Heparin-Coated Dendronized Hyperbranched Polymers for Antimalarial Targeted Delivery

Abstract

The rampant evolution of resistance in Plasmodium to all existing antimalarial drugs calls for the development of improved therapeutic compounds and of adequate targeted delivery strategies for them. Loading antimalarials in nanocarriers specifically targeted to the parasite will contribute to the administration of lower overall doses, with reduced side effects for the patient, and of higher local amounts to parasitized cells for an increased lethality toward the pathogen. Here, we report the development of dendronized hyperbranched polymers (DHPs), with capacity for antimalarial loading, that are coated with heparin for their specific targeting to red blood cells parasitized by Plasmodium falciparum. The resulting DHP–heparin complexes exhibit the intrinsic antimalarial activity of heparin, with an IC50 of ca. 400 nM, added to its specific targeting to P. falciparum-infected (vs noninfected) erythrocytes. DHP–heparin nanocarriers represent a potentially interesting contribution to the limited family of structures described so far for the loading and targeted delivery of current and future antimalarial compounds.

Progress in Treatment and Diagnostics of Infectious Disease with Polymers

“…147 Heparin coated hyperbranched dendronized polymers were also designed to deliver antimalarial drugs effectively. 148 Polymer-Drug/Peptide Conjugates. Polymers such as PGA, PVA, PLGA, PEG, PAMAM and chitosan are the foremost polymers used to design polymer-drug conjugates to treat malaria.…”

“…Very recently an epitope coated biopolymer (polyhydroxybutyrate) elicited specific binding with surface plasmodium sporozoites and transverse human hepatocytes . Heparin coated hyperbranched dendronized polymers were also designed to deliver antimalarial drugs effectively …”

Nanotherapeutics against malaria: A decade of advancements in experimental models

“…The encapsulated drug displayed higher antiplasmodial activities against a CQ-sensitive (D6) strain of P. falciparum compared to free CQ (IC 50 of 2.41 and 5.81 ng/mL, respectively). Following the same line, San Anselmo et al recently developed different dendronized hyperbranched polymers (DHPs) of bMPA and bGMPA coated with heparin to achieve specific targeting to pRBCs (San Anselmo et al, 2023). The generated DHP-heparin complexes exhibited the intrinsic antimalarial activity of free heparin (IC 50 $ 400 nM) with an improved targeting ability.…”

Pathogen‐binding nanoparticles to inhibit host cell infection by heparan sulfate and sialic acid dependent viruses and protozoan parasites

“…Electrostatically conjugating heparin in the side-on configuration on cationic chitosan NPs or dendrimers also caused these NPs to show invasion inhibitory activity against Plasmodium falciparum, although again no improved activity was found when compared to soluble heparin. 122,124 To build membranous NPs with higher physicochemical stability and a more biomimetic presentation of heparin, polymer-based vesicles (polymersomes) were employed. 125 A block copolymer was synthesized with end-on attached heparin serving as the hydrophilic block, which was subsequently mixed with a vesicle-forming copolymer.…”

“…Thus, the authors shifted their focus to drug delivery, using a combined action of heparin‐liposomes loaded with a conventional antimalarial drug. Electrostatically conjugating heparin in the side‐on configuration on cationic chitosan NPs or dendrimers also caused these NPs to show invasion inhibitory activity against Plasmodium falciparum , although again no improved activity was found when compared to soluble heparin 122,124 . To build membranous NPs with higher physicochemical stability and a more biomimetic presentation of heparin, polymer‐based vesicles (polymersomes) were employed 125 .…”