Targetable water-soluble polymer-drug conjugates for the treatment of visceral leishmaniasis

Nan, A; Croft, SL; Yardley, V; Ghandehari, H; (2004) Targetable water-soluble polymer-drug conjugates for the treatment of visceral leishmaniasis. Journal of controlled release, 94 (1). pp. 115-127. ISSN 0168-3659 DOI:

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The present work describes the synthesis, characterization, and biological evaluation of targetable N-(2- hydroxypropyl)methacrylamide (HPMA) copolymer-anti-leishmanial drug conjugates for the treatment of visceral leishmaniasis (VL). Conjugates of HPMA copolymer with NPC1161, an 8- aminoquinoline analog with anti-leishmanial activity, containing N-acetylmannosamine (ManN) in the side chains were synthesized and characterized. In vitro anti-leishmanial efficacy of the conjugates was determined in mouse peritoneal macrophages infected with Leishmania donovani amastigotes. The conjugates were tested against mammalian KB cells for cytotoxicity. The effect of ManN content on uptake was evaluated in RAW 264 murine macrophages. In vivo anti- leishmanial efficacy was evaluated at 1 mg/kg intravenous dose in BALB/c mice. HPMA copolymer-NPC 1161 conjugates with 5 mole% or higher ManN content were significantly (p < 0.0001) more active (ED50 < 15 mug/ml) than nontargeted conjugates (ED50>30 mug/ml). All conjugates were relatively nontoxic towards the mammalian cells. Significantly (p < 0.003) higher uptake was observed for targeted conjugates compared to nontargeted conjugates. The targeted conjugates were significantly more effective in vivo (67-80% inhibition, p < 0.0001) than nontargeted conjugate (47% inhibition). HPMA copolymers containing ManN in the side chains can potentially reduce the toxicity and increase efficacy of anti-leishmanial drugs for the treatment of VL. (C) 2003 Elsevier B.V. All rights reserved.

Item Type: Article
Keywords: HPMA copolymers, Phagolysosomes, Leishmania donovani, targeted, drug delivery, Visceral leishmaniasis, amphotericin-b, in-vitro, n-(2-hydroxypropyl)methacrylamide, copolymers, free bisphosphonates, delivery system, macrophage-, like, derivatives, parasites, liposomes, cells
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Antimicrobial Resistance Centre (AMR)
Leishmaniasis Group
Neglected Tropical Diseases Network
PubMed ID: 14684276
Web of Science ID: 188289200010


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