Surface-Engineered Dendrimeric Nanoconjugates for Macrophage-Targeted Delivery of Amphotericin B: Formulation Development andIn VitroandIn VivoEvaluation

Abstract

The present study aimed to develop an optimized dendrimeric delivery system for amphotericin B (AmB). Fifth-generation (5.0G) poly(propylene imine) (PPI) dendrimers were synthesized, conjugated with mannose, and characterized by use of various analytical techniques, including Fourier transform infrared spectroscopy (FTIR), 1 H nuclear magnetic resonance ( 1 H-NMR) spectroscopic analysis, and atomic force microscopy (AFM). Mannose-conjugated 5.0G PPI (MPPI) dendrimers were loaded with AmB and evaluated for drug loading efficiency, in vitro drug release profile, stability, hemolytic toxicity to human erythrocytes, cytotoxicity to and cell uptake by J774A.1 macrophage cells, antiparasitic activity against intracellular Leishmania donovani amastigotes, in vivo pharmacokinetic and biodistribution profiles, drug localization index, toxicity, and antileishmanial activity. AFM showed the nanometric size of the MPPI dendrimers, with a nearly globular architecture. The conjugate showed a good entrapment efficiency for AmB, along with pHsensitive drug release. Highly significant reductions in toxicity toward human erythrocytes and macrophage cells, without compromising the antiparasitic activity of AmB, were observed. The dendrimeric formulation of AmB showed a significant enhancement of the parasiticidal activity of AmB toward intramacrophagic L. donovani amastigotes. In the in vitro cell uptake studies, the formulation showed selectivity toward macrophages, with significant intracellular uptake. Further pharmacokinetic and organ distribution studies elucidated the controlled delivery behavior of the formulation. The drug localization index was found to increase significantly in macrophage-rich organs. In vivo studies showed a biocompatible behavior of MPPIA, with negligible toxicity even at higher doses, and promising antileishmanial activity. From the results, we concluded that surface-engineered dendrimers may serve as optimized delivery vehicles for AmB with enhanced activity and low or negligible toxicity. Nanomedicine has immense potential in drug delivery because of nanoscale size-derived chemical, physical, and biological properties. Dendritic polymers, including dendrigrafts, dendrimers, and dendrons, are providing new directions in nanomaterialbased drug delivery due to their nanostructure, monodispersity, versatility, well-defined molecular size, tailor-made surface groups, and chemical stability. The unique physicochemical and biological properties of dendrimers are due to their stepwise controlled synthesis, which is accomplished by sequential addition of layers/generations surrounding the core (1-4).Scientists are continuously investigating approaches for targeted delivery of antiparasitic drugs to macrophages because parasites reside and multiply within host macrophages in infectious diseases such as salmonellosis, leishmaniasis, histoplasmosis, listeriosis, cryptococcosis, candidiasis, AIDS, etc. Targeted delivery to macrophages in cases of infectious disease is expected to improve the therapeutic index by...

Perspective: Dendrimer drugs for infection and inflammation

“…This has not proven to be the case because the cost of new drug delivery dendrimer platforms has not been commercially viable when compared to the low cost of the generic small molecule antiinfective drugs being delivered [21]. In this specific context, we have recently shown, in two in vivo mouse model systems, that very small MWt and very well characterised and low cost polymethacrylic acid of MWt 3.52 kDa can be used to effectively deliver amphotericin B to the site of infection for the cure of parasitic (cutaneous leishmaniasis) and fungal (invasive aspergillosis) infections [22,23].…”

Dendrimer Structure Diversity and Tailorability as a Way to Fight Infectious Diseases

“…Such formulation was compared to AmB commercial formulations: Fungizone and AmBisome assessing its toxicity and antiparasitic activity. The results indicated that this dendrimer significantly reduced the haemolytic toxicity of AmB to human erythrocytes, as well as cytotoxicity against J774A.1 macrophage cell line as shown [78]. They reported G5 PPI dendrimer partially end-capped with mannose groups.…”

Development of mannose-anchored Thiolated Amphotericin B Nanocarriers for Treatment of Visceral Leishmaniasis

“…The obligate intracellular Leishmania donovani amastigotes replicate within membrane-bound MP subcellular organelles. Current medical management is not effective for eliciting microbial clearance due to drug resistance, toxicity, bioavailability and cost [2]. Chemotherapy for VL is based on the use of antimony.…”

“…Chemotherapy for VL is based on the use of antimony. However, the emergence of resistance has transformed medical management to the use of amphotericin B (AmB) for VL treatment [2,3]. Notably, targeted intracellular delivery of AmB has now emerged as a first-line medical strategy to facilitate pathogen clearance.…”

“…This idea is based on the target macrophage surface receptor distribution [2–4]. Proof of concept for such an approach includes, but is not limited to, drugs such as muramyl dipeptide, efavirenz and rifampin [5–7].…”