Sustained Intrathecal Delivery of Amphotericin B Using an Injectable and Biodegradable Thermogel

Overview

Journal Drug Deliv

Specialty Pharmacology

Date 2021 Mar 4

PMID 33657949

Citations 5

Authors

Wenting Lin

Tao Xu

Zhongzhi Wang

Jianghan Chen

Affiliations

Soon will be listed here.

Abstract

Cryptococcal meningitis is a fungal infectious disease with a poor prognosis and high mortality. Amphotericin B (AMB) is the first choice for the treatment of cryptococcal meninges. The blood-brain barrier (BBB) is the major barrier for the effective delivery of drugs to the brain. In this study, AMB was incorporated in a thermosensitive gel for intrathecal injection. We first synthesized AMB-loaded thermogel, investigated its in vitro cumulative release, and in vivo neurotoxicity, and therapeutic effect. The thermosensitive gel was comprised of 25 wt% poly (lactic acid-co-glycolic acid)-poly (ethylene glycol)-poly (lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock polymer aqueous solution. The AMB loaded in the thermosensitive gel (AMB in gel) had low viscosity at low temperature and resulted in the formation of a non-flowing gel at 37 °C (physiological temperature). AMB loading in gel sustained its release for 36 days and the cumulative release rate was satisfactory. Compared with the AMB solution, intrathecal administration of AMB in gel could reduce the neurovirulence of AMB and get a better treatment effect. The findings of the current study show that the injectable PLGA-PEG-PLGA thermogel is a biocompatible carrier for the delivery of drugs into the intrathecal.

Citing Articles

Comprehensive Therapeutic Approaches to Tuberculous Meningitis: Pharmacokinetics, Combined Dosing, and Advanced Intrathecal Therapies.

Madadi A, Sohn M Pharmaceutics. 2024; 16(4).

PMID: 38675201 PMC: 11054600. DOI: 10.3390/pharmaceutics16040540.

Clinical treatment of cryptococcal meningitis: an evidence-based review on the emerging clinical data.

Liu M, Dai X, Zeng M, Chen E J Neurol. 2024; 271(6):2960-2979.

PMID: 38289535 DOI: 10.1007/s00415-024-12193-8.

UV-Vis spectrophotometry for rapid and specific quantification of amphotericin B: analytical method validation for ex vivo and in vivo studies in the development of nanoemulsion-incorporated thermosensitive gel.

Mualim E, Hukman S, Siagian J, Mantong T, Dahlan R, Permana A Anal Sci. 2024; 40(4):615-631.

PMID: 38238533 DOI: 10.1007/s44211-023-00493-4.

Intracranial In Situ Thermosensitive Hydrogel Delivery of Temozolomide Accomplished by PLGA-PEG-PLGA Triblock Copolymer Blending for GBM Treatment.

Gu W, Fan R, Quan J, Cheng Y, Wang S, Zhang H Polymers (Basel). 2022; 14(16).

PMID: 36015626 PMC: 9413267. DOI: 10.3390/polym14163368.

Biodegradable gemcitabine-loaded microdevice with sustained local drug delivery and improved tumor recurrence inhibition abilities for postoperative pancreatic tumor treatment.

Kong X, Feng M, Wu L, He Y, Mao H, Gu Z Drug Deliv. 2022; 29(1):1595-1607.

PMID: 35612309 PMC: 9176693. DOI: 10.1080/10717544.2022.2075984.

References

Lei K, Chen Y, Wang J, Peng X, Yu L, Ding J . Non-invasive monitoring of in vivo degradation of a radiopaque thermoreversible hydrogel and its efficacy in preventing post-operative adhesions. Acta Biomater. 2017; 55:396-409. DOI: 10.1016/j.actbio.2017.03.042. View

DuVall G, Tarabar D, Seidel R, Elstad N, Fowers K . Phase 2: a dose-escalation study of OncoGel (ReGel/paclitaxel), a controlled-release formulation of paclitaxel, as adjunctive local therapy to external-beam radiation in patients with inoperable esophageal cancer. Anticancer Drugs. 2009; 20(2):89-95. DOI: 10.1097/CAD.0b013e3283222c12. View

Hoang Thi T, Sinh L, Huynh D, Nguyen D, Huynh C . Self-Assemblable Polymer Smart-Blocks for Temperature-Induced Injectable Hydrogel in Biomedical Applications. Front Chem. 2020; 8:19. PMC: 7005785. DOI: 10.3389/fchem.2020.00019. View

