Liver-targeted polymeric prodrugs of 8-aminoquinolines for malaria radical cure

Srinivasan, Siddarth; Roy, Debashish; Chavas, Thomas E. J.; Vlaskin, Vladimir A.; Ho, Duy‐Khiet; Pottenger, Ayumi; LeGuyader, Clare L. M.; Maktabi, Mahdi; Strauch, Pamela; Jackson, Conner; Flaherty, Siobhan; Lin, Hsiuling; Zhang, Jing; Pybus, Brandon; Li, Qigui; Huber, Hans E.; Burke, Paul A.; Wesche, David; Rochford, Rosemary; Stayton, Patrick S.

doi:10.1016/j.jconrel.2020.12.046

Cited by 10 publications

(18 citation statements)

References 56 publications

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“…Reversible addition–fragmentation chain‐transfer (RAFT) synthesis was used to control the incorporation ratios of the sterically complex prodrug and fluorescein monomers. [ 39,40,57 ] The chemical structure and synthetic route for the PI‐103 prodrug monomer are provided in Figure A. The PI‐103 and fluorescein monomer syntheses were confirmed by 1 H NMR (Figures S1B and S2B, Supporting Information) and mass spectrometry analyses (Figure and, Supporting Information).…”

Section: Resultsmentioning

confidence: 92%

“…The polymeric prodrugs with designable linkers are synthesized using a functionalized monomer approach, providing a new route to incorporating a more sophisticated small molecule drug and linker repertoire, together with the high affinity ligand to direct cell arming, and water solubilizing monomers. [37][38][39][40] This cell backpacking system has been first demonstrated with phosphoinositide 3-kinase (PI3K) inhibitor drugamers to arm GEM therapeutics. The versatility of this arming system was further demonstrated by engineering T cells with the same construct.…”

Section: Introductionmentioning

confidence: 99%

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Arming Immune Cell Therapeutics with Polymeric Prodrugs

Lopez

Brempelis

Matthaei³

et al. 2021

Adv Healthcare Materials

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Engineered immune cells are an exciting therapeutic modality, which survey and attack tumors. Backpacking strategies exploit cell targeting capabilities for delivery of drugs to combat tumors and their immune‐suppressive environments. Here, a new platform for arming cell therapeutics through dual receptor and polymeric prodrug engineering is developed. Macrophage and T cell therapeutics are engineered to express a bioorthogonal single chain variable fragment receptor. The receptor binds a fluorescein ligand that directs cell loading with ligand‐tagged polymeric prodrugs, termed “drugamers.” The fluorescein ligand facilitates stable binding of drugamer to engineered macrophages over 10 days with 80% surface retention. Drugamers also incorporate prodrug monomers of the phosphoinositide‐3‐kinase inhibitor, PI‐103. The extended release of PI‐103 from the drugamer sustains antiproliferative activity against a glioblastoma cell line compared to the parent drug. The versatility and modularity of this cell arming system is demonstrated by loading T cells with a second fluorescein‐drugamer. This drugamer incorporates a small molecule estrogen analog, CMP8, which stabilizes a degron‐tagged transgene to provide temporal regulation of protein activity in engineered T cells. These results demonstrate that this bioorthogonal receptor and drugamer system can be used to arm multiple immune cell classes with both antitumor and transgene‐activating small molecule prodrugs.

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Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Arming Immune Cell Therapeutics with Polymeric Prodrugs

Lopez

Brempelis

Matthaei³

et al. 2021

Adv Healthcare Materials

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“…To overcome or reduce the risk of hemolysis because of G6PD deficiency, Srinivasan et al 99 have given initial consideration to the idea of a non-oral route of drug administration, based on the assumption that TQ acts against hypnozoites. Murine experiments with P. berghei showed that there was reduced drug-associated hemotoxicity when compounds were not administered via the gastrointestinal tract.…”

Section: Drug Injectionmentioning

confidence: 99%

“…The ultimate goal of this ongoing research is to produce a single-dose subcutaneous therapeutic that eliminates hypnozoites but has minimal hemotoxicity in G6PD-deficient humans. 99 …”

Section: Drug Injectionmentioning

confidence: 99%

Safety and Efficacy of Tafenoquine for Plasmodium vivax Malaria Prophylaxis and Radical Cure: Overview and Perspectives

Markus¹

2021

TCRM

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This article is inter alia a brief, first-stop guide to possible adverse events (AEs) associated with tafenoquine (TQ) intake. Safety and efficacy findings for TQ in Plasmodium vivax malaria prophylaxis and radical cure are summarized and some of the latest TQ-related studies (published in 2020 and 2021) are highlighted. In addition, little-known biological and other matters concerning malaria parasites and 8-aminoquinoline (8-AQ) drug action are discussed and some correct terminology pertinent to malaria is explained.

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“…Therefore, the prodrug with disulfide bonds releases the parent drug effectively in tumor cells and improves the drug utilization ( Wang et al, 2020 ; Zuo et al, 2020 ). The design and study of enzyme-triggered polymeric prodrugs have potential clinical applications ( Srinivasan et al, 2021 ; Tan et al, 2021 ). Phospholipases, oxidoreductases, and proteases overexpressed by tumor cells can act as selective triggers for enzyme-sensitive drug delivery vehicles.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in Stimuli-Sensitive Amphiphilic Polymer-Paclitaxel Prodrugs

Zhou

Wen

Wang

et al. 2022

Front. Bioeng. Biotechnol.

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Paclitaxel (PTX) is a broad-spectrum chemotherapy drug employed in the treatment of a variety of tumors. However, the clinical applications of PTX are limited by its poor water solubility. Adjuvants are widely used to overcome this issue. However, these adjuvants often have side effects and poor biodistribution. The smart drug delivery system is a promising strategy for the improvement of solubility, permeability, and stability of drugs, and can promote sustained controlled release, increasing therapeutic efficacy and reducing side effects. Polymeric prodrugs show great advantages for drug delivery due to their high drug loading and stability. There has been some groundbreaking work in the development of PTX-based stimulus-sensitive polymeric prodrug micelles, which is summarized in this study. We consider these in terms of the four main types of stimulus (pH, reduction, enzyme, and reactive oxygen species (ROS)). The design, synthesis, and biomedical applications of stimulus-responsive polymeric prodrugs of PTX are reviewed, and the current research results and future directions of the field are summarized.

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Liver-targeted polymeric prodrugs of 8-aminoquinolines for malaria radical cure

Cited by 10 publications

References 56 publications

Arming Immune Cell Therapeutics with Polymeric Prodrugs

Arming Immune Cell Therapeutics with Polymeric Prodrugs

Safety and Efficacy of Tafenoquine for Plasmodium vivax Malaria Prophylaxis and Radical Cure: Overview and Perspectives

Recent Advances in Stimuli-Sensitive Amphiphilic Polymer-Paclitaxel Prodrugs

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