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    Drug Delivery

    (M-485) A Modified Enzyme-Cleavable Peptide Linker on Liver-Targeted Polymeric Prodrugs for the Radical Cure of Plasmodium vivax Malaria

    Saturday, October 14, 2023
    9:30 AM – 10:30 AM PDT
    Location: Exhibit Hall - Row M - Poster # 485
    Introduction::

    Roughly 2.5 billion people live within the geographical range of Plasmodium vivax malaria transmission (1, 2). Infection can result in dormant, liver-stage hypnozoites which cause recurring bouts of malaria. Tafenoquine (TQ) was approved in 2018 as only the second “radical cure” drug which clears liver-stage hypnozoites. A single oral dose of TQ is sufficient to eliminate hypnozoites. However, TQ is contraindicated in individuals with G6PD-deficiency due to the risk of hemotoxicity leading to hemolytic anemia. This contraindication prevents mass administration without G6PD deficiency diagnostics, a difficulty in resource-poor regions. Previous work describes polymeric drug carriers synthesized to deliver TQ to hepatocytes while avoiding premature drug release in circulation (3). These polymers utilized a N-acetylgalactosamine (GalNAc) targeting moiety as well as the clinically validated valine-citrulline-PABC linker which is cleaved by the intracellular enzyme cathepsin. Here, alternative peptide linker designs and polymers with varying molecular weights were synthesized and their ability to alter the pharmacokinetic (PK) profile as well as improve the therapeutic index of TQ was explored.




    Materials and Methods::

    Pharmacokinetic studies in mice were performed and drug release in plasma and liver was quantified via LCMS/MS to identify the lead polymer design. Improvements in prophylactic anti-parasite activity were demonstrated by dosing mice with polymer or oral TQ prior to inoculation with Plasmodium berghei parasites. Lastly, NOD/SCID mice engrafted with G6PD-deficient human red blood cells were dosed with polymer in order to study the hemotoxic effects of the polymer relative to oral free TQ.



    Results, Conclusions, and Discussions::

    Of the polymers studied, the best linker design was the valine-citrulline peptide sequence without the PABC spacer. The optimal molecular weight was roughly 14 kDa. This design showed improved liver:plasma drug exposure, efficacy against P. berghei after one dose, and reduced hemotoxicity in the G6PD-deficient mouse model. Taken together, this linker incorporated into a polymeric drug carrier shows potential for P. vivax eradication campaigns.



    Acknowledgements (Optional): : This work was supported by the Bill and Melinda Gates Foundation.

    References (Optional): :

    1.            Global Malaria Programme. (World Health Organization, Geneva, 2022), vol. License: CC BY-NC-SA 3.0 IGO.


    2.            K. E. Battle et al., Mapping the global endemicity and clinical burden of Plasmodium vivax, 2000-17: a spatial and temporal modelling study. Lancet 394, 332-343 (2019).


    3.            S. Srinivasan et al., Liver-targeted polymeric prodrugs of 8-aminoquinolines for malaria radical cure. J Control Release 331, 213-227 (2020).