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Abstract

A drug that is administered through a catheter into the bladder is referred to as an intravesical drug delivery system. The aim of this work is to improvise intravesical drug delivery of Tacrolimus loaded lipid polymer hybrid nanoparticles thermosensitive gel for bladder wall to provide control release, increase intravesical residence time and avoid fast removal by urination. The Tacrolimus loaded lipid polymer hybrid nanoparticles mimic cell membrane and enhance cellular uptakes. Our data reveals nanocarrier formation with a mean particle size, zeta potential and entrapment efficiency of optimal formula was found to be 124±0.01 nm,-27.5±0.102mv and 72% ± 0.15% respectively. In situ gelling formulations containing TAC-CS-LPHNs can adhere to the mucosal layer of the bladder and help in the diffusion of therapeutic agent across the bladder wall. To impart mechanical strength and mucoadhesive properties, the chitosan concentration was adjusted to 0.5% and 0.25%.The image of field emission scanning electron microscope shows an irregular surface with filled pores with nanoparticles. The gel was syringeable and had reasonable viscosity within room temperature. A Tissue uptake study reveals that Tacrolimus loaded lipid polymer hybrid nanoparticles have been penetrating bladder tissues and accumulated inside the cytoplasm and nucleus of urothelium epithelial cells. In addition, the bioimaging study shows that the gel resided inside the bladder for up to 2 hrs and completely urinated out of the bladder with negligible distribution to other tissues.

