Amphotericin B LIPOMER for Enhanced Splenic Delivery

Nagarsekar, Kalpa; Galdhar, C. N.; Gaikwad, R. V.; Samad, Abdul; Devarajan, Padma V.

doi:10.2174/2210303104666140807232823

Cited by 6 publications

(4 citation statements)

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“…The stearate–polymer combination was designed as LIPOMER (lipid polymer hybrid nanoparticles) using three stearates, namely, stearic acid (SA), glyceryl monostearate (GMS), and polyglyceryl-6-distearate (PGDS) with GZ. LIPOMER using GMS and PGDS for targeted delivery of AmB, doxycycline hydrochloride, rifampicin, and doxorubicin hydrochloride, reported earlier by our group, confirms the feasibility of combining stearates with GZ. To understand the role of stearate lipids and GZ on AmB aggregation state, solid lipid nanoparticles (SLNs) of AmB using only the three stearate lipids and only GZ nanoparticles were also prepared.…”

Section: Introductionsupporting

confidence: 81%

“…The DSC thermogram of AmB showed a gradual dip from 80 °C with an endothermic peak at 115.63 and 202.64 °C reflecting drug decomposition without melting, , while the lipids demonstrated sharp endothermic peaks between 50 and 70 °C. The freeze-dried blank and AmB loaded nanoformulations demonstrated a reduction in the intensity of the sharp lipid endotherms and a drastic decrease in enthalpy values, which indicated that nanoparticle formation was associated with decreased crystallinity of the lipids (Figure a–c).…”

Section: Resultsmentioning

confidence: 99%

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Enhancing Safety and Efficacy by Altering the Toxic Aggregated State of Amphotericin B in Lipidic Nanoformulations

Das

Devarajan

2020

Mol. Pharmaceutics

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The toxicity of Amphotericin B (AmB) is contributed by the small, water-soluble aggregates of the drug. Hence, AmB lipid polymer hybrid nanoparticles (LIPOMER), comprising stearate lipids with a hydrophilic polymer Gantrez (GZ), and solid lipid nanoparticles (SLN), comprising only stearates, were prepared with the objective of monomerizing AmB. While intercalation of stearates with the hydrophobic polyene chain could hinder AmB–AmB interactions, enabling monomerization, it was hypothesized that GZ could aid in the stabilization of the monomers through hydrophilic interactions. AmB LIPOMERs and SLNs, prepared by nanoprecipitation, exhibited an average size of 350–500 nm with negative ζ potential. Polyglyceryl-6-distearate (PGDS) SLN exhibited maximum monomerization, with the highest peak IV (410 nm) to peak I (350 nm) ratio in the UV–visible spectrum. In total contrast, LIPOMERs and GZ nanoparticles revealed a hypsochromic shifted peak I between 321 and 324 nm, indicative of AmB super-aggregate formation. Super-aggregates, which result due to condensation of multiple aggregates with monomers, were attributed to extensive GZ–AmB and GZ–GZ interactions and could provide advantages of enhanced thermodynamic stability, with safety and efficacy similar to the monomeric form. Safety was confirmed by low and comparable erythrocyte toxicity exhibited by the LIPOMERs and SLNs. An in vitro efficacy study of PGDS LIPOMER and SLN against intracellular amastigotes revealed significantly lower IC50 values, which translated to a 7.1- and 6.1-fold enhancement in efficacy compared to commercial nanoformulations Amfocare (micellar AmB) and 1.79- and 1.54-fold enhancement in efficacy compared to Fungisome (liposomal AmB). High efficacy coupled with a higher selectivity index indicated the superiority of the developed AmB nanoformulations and substantiated that altering the toxic aggregated state of AmB can offer a promising approach for the design of safe and efficacious AmB lipidic nanoformulations.

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Section: Introductionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Enhancing Safety and Efficacy by Altering the Toxic Aggregated State of Amphotericin B in Lipidic Nanoformulations

Das

Devarajan

2020

Mol. Pharmaceutics

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“…as polymer in rat, rabbit, and dog [25,40]. Later, they also demonstrated enhanced splenic uptake of amphotericin B-loaded GMS LIPOMER in rats [82]. Irregular shape was cited as the reason for enhanced splenic uptake of GMS LIPOMER.…”

Section: Isolated Hepatic and Splenic Cells In Suspensionmentioning

confidence: 95%

Nanocarriers for spleen targeting: anatomo-physiological considerations, formulation strategies and therapeutic potential

Jindal

2016

Drug Deliv. and Transl. Res.

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There are several clinical advantages of spleen targeting of nanocarriers. For example, enhanced splenic concentration of active agents could provide therapeutic benefits in spleen resident infections and hematological disorders including malaria, hairy cell leukemia, idiopathic thrombocytopenic purpura, and autoimmune hemolytic anemia. Furthermore, spleen delivery of immunosuppressant agents using splenotropic carriers may reduce the chances of allograft rejection in organ transplantation. Enhanced concentration of radiopharmaceuticals in the spleen may improve visualization of the organ, which could provide benefit in the diagnosis of splenic disorders. Unique anatomical features of the spleen including specialized microvasculature environment and slow blood circulation rate enable it an ideal drug delivery site. Because there is a difference in blood flow between spleen and liver, splenic delivery is inversely proportional to the hepatic uptake. It is therefore desirable engineering of nanocarriers, which, upon intravenous administration, can avoid uptake by hepatic Kupffer cells to enhance splenic localization. Stealth and non-spherical nanocarriers have shown enhanced splenic delivery of active agents by avoiding hepatic uptake. The present review details the research in the field of splenotropy. Formulation strategies to design splenotropic drug delivery systems are discussed. The review also highlights the clinical relevance of spleen targeting of nanocarriers and application in diagnostics.

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“…3A) revealed two broad peaks 115.63 °C and 202.64 °C for AmB, corroborated earlier reports. 31,32 The disappearance of these characteristic peaks in the AmB-ACEM LIPOMER suggests decreased crystallinity and partial amorphization of AmB in the NPs. Such a decrease indicates enhanced dissolution.…”

Section: Dsc and Xrd Analysesmentioning

confidence: 99%

Is receptor mediated active macrophage targeting of amphotericin B nanoformulations a promising approach?

Das,

Todke,

Madkaikar

et al. 2024

RSC Pharm.

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Amphotericin B LIPOMER for Enhanced Splenic Delivery

Cited by 6 publications

References 0 publications

Enhancing Safety and Efficacy by Altering the Toxic Aggregated State of Amphotericin B in Lipidic Nanoformulations

Enhancing Safety and Efficacy by Altering the Toxic Aggregated State of Amphotericin B in Lipidic Nanoformulations

Nanocarriers for spleen targeting: anatomo-physiological considerations, formulation strategies and therapeutic potential

Is receptor mediated active macrophage targeting of amphotericin B nanoformulations a promising approach?

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