Cell-mediated enzyme prodrug cancer therapies

Mooney, Rachael; Majid, Asma Abdul; Batalla, Jennifer; Annala, Alexander J.; Aboody, Karen S.

doi:10.1016/j.addr.2017.09.003

“…Owing to their immune-privilege and tumour-nesting properties, mesenchymal stem cells (MSCs) have been explored as cellular vehicles for cell-directed enzyme prodrug therapy (CDEPT) in targeting GBM [11][12][13][14][15]. CDEPT is one of the safer alternatives to conventional chemotherapy as it overcomes dose-limiting toxicities by enabling maximum cytotoxic effect at the vicinity of tumours through the in situ conversion of a non-toxic prodrug into active drug [16,17]. Proof-of-concept and safety was reported in a first-in-human study (NCT01172964) where a neural stem cell (NSC)-mediated cytosine deaminase/5-fluorocytosine (CD/5FC) prodrug system was tested in patients with recurrent GBM [18].…”

Section: Introductionmentioning

confidence: 99%

A facile and scalable in production non-viral gene engineered mesenchymal stem cells for effective suppression of temozolomide-resistant (TMZR) glioblastoma growth

Tu

¹

,

Ho

²

,

Ng

³

et al. 2020

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Background Mesenchymal stem cells (MSCs) serve as an attractive vehicle for cell-directed enzyme prodrug therapy (CDEPT) due to their unique tumour-nesting ability. Such approach holds high therapeutic potential for treating solid tumours including glioblastoma multiforme (GBM), a devastating disease with limited effective treatment options. Currently, it is a common practice in research and clinical manufacturing to use viruses to deliver therapeutic genes into MSCs. However, this is limited by the inherent issues of safety, high cost and demanding manufacturing processes. The aim of this study is to identify a facile, scalable in production and highly efficient non-viral method to transiently engineer MSCs for prolonged and exceptionally high expression of a fused transgene: yeast cytosine deaminase::uracil phosphoribosyl-transferase::green fluorescent protein (CD::UPRT::GFP). Methods MSCs were transfected with linear polyethylenimine using a cpg-free plasmid encoding the transgene in the presence of a combination of fusogenic lipids and β tubulin deacetylase inhibitor (Enhancer). Process scalability was evaluated in various planar vessels and microcarrier-based bioreactor. The transfection efficiency was determined with flow cytometry, and the therapeutic efficacy of CD::UPRT::GFP expressing MSCs was evaluated in cocultures with temozolomide (TMZ)-sensitive or TMZ-resistant human glioblastoma cell lines. In the presence of 5-fluorocytosine (5FC), the 5-fluorouracil-mediated cytotoxicity was determined by performing colometric MTS assay. In vivo antitumor effects were examined by local injection into subcutaneous TMZ-resistant tumors implanted in the athymic nude mice. Results At > 90% transfection efficiency, the phenotype, differentiation potential and tumour tropism of MSCs were unaltered. High reproducibility was observed in all scales of transfection. The therapeutically modified MSCs displayed strong cytotoxicity towards both TMZ-sensitive and TMZ-resistant U251-MG and U87-MG cell lines only in the presence of 5FC. The effectiveness of this approach was further validated with other well-characterized and clinically annotated patient-derived GBM cells. Additionally, a long-term suppression (> 30 days) of the growth of a subcutaneous TMZ-resistant U-251MG tumour was demonstrated. Conclusions Collectively, this highly efficient non-viral workflow could potentially enable the scalable translation of therapeutically engineered MSC for the treatment of TMZ-resistant GBM and other applications beyond the scope of this study.

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“…Such localized drug synthesis has been accomplished by enzyme prodrug therapies (EPT) that differ in the approach to localize the enzyme at the tumor site. Most notably, this localization has been accomplished using antibodies, localized gene expression, and/or by engineering enzymes into implantable biomaterials . An elegant, unique strategy for therapeutic cancer intervention lies in using the enzymatic repertoire of the tumor itself, by an innate, disease‐mediated EPT ( i ‐EPT, Scheme ) .…”

Section: Methodsmentioning

confidence: 99%

Molecular, Macromolecular, and Supramolecular Glucuronide Prodrugs: Lead Identified for Anticancer Prodrug Monotherapy

Olesen

¹

,

Walther

²

,

Poier

³

et al. 2020

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In this work, a tumor growth intervention by localized drug synthesis within the tumor volume, using the enzymatic repertoire of the tumor itself, is presented. Towards the overall success, molecular, macromolecular, and supramolecular glucuronide prodrugs were designed 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 only a few prodrug molecules created a concentration of MMAE sufficient enough 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.

show abstract

“…Such localized drug synthesis has been accomplished by enzyme prodrug therapies (EPT) that differ in the approach to localize the enzyme at the tumor site. Most notably, this localization has been accomplished using antibodies, localized gene expression, and/or by engineering enzymes into implantable biomaterials . An elegant, unique strategy for therapeutic cancer intervention lies in using the enzymatic repertoire of the tumor itself, by an innate, disease‐mediated EPT ( i ‐EPT, Scheme ) .…”

Section: Methodsmentioning

confidence: 99%

Molecular, Macromolecular, and Supramolecular Glucuronide Prodrugs: Lead Identified for Anticancer Prodrug Monotherapy

Olesen

¹

,

Walther

²

,

Poier

³

et al. 2020

View full text Add to dashboard Cite

In this work, a tumor growth intervention by localized drug synthesis within the tumor volume, using the enzymatic repertoire of the tumor itself, is presented. Towards the overall success, molecular, macromolecular, and supramolecular glucuronide prodrugs were designed 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 only a few prodrug molecules created a concentration of MMAE sufficient enough 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.

show abstract

Cell-mediated enzyme prodrug cancer therapies

Cited by 48 publications

References 187 publications

A facile and scalable in production non-viral gene engineered mesenchymal stem cells for effective suppression of temozolomide-resistant (TMZR) glioblastoma growth

A facile and scalable in production non-viral gene engineered mesenchymal stem cells for effective suppression of temozolomide-resistant (TMZR) glioblastoma growth

Molecular, Macromolecular, and Supramolecular Glucuronide Prodrugs: Lead Identified for Anticancer Prodrug Monotherapy

Molecular, Macromolecular, and Supramolecular Glucuronide Prodrugs: Lead Identified for Anticancer Prodrug Monotherapy

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