Sustained intrathecal delivery of amphotericin B using an injectable and biodegradable thermogel

Area of Science:

• Neuroscience
• Pharmacology
• Biomaterials Science

Background:

• Cryptococcal meningitis has a high mortality rate, with Amphotericin B (AMB) as a primary treatment.
• The blood-brain barrier (BBB) limits effective drug delivery to the brain for meningitis treatment.
• Intrathecal drug delivery offers a direct route to the central nervous system.

Purpose of the Study:

• To develop and evaluate an injectable thermosensitive gel for intrathecal delivery of AMB.
• To assess the in vitro drug release, in vivo neurotoxicity, and therapeutic efficacy of AMB-loaded gel.
• To determine the suitability of PLGA-PEG-PLGA triblock copolymer as a biocompatible carrier for intrathecal drug delivery.

Main Methods:

• Synthesis of AMB-loaded thermosensitive gel using PLGA-PEG-PLGA triblock copolymer.
• In vitro cumulative release studies of AMB from the gel.
• In vivo assessment of AMB neurotoxicity and therapeutic effect following intrathecal administration.
• Characterization of the gel's thermosensitive properties (viscosity and gelation at physiological temperature).

Main Results:

• The AMB-loaded thermosensitive gel exhibited sustained AMB release for 36 days with satisfactory in vitro cumulative release.
• Intrathecal administration of AMB in gel showed reduced neurotoxicity compared to AMB solution.
• The AMB-loaded gel demonstrated a superior therapeutic effect in treating cryptococcal meningitis.
• The PLGA-PEG-PLGA thermogel displayed low viscosity at low temperatures and formed a non-flowing gel at 37°C.

Conclusions:

• Injectable PLGA-PEG-PLGA thermosensitive gel is a promising biocompatible carrier for intrathecal drug delivery.
• This formulation enhances AMB delivery, reduces its neurotoxicity, and improves treatment outcomes for cryptococcal meningitis.
• Thermosensitive hydrogels offer a viable strategy for localized drug delivery across the blood-brain barrier.