Molecular, macromolecular, and supramolecular glucuronide prodrugs: an unexpected lead identified for anticancer prodrug monotherapy.

In this work, we perform tumor growth intervention via localized drug synthesis within the tumor volume, using the enzymatic repertoire of the tumor itself. Towards the overall success, we design molecular, macromolecular, and supramolecular glucuronide prodrugs for a highly potent toxin, monomethyl auristatin E (MMAE). The lead candidate exhibited a fold difference in toxicity between the prodrug and the drug of 175, had an engineered mechanism to enhance the deliverable payload to tumours, and contained a highly potent toxin such that bioconversion of few prodrug molecules created concentration of MMAE sufficient for efficient suppression of tumor growth. Each of these points is highly significant and together afford a safe, selective anticancer measure, making tumor-targeted glucuronides attractive for translational medicine.

[1]  A. Zelikin.  Unique enzymatic repertoire reveals the tumour , 2019, Nature Chemistry.

[2]  P. Poinot,et al.  Volatile Organic Compound (VOC)-Based Probe for Induced Volatolomics of Cancers. , 2019, Angewandte Chemie.

[3]  A. Zelikin,et al.  Extended scaffold glucuronides: en route to the universal synthesis of O-aryl glucuronide prodrugs. , 2019, Organic & biomolecular chemistry.

[4]  Kyung Soo Park,et al.  Cancer nanomedicine for combination cancer immunotherapy , 2019, Nature Reviews Materials.

[5]  T. Yankeelov,et al.  Assessing metastatic potential of breast cancer cells based on EGFR dynamics , 2019, Scientific Reports.

[6]  D. Rognan,et al.  Novel auristatin E‐based albumin‐binding prodrugs with superior anticancer efficacy in vivo compared to the parent compound , 2019, Journal of controlled release : official journal of the Controlled Release Society.

[7]  F. Bénard,et al.  Bench to Bedside: Albumin Binders for Improved Cancer Radioligand Therapies. , 2019, Bioconjugate chemistry.

[8]  M. Grinstaff,et al.  Polymer–drug conjugate therapeutics: advances, insights and prospects , 2018, Nature Reviews Drug Discovery.

[9]  Yatin R. Gokarn,et al.  Non-invasive delivery strategies for biologics , 2018, Nature Reviews Drug Discovery.

[10]  M. J. Olesen,et al.  Bi‐Enzymatic Embolization Beads for Two‐Armed Enzyme‐Prodrug Therapy , 2018, Advanced Therapeutics.

[11]  Fabian Kiessling,et al.  Tumor targeting via EPR: Strategies to enhance patient responses. , 2018, Advanced drug delivery reviews.

[12]  S. Wulhfard,et al.  Enhanced Therapeutic Activity of Non-Internalizing Small-Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination with Targeted Interleukin-2 , 2018, Clinical Cancer Research.

[13]  Dario Neri,et al.  Chemically Defined Antibody- and Small Molecule-Drug Conjugates for in Vivo Tumor Targeting Applications: A Comparative Analysis. , 2018, Journal of the American Chemical Society.

[14]  F. Borgna,et al.  Synthesis, Radiolabeling, and Characterization of Plasma Protein-Binding Ligands: Potential Tools for Modulation of the Pharmacokinetic Properties of (Radio)Pharmaceuticals. , 2017, Bioconjugate chemistry.

[15]  Jarkko Rautio,et al.  Prodrugs in medicinal chemistry and enzyme prodrug therapies , 2017, Advanced drug delivery reviews.

[16]  A. Zelikin,et al.  Recent advances in macromolecular prodrugs , 2017 .

[17]  Sur Sharma,et al.  Antibody Directed Enzyme Prodrug Therapy (ADEPT): Trials and tribulations , 2017, Advanced drug delivery reviews.

[18]  A. Annala,et al.  Cell‐mediated enzyme prodrug cancer therapies , 2017, Advanced drug delivery reviews.

[19]  A. Zelikin,et al.  Enzyme prodrug therapies and therapeutic enzymes. , 2017, Advanced drug delivery reviews.

[20]  A. Zelikin,et al.  Substrate mediated enzyme prodrug therapy , 2017, Advanced drug delivery reviews.

[21]  P. Poinot,et al.  Targeting the tumour microenvironment with an enzyme-responsive drug delivery system for the efficient therapy of breast and pancreatic cancers† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc00472a Click here for additional data file. , 2017, Chemical science.

[22]  J. Zweier,et al.  Synthesis and Characterization of PEGylated Trityl Radicals: Effect of PEGylation on Physicochemical Properties. , 2017, The Journal of organic chemistry.

[23]  Anne Marie Healy,et al.  Materials and methods for delivery of biological drugs. , 2016, Nature chemistry.

[24]  T. Kruse,et al.  Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. , 2015, Journal of medicinal chemistry.

[25]  F. Szoka,et al.  The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy. , 2015, Advanced drug delivery reviews.

[26]  Karly P Garnock-jones.  Naloxegol: A Review of Its Use in Patients with Opioid-Induced Constipation , 2015, Drugs.

[27]  J. Zweier,et al.  Characterization of the Binding of the Finland Trityl Radical with Bovine Serum Albumin. , 2014, RSC advances.

[28]  Gregory L. Szeto,et al.  Structure-based programming of lymph-node targeting in molecular vaccines , 2014, Nature.

[29]  X. Meng,et al.  Glucuronides from metabolites to medicines: a survey of the in vivo generation, chemical synthesis and properties of glucuronides. , 2013, Natural product reports.

[30]  J. Zweier,et al.  Esterified dendritic TAM radicals with very high stability and enhanced oxygen sensitivity. , 2013, The Journal of organic chemistry.

[31]  P. Senter,et al.  The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma , 2012, Nature Biotechnology.

[32]  Felix Kratz,et al.  Impact of albumin on drug delivery--new applications on the horizon. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[33]  W. Wilson,et al.  Targeting hypoxia in cancer therapy , 2011, Nature Reviews Cancer.

[34]  B. Sammet.  4-Nitrophenyl Chloroformate: AVersatile Coupling Reagent , 2009 .

[35]  Richard B Greenwald,et al.  Effective drug delivery by PEGylated drug conjugates. , 2003, Advanced drug delivery reviews.

[36]  S. Brüsselbach,et al.  Secreted human β-glucuronidase: a novel tool for gene-directed enzyme prodrug therapy , 2000, Gene Therapy.

[37]  H. Kroemer,et al.  Elucidation of the mechanism enabling tumor selective prodrug monotherapy. , 1998, Cancer research.

[38]  J. Backman,et al.  The Role of β-Glucuronidase in Drug Disposition and Drug Targeting in Humans , 1997 .

[39]  J. Katzenellenbogen,et al.  A novel connector linkage applicable in prodrug design. , 1981, Journal of medicinal chemistry.