuir. 2008;24(6):2573–9. https://doi.org/10.1021/la702680x.

    Article  CAS  PubMed  Google Scholar 

  48. Takeuchi H, Thongborisute J, Matsui Y, Sugihara H, Yamamoto H, Kawashima Y. Novel mucoadhesion tests for polymers and polymer-coated particles to design optimal mucoadhesive drug delivery systems. Adv Drug Deliv Rev. 2005;57(11):1583–94. https://doi.org/10.1016/j.addr.2005.07.008.

    Article  CAS  PubMed  Google Scholar 

  49. de Sousa IP, Steiner C, Schmutzler M, Wilcox MD, Veldhuis GJ, Pearson JP, et al. Mucus permeating carriers: formulation and characterization of highly densely charged nanoparticles. Eur J Pharm Biopharm. 2015;97:273–9. https://doi.org/10.1016/j.ejpb.2014.12.024.

    Article  CAS  Google Scholar 

  50. Griffiths PC, Cattoz B, Ibrahim MS, Anuonye JC. Probing the interaction of nanoparticles with mucin for drug delivery applications using dynamic light scattering. Eur J Pharm Biopharm. 2015;97:218–22. https://doi.org/10.1016/j.ejpb.2015.05.004.

    Article  CAS  PubMed  Google Scholar 

  51. Ren Y, Wu W, Zhang X. The feasibility of oral targeted drug delivery: Gut immune to particulates? Acta Pharmaceutica Sinica B. 2023;13(6):2544–58. https://doi.org/10.1016/j.apsb.2022.10.020.

    Article  CAS  PubMed  Google Scholar 

  52. Dos Santos AM, Carvalho SG, Meneguin AB, Sábio RM, Gremião MPD, Chorilli M. Oral delivery of micro/nanoparticulate systems based on natural polysaccharides for intestinal diseases therapy: Challenges, advances and future perspectives. J Control Release. 2021;334:353–66. https://doi.org/10.1016/j.jconrel.2021.04.026.

    Article  CAS  PubMed  Google Scholar 

  53. Froehlich E, Roblegg E. Mucus as barrier for drug delivery by nanoparticles. J Nanosci Nanotechnol. 2014;14(1):126–36. https://doi.org/10.1166/jnn.2014.9015.

    Article  CAS  Google Scholar 

  54. Teubl BJ, Meindl C, Eitzlmayr A, Zimmer A, Fröhlich E, Roblegg E. In-vitro permeability of neutral polystyrene particles via buccal mucosa. Small. 2013;9(3):457–66. https://doi.org/10.1002/smll.201201789.

    Article  CAS  PubMed  Google Scholar 

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Funding

The financial support for Junior Research Fellowship from Department of Atomic Energy (DAE-ICT), Government of India to Esha S. Attar is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology Matunga (E), Mumbai, 400019, India

    Esha S. Attar & Padma V. Devarajan

  2. Radiation Biology and Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India

    S. Jayakumar

  3. Homi Bhabha National Institute, Anushaktinagar, Mumbai, 400094, India

    S. Jayakumar

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Esha Attar: Investigation, Methodology, Validation, Writing—original draft, S. Jayakumar- Writing—review & editing, Padma V. Devarajan: Conceptualization, Supervision, Resources, funding acquisition and writing and editing the final draft.

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Correspondence to Padma V. Devarajan.

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Attar, E.S., Jayakumar, S. & Devarajan, P.V. Oral In-Situ Nanoplatform with Balanced Hydrophobic-Hydrophilic Property for Transport Across Gastrointestinal Mucosa. AAPS PharmSciTech 25, 113 (2024). https://doi.org/10.1208/s12249-024-02824-8

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