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Modification of amphotericin B's therapeutic index by increasing its association with serum high-density lipoproteins
1Department of Cell Biology, Cleveland Clinic Foundation, Ohio 44195.
Abstract:
AmpB remains one of the drugs of choice in the treatment of systemic fungal infection; however, its therapy is limited by the development of renal toxicity. When AmpB was incorporated into negatively charged liposomes composed of DMPC and DMPG (L-AmpB), it was less toxic but as effective as free AmpB. However, the mechanism of L-AmpB's enhanced therapeutic index remains unknown. We have demonstrated that AmpB predominantly associates with HDL when incorporated into positively and negatively charged liposomes. To further understand the therapeutic importance of AmpB predominantly associating with HDL, we next examined the influence of lipoproteins on the antifungal activity and renal cytotoxicity of AmpB. The antifungal activity of AmpB and L-AmpB was not altered in the presence of HDL or LDL. The reduced nephrotoxicity associated with the use of L-AmpB, however, was related to a decreased uptake of AmpB by renal cells when AmpB was associated with HDL, and it may be a result of the low expression of HDL receptors in the LLC PK1 renal cells.
Insights
Amphotericin B (AmpB) liposomes reduce kidney toxicity by decreasing renal cell uptake, potentially due to HDL receptor expression. This improves treatment for systemic fungal infections.
Area of Science:
- Pharmacology
- Toxicology
- Drug Delivery
Background:
- Amphotericin B (AmpB) is a key antifungal drug but causes significant renal toxicity.
- Liposomal formulations (L-AmpB) reduce AmpB toxicity while maintaining efficacy.
- The mechanism behind L-AmpB's improved therapeutic index is not fully understood.
Purpose of the Study:
- To investigate the role of lipoproteins, particularly high-density lipoprotein (HDL), in AmpB's antifungal activity and renal toxicity.
- To elucidate the mechanism by which liposomal encapsulation influences AmpB's interaction with renal cells.
Main Methods:
- Incorporation of AmpB into negatively charged liposomes (L-AmpB).
- Association of AmpB with high-density lipoprotein (HDL) and low-density lipoprotein (LDL).
- Assessment of antifungal activity and renal cytotoxicity of AmpB and L-AmpB in the presence of lipoproteins.
- Evaluation of AmpB uptake by LLC PK1 renal cells.
Main Results:
- AmpB predominantly associates with HDL when incorporated into liposomes.
- Antifungal activity of AmpB and L-AmpB was unaffected by HDL or LDL.
- Reduced nephrotoxicity of L-AmpB correlated with decreased AmpB uptake by renal cells.
- Lower renal cell uptake of HDL-associated AmpB may be due to low HDL receptor expression.
Conclusions:
- AmpB's association with HDL influences its renal toxicity profile.
- Reduced renal uptake of HDL-associated AmpB contributes to its decreased nephrotoxicity.
- Lipoprotein interactions, particularly with HDL, are crucial for understanding L-AmpB's therapeutic benefits.