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Cascade-targeting polymeric particles eliminate intracellular C. neoformans in fungal infection therapy
Yinglan Yu1, Xuefeng Tang2, Liya Zhou1
1College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
Abstract:
C. neoformans, a life-threatening invasive fungal pathogen, can hijack the pulmonary macrophages as 'Trojan horse', leading to cryptococcal meningitis and recurrence. Combatting these elusive fungi has posed a long-standing challenge. Here, we report an inhaled cascade-targeting drug delivery platform that can sequentially target host cells and intracellular fungi. The delivery system involves encapsulating amphotericin B (AMB) into polymeric particles decorated with AMB, creating a unique surface pattern, denoted as APP@AMB. The surface topology of APP@AMB guides the efficient macrophages internalization and intracellular drugs accumulation. Following endocytosis, the surface-functionalized AMB specifically targets intracellular fungi by binding to ergosterol in the fungal membrane, as demonstrated through co-localization studies using confocal microscopy. Through on-site AMB delivery, APP@AMB displays superior efficacy in eliminating C. neoformans in the lungs and brain compared to free AMB following inhalation in infected mice. Additionally, APP@AMB significantly alleviates the nephrotoxicity associated with free AMB inhalation therapy. Thus, this biocompatible delivery system enabling host cells and intracellular fungi targeting in a cascade manner, provides a new avenue for the therapy of fungal infection.
Insights
A novel inhaled drug delivery system, APP@AMB, effectively targets pulmonary macrophages and intracellular fungi, offering a promising new therapy for fungal infections with reduced toxicity.
Area of Science:
- Mycology
- Nanotechnology
- Pharmacology
Background:
- Cryptococcus neoformans (C. neoformans) is a dangerous fungal pathogen that can infect the lungs and brain.
- Pulmonary macrophages can be exploited by C. neoformans, leading to cryptococcal meningitis and recurrent infections.
- Developing effective treatments against C. neoformans remains a significant challenge.
Purpose of the Study:
- To develop an inhaled drug delivery platform for sequential targeting of host cells and intracellular fungi.
- To create a novel nanoparticle system, APP@AMB, for enhanced delivery of amphotericin B (AMB).
Main Methods:
- Amphotericin B (AMB) was encapsulated into polymeric particles and surface-decorated with AMB, forming APP@AMB.
- The APP@AMB system was designed for efficient macrophage internalization and intracellular drug accumulation.
- Confocal microscopy was used to confirm the specific targeting of intracellular fungi by surface-functionalized AMB via ergosterol binding.
Main Results:
- APP@AMB demonstrated superior efficacy in eliminating C. neoformans in the lungs and brain compared to free AMB in infected mice.
- The delivery system facilitated targeted on-site AMB delivery to intracellular fungi.
- APP@AMB significantly reduced the nephrotoxicity commonly associated with free AMB inhalation therapy.
Conclusions:
- The APP@AMB platform enables cascade targeting of host cells and intracellular fungi.
- This biocompatible delivery system presents a novel therapeutic strategy for invasive fungal infections.
- The study highlights a promising approach to combat C. neoformans with improved safety and efficacy.
