Prodrug Cancer Therapy Research Articles

Novel Prodrug Strategies for the Treatment of Tuberculosis.

The emergence of drug-resistant strains of Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis, is on the rise and increasing antimicrobial resistance is a global threat. This phenomenon necessitates new drug design methods such as a prodrug strategy to develop novel antitubercular agents. The prodrug strategy is a viable and useful means to improve the absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles of pharmacologically active agents. Granulomas are a pathological hallmark of M.tb infection and bear a remarkable resemblance to the tumour microenvironment, including regions of hypoxia. The hypoxic environment observed in the two structures offer an exceptional opportunity