Yu L, Zhang Z, Zhang H, Ding J . Mixing a sol and a precipitate of block copolymers with different block ratios leads to an injectable hydrogel. Biomacromolecules. 2009; 10(6):1547-53. DOI: 10.1021/bm900145g. View

Song Y, Agrawal N, Griffin J, Schmidt C . Recent advances in nanotherapeutic strategies for spinal cord injury repair. Adv Drug Deliv Rev. 2018; 148:38-59. PMC: 6959132. DOI: 10.1016/j.addr.2018.12.011. View

Yu L, Zhang Z, Zhang H, Ding J . Biodegradability and biocompatibility of thermoreversible hydrogels formed from mixing a sol and a precipitate of block copolymers in water. Biomacromolecules. 2010; 11(8):2169-78. DOI: 10.1021/bm100549q. View

Chen X, Wang M, Yang X, Wang Y, Yu L, Sun J . Injectable hydrogels for the sustained delivery of a HER2-targeted antibody for preventing local relapse of HER2+ breast cancer after breast-conserving surgery. Theranostics. 2019; 9(21):6080-6098. PMC: 6735507. DOI: 10.7150/thno.36514. View

TARLOV I . Acute spinal cord compression paralysis. J Neurosurg. 1972; 36(1):10-20. DOI: 10.3171/jns.1972.36.1.0010. View

Yu L, Chang G, Zhang H, Ding J . Injectable block copolymer hydrogels for sustained release of a PEGylated drug. Int J Pharm. 2007; 348(1-2):95-106. DOI: 10.1016/j.ijpharm.2007.07.026. View

10.

Bao X, Zhu L, Huang X, Tang D, He D, Shi J . 3D biomimetic artificial bone scaffolds with dual-cytokines spatiotemporal delivery for large weight-bearing bone defect repair. Sci Rep. 2017; 7(1):7814. PMC: 5552682. DOI: 10.1038/s41598-017-08412-0. View

11.

Householder K, Dharmaraj S, Sandberg D, Wechsler-Reya R, Sirianni R . Fate of nanoparticles in the central nervous system after intrathecal injection in healthy mice. Sci Rep. 2019; 9(1):12587. PMC: 6715675. DOI: 10.1038/s41598-019-49028-w. View

12.

Asthana S, Jaiswal A, Gupta P, Dube A, Chourasia M . Th-1 biased immunomodulation and synergistic antileishmanial activity of stable cationic lipid-polymer hybrid nanoparticle: biodistribution and toxicity assessment of encapsulated amphotericin B. Eur J Pharm Biopharm. 2014; 89:62-73. DOI: 10.1016/j.ejpb.2014.11.019. View

13.

Liu D, Jiang T, Cai W, Chen J, Zhang H, Hietala S . An In Situ Gelling Drug Delivery System for Improved Recovery after Spinal Cord Injury. Adv Healthc Mater. 2016; 5(12):1513-21. DOI: 10.1002/adhm.201600055. View

14.

Shi E, Jiang X, Kazui T, Washiyama N, Yamashita K, Terada H . Controlled low-pressure perfusion at the beginning of reperfusion attenuates neurologic injury after spinal cord ischemia. J Thorac Cardiovasc Surg. 2007; 133(4):942-8. DOI: 10.1016/j.jtcvs.2006.12.017. View

15.

Fries B, Lee S, Kennan R, Zhao W, Casadevall A, Goldman D . Phenotypic switching of Cryptococcus neoformans can produce variants that elicit increased intracranial pressure in a rat model of cryptococcal meningoencephalitis. Infect Immun. 2005; 73(3):1779-87. PMC: 1064965. DOI: 10.1128/IAI.73.3.1779-1787.2005. View

16.

Hamill R . Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013; 73(9):919-34. DOI: 10.1007/s40265-013-0069-4. View

17.

Carroll S, Guillot L, Qureshi S . Mammalian model hosts of cryptococcal infection. Comp Med. 2007; 57(1):9-17. View

18.

Nau R, Blei C, Eiffert H . Intrathecal Antibacterial and Antifungal Therapies. Clin Microbiol Rev. 2020; 33(3). PMC: 7194852. DOI: 10.1128/CMR.00190-19. View

19.

Tyler B, Fowers K, Li K, Recinos V, Caplan J, Hdeib A . A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats. J Neurosurg. 2009; 113(2):210-7. DOI: 10.3171/2009.11.JNS08162. View

20.

Wang Y, Cooke M, Sachewsky N, Morshead C, Shoichet M . Bioengineered sequential growth factor delivery stimulates brain tissue regeneration after stroke. J Control Release. 2013; 172(1):1-11. DOI: 10.1016/j.jconrel.2013.07.032. View