title: Surface-engineered dendrimeric nanoconjugates for macrophage-targeted delivery of amphotericin B: formulation development and in vitro and in vivo evaluation.
abstract: The present study aimed to develop an optimized dendrimeric delivery system for amphotericin B (AmB). Fifth-generation (5.0 G) 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 5.0 G 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 pH-sensitive 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.
authors: Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour Central University, Sagar, India Pharmaceutical Nanotechnology Laboratory, ISF College of Pharmacy, Moga, India keertijain02@gmail.com jnarendr@yahoo.co.in.
authors: Keerti
authors: K
authors: Jain
authors: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, India.
authors: Ashwni Kumar
authors: AK
authors: Verma
authors: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, India.
authors: Prabhat Ranjan
authors: PR
authors: Mishra
authors: Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour Central University, Sagar, India Pharmaceutical Nanotechnology Laboratory, ISF College of Pharmacy, Moga, India keertijain02@gmail.com jnarendr@yahoo.co.in.
authors: Narendra Kumar
authors: NK
authors: Jain
mesh_terms: D000666:Amphotericin B / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000981:Antiprotozoal Agents / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D016503:Drug Delivery Systems / Q000592:standards; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D058726:Nanoconjugates / Q000737:chemistry*; D011126:Polypropylenes / Q000737:chemistry
chemical_list: D000981:Antiprotozoal Agents; D058726:Nanoconjugates; D011126:Polypropylenes; C443641:poly(propyleneimine); D000666:Amphotericin B
references: J Drug Target. 2007 Jan;15(1):89-98
references: 17365278
references: Biomed Res Int. 2013;2013:150478
references: 23971023
references: Biomed Chromatogr. 2008 Apr;22(4):402-7
references: 18059059
references: J Control Release. 2014 Nov 28;194:341-9
references: 25220160
references: Drug Discov Today. 2013 Dec;18(23-24):1272-81
references: 23973338
references: J Immunol. 1997 Jun 1;158(11):5357-65
references: 9164956
references: Nanomedicine. 2011 Jun;7(3):295-304
references: 21070888
references: J Chromatogr A. 1998 Sep 11;819(1-2):171-6
references: 9781419
references: Biomaterials. 2011 Nov;32(31):8029-39
references: 21807409
references: Int J Pharm. 2010 Jul 15;394(1-2):122-42
references: 20433913
references: Pharm Res. 2009 Dec;26(12):2588-98
references: 19842021
references: J Control Release. 2012 Aug 10;161(3):795-803
references: 22641062
references: Int J Pharm. 2013 Oct 1;454(2):641-8
references: 23726904
references: Int J Nanomedicine. 2013;8:3715-28
references: 24106427
references: Antimicrob Agents Chemother. 2013 Apr;57(4):1714-22
references: 23357762
references: Eur J Pharm Sci. 2013 Mar 12;48(4-5):668-79
references: 23298577
references: Sci Transl Med. 2012 Feb 1;4(119):119re1
references: 22301556
references: J Antimicrob Chemother. 2011 Apr;66(4):874-9
references: 21393222
references: J Drug Target. 2002 Feb;10(1):41-5
references: 11996085
references: J Biomed Nanotechnol. 2013 Jun;9(6):1076-87
references: 23858973
references: Biomaterials. 2008 Aug-Sep;29(24-25):3469-76
references: 18501424
references: J Am Chem Soc. 2013 Jun 19;135(24):9055-77
references: 23692629
references: J Cytol Mol Biol. 2014 Jan 10;1(1):null
references: 24672807
references: Biomaterials. 2012 Jun;33(16):4166-86
references: 22398205
references: Eur J Pharm Biopharm. 2014 Aug;87(3):500-9
references: 24698808
references: Nanomedicine. 2015 Apr;11(3):705-13
references: 25596078
references: J Microencapsul. 1989 Oct-Dec;6(4):427-62
references: 2685222
references: Int J Pharm. 2013 Nov 1;456(1):31-40
references: 23994363
references: J Nanosci Nanotechnol. 2014 Jul;14(7):5075-87
references: 24757983
references: J Control Release. 2010 Oct 1;147(1):118-26
references: 20609375
references: J Drug Target. 2012 Aug;20(7):593-604
references: 22690657
references: Org Biomol Chem. 2013 Sep 14;11(34):5656-65
references: 23877421
references: Proc Natl Acad Sci U S A. 2013 May 28;110(22):8795-800
references: 23671078
references: Curr Opin Pharmacol. 2014 Apr;15:97-106
references: 24598376