References

  1. He C, Hu Y, Yin L, Tang C, Yin C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 2010;31(13):3657e66. https://doi.org/10.1016/j.biomaterials.2010.01.065.
  2. S¸ enyigit ZA, Karavana SY, _Ilem- € Ozdemir D, Çalõs¸kan Ç, Waldner C, S¸ en S, et al. Design and evaluation of an intravesical delivery system for superficial bladder cancer: preparation of gemcitabine HCl-loaded chitosan-thioglycolic acid nanoparticles and comparison of chitosan/poloxamer gels as carriers. Int J Nanomed 2015;10:6493e507. https://doi.org/10.2147/IJN.S93750.
  3. Tyagi P, Tyagi S, Kaufman J, Huang L, de Miguel F. Local drug delivery to bladder using technology innovations. Urol Clin 2006;33(4):519e30. https://doi.org/10.1016/j.ucl.2006.06.012.
  4. Grabnar I, Bogataj M, Belic A, Logar V, Karba R, Mrhar A. Kinetic model of drug distribution in the urinary bladder wall following intravesical instillation. Int J Pharm 2006;322(1e2):52e9. https://doi.org/10.1016/j.ijpharm.2006.05.026.
  5. Martin DT, Steinbach JM, Liu J, Shimizu S, Kaimakliotis HZ, Wheeler MA, et al. Surface-modified nanoparticles enhance transurothelial penetration and delivery of survivin siRNA in treating bladder cancer. Mol Cancer Therapeut 2014;13(1):71e81. https://doi.org/10.1158/1535-7163.MCT-13-0502.
  6. Tamura K, Kikuchi E, Konno T, Ishihara K, Matsumoto K, Miyajima A, et al. Therapeutic effect of intravesical administration of paclitaxel solubilized with poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) in an orthotopic bladder cancer model. BMC Cancer 2015;15(1):317. https://doi.org/10.1186/s12885-015-1338-2.
  7. Bassi PF, Costantini E, Foley S, Palea S. Glycosaminoglycan therapy for bladder diseases: emerging new treatments. Eur Urol Suppl 2011;10(6):451e9. https://doi.org/10.1016/j.eursup.2011.06.001.
  8. Shen Z, Shen T, Wientjes MG, O'Donnell MA, Au JL-S. Intravesical treatments of bladder cancer: review. Pharm Res (N Y) 2008;25(7):1500e10. https://doi.org/10.1007/s11095-008-9566-7.
  9. Tyagi P, Li Z, Chancellor M, De Groat WC, Yoshimura N, Huang L. Sustained intravesical drug delivery using thermosensitive hydrogel. Pharm Res (N Y) 2004;21(5):832e7. https://doi.org/10.1023/b:pham.0000026436.62869.9c.
  10. Chen J-P, Cheng T-H. Preparation and evaluation of thermoreversible copolymer hydrogels containing chitosan and hyaluronic acid as injectable cell carriers. Polymer 2009;50(1):107e16. https://doi.org/10.1016/j.polymer.2008.10.045.
  11. Parsons CL, Argade S, Evans RJ, Proctor J, Nickel JC,Rosenberg MT, et al. Role of urinary cations in the etiology of interstitial cystitis: a multisite study.Int J Urol 2020;27(9):731e5. https://doi.org/10.1111/iju.14293.
  12. Payne CK, Joyce GF, Wise M, Clemens JQ.Urologic Diseases in America Project.Interstitial cystitis and painful bladder syndrome.J Urol 2007;177(6):2042e9. https://doi.org/10.1016/j.juro.2007.01.124.
  13. Chuang Y-C, Tyagi P, Huang H-Y,Yoshimura N,Wu M,Kaufman J, et al.Intravesical immune suppression by liposomal tacrolimus in cyclophosphamide-induced inflammatory cystitis.Neurourol Urodyn 2011;30(3):421e7. https://doi.org/10.1002/nau.20981.
  14. Fang RH,Aryal S,Hu C-MJ,Zhang LQuick synthesis of lipid-polymer hybrid nanoparticles with low polydispersity using a single-step sonication method.Langmuir 2010;26(22):16958e62. https://doi.org/10.1021/la103576a.
  15. Miller SC, Donovan MD.Effect of poloxamer 407 gel on the miotic activity of pilocarpine nitrate in rabbits.Int J Pharm 1982;12(2e3):147e52. https://doi.org/10.1016/0378-5173(82)90114-4.
  16. Garala K,Joshi P,Shah M,Ramkishan A,Patel J.Formulation and evaluation of periodontal in situ gel.Int J Pharm Investig 2013;3(1):29e41. https://doi.org/10.4103/2230-973X.108961.
  17. Sim~oes SMN,Veiga F,Torres-Labandeira JJ,Ribeiro ACF, Concheiro A,Alvarez-Lorenzo C.Syringeable selfassembled cyclodextrin gels for drug delivery.Curr Top Med Chem 2014;14(4):494e509. https://doi.org/10.2174/1568026613666131219124308.
  18. Dabhi MR,Nagori SA,Gohel MC,Parikh RK,Sheth NR.Formulation development of smart gel periodontal drug delivery system for local delivery of chemotherapeutic agents with application of experimental design.Drug Deliv 2010;17(7):520e31. https://doi.org/10.3109/10717544.2010.490247.
  19. Khodaverdi E,Tafaghodi M,Ganji F,Abnoos K, Naghizadeh H.In vitro insulin release from thermosensitive chitosan hydrogel.AAPS PharmSciTech 2012;13(2):460e6. https://doi.org/10.1208/s12249-012-9764-9.
  20. Aher ND, Nair HA. Bilayered films based on novel polymer derivative for improved ocular therapy of gatifloxacin. Sci World J 2014;2014:297603. https://doi.org/10.1155/2014/297603.
  21. Kates M, Date A, Yoshida T, Afzal U, Kanvinde P, Babu T, et al. Preclinical evaluation of intravesical cisplatin nanoparticles for nonemuscle-invasive bladder cancer. Clin Cancer Res 2017;23(21):6592e601. https://doi.org/10.1158/1078-0432.ccr-17-1082.
  22. GuhaSarkar S, More P, Banerjee R. Urothelium-adherent, ion-triggered liposome-in-gel system as a platform for intravesical drug delivery. J Contr Release 2017;245:147e56. https://doi.org/10.1016/j.jconrel.2016.11.031.
  23. GuhaSarkar S, Banerjee R. Intravesical drug delivery: challenges, current status, opportunities and novel strategies. J Contr Release 2010;148(2):147e59. https://doi.org/10.1016/j.jconrel.2010.08.031.
  24. Khutoryanskiy VV. Advances in mucoadhesion and mucoadhesive polymers: advances in mucoadhesion and mucoadhesive polymers. Macromol Biosci 2011;11(6):748e64. https://doi.org/10.1002/mabi.201000388.
  25. Kojarunchitt T, Baldursdottir S, Dong Y-D, Boyd BJ, Rades T, Hook S. Modified thermoresponsive Poloxamer 407 and chitosan sol-gels as potential sustained-release vaccine delivery systems. Eur J Pharm Biopharm 2015;89:74e81. https://doi.org/10.1016/j.ejpb.2014.11.026.
  26. Mohammad Hussein A, Ghareeb Mowafaq M, Akrami Mohammed, Sahib Ameer S. Design and characterization of Tacrolimus monohydrate loaded core-shell lipid polymer hybrid nanoparticle. J Complement Med Res 2020;11(5):204e14. https://doi.org/10.6084/m9.figshare.21152149.

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