Non-ionic self-assembling amphiphilic polyester dendrimers as new drug delivery excipients

Abstract

Solubility enhancement of poorly soluble antibiotics via self-assembling nano systems could be a promising approach to effectively treat bacterial infections in the current scenario of evolving resistant species. The study in this paper reports the synthesis of novel biocompatible G2 and G3 polyester amphiphilic dendrimers (ADs) (GMOA-G2-OH, GMOA-G3-OH, GMS-G2-OH and GMS-G3-OH) and their application as: (i) solubility enhancers for fusidic acid (FSD) as a model antibiotic with poor aqueous solubility and (ii) as stearic stabilizers in the preparation of solid lipid nanoparticles (SLNs). Two different series of ADs from glycerol monostearate (GMS) and glycerol monooleate (GMOA) were synthesized and their structures were confirmed employing FT-IR, NMR (¹H and ¹³C) and HR-MS. The MTT assay confirmed their non-toxicity to mammalian cells. The critical aggregation concentration value order for ADs was GMS-G3-OH (5 × 10⁻⁶ mol l⁻¹) < GMOA-G3-OH (7 × 10⁻⁶ mol l⁻¹) < GMOA-G2-OH = GMS-G2-OH (5 × 10⁻⁵ mol l⁻¹). All ADs formed micelles in the size range of 6.48 ± 0.04 nm to 12.38 ± 0.36 nm. At 1% w/w concentration FSD solubility enhancement in GMOA-G2-OH, GMOA-G3-OH, GMS-G2-OH and GMS-G3-OH was 43, 11, 9.1 and 6.8-fold respectively compared to water. As GMOA-G2-OH enabled the highest solubility of FSD, it was further evaluated for its antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). The minimum inhibitory concentration values for FSD with and without GMOA-G2-OH against S. aureus were 0.23 μg ml⁻¹ and 0.53 μg ml⁻¹ respectively whereas the values were 0.23 μg ml⁻¹ and 0.39 μg ml⁻¹ against MRSA respectively. These results suggested that GM-OA-G2 not only enhanced the solubility but also enhanced antibacterial potency of FSD. Furthermore, these ADs showed their potential as promising pharmaceutical excipients as they acted as stearic stabilizers in the preparation of SLNs. Using these ADs stable SLNs with zeta potential value in the range of −15.30 ± 1.44 to −38.46 ± 3.04 were formed.