Biodegradable functional polycarbonate micelles for controlled release of amphotericin B.
Amphotericin B (AmB), a poorly soluble and toxic antifungal drug, was encapsulated into polymeric micelles self-assembled from phenylboronic acid-functionalized polycarbonate/PEG (PEG-PBC) and urea-functionalized polycarbonate/PEG (PEG-PUC) diblock copolymers via hydrogen-bonding, boronate ester bond, and/or ionic interactions between the boronic acid group in the micellar core and amine group in AmB. Three micellar formulations were prepared: AmB/B micelles using PEG-PBC, AmB/U micelles using PEG-PUC and AmB/B+U mixed micelles using 1:1molar ratio of PEG-PBC and PEG-PUC. The average particle sizes of the micelles were in the range of 54.4-84.8nm with narrow size distribution and zeta potentials close to neutral. UV-Vis absorption analysis indicated that AmB/B micelles significantly reduced AmB aggregation status due to the interactions between AmB and the micellar core, while Fungizone® and AmB/U micelles had no effect. AmB/B+U mixed micelles exerted an intermediate effect. Both AmB/B micelles and AmB/B+U mixed micelles showed sustained drug release, with 48.6±2.1% and 59.2±1.8% AmB released respectively after 24hunder sink conditions, while AmB/U micelles displayed a burst release profile. All AmB-loaded micelles showed comparable antifungal activity to free AmB or Fungizone®, while AmB/B micelles and AmB/B+U mixed micelles were much less hemolytic than other formulations. Histological examination showed that AmB/B and AmB/B+U micelles led to a significantly lower number of apoptotic cells in the kidneys compared to Fungizone®, suggesting reduced nephrotoxicity of the micellar formulations in vivo. These phenylboronic acid-functionalized polymeric micelle systems are promising drug carriers for AmB to reduce non-specific toxicities without compromise in antifungal activity.



There is a pressing need for a novel and cost-effective delivery system to reduce the toxicity induced by the antifungal agent, amphotericin B (AmB). In this study, phenylboronic acid-functionalized polycarbonate/PEG diblock copolymers were used to fabricate micelles for improved AmB-micelle interaction via the manipulation of hydrogen-bonding, boronate ester bond, ionic and hydrophobic interactions. Compared to free AmB and Fungizone®, the resultant micellar systems displayed improved stability while reducing non-specific toxicities without a compromise in antifungal activity. These findings demonstrate the potential of biodegradable functional polycarbonate micellar systems as promising carriers of AmB for the treatment of systemic fungal infections.
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Ying
Y
Wang
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore.
Xiyu
X
Ke
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore.
Zhi Xiang
ZX
Voo
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Serene Si Ling
SSL
Yap
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore.
Chuan
C
Yang
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore.
Shujun
S
Gao
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore.
Shaoqiong
S
Liu
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore.
Shrinivas
S
Venkataraman
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Sybil Akua Okyerewa
SAO
Obuobi
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Jasmeet Singh
JS
Khara
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore. Electronic address: yyyang@ibn.a-star.edu.sg.
Yi Yan
YY
Yang
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Electronic address: phaeplr@nus.edu.sg.
Pui Lai Rachel
PLR
Ee
D000666:Amphotericin B / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001672:Biocompatible Materials / Q000494:pharmacology*; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000494:pharmacology; D065546:Drug Liberation; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D008807:Mice, Inbred BALB C; D008823:Micelles; D008826:Microbial Sensitivity Tests; D010316:Particle Size; D011076:Polycarboxylate Cement / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D013057:Spectrum Analysis; D055672:Static Electricity
D000935:Antifungal Agents; D001672:Biocompatible Materials; D001897:Boronic Acids; D003692:Delayed-Action Preparations; D008823:Micelles; D011076:Polycarboxylate Cement; C005506:polycarbonate; D011092:Polyethylene Glycols; D000666:Amphotericin B; C010686:benzeneboronic acid
Amphotericin B; Phenylboronic acid; Polycarbonate; Polymeric micelles; Systemic fungal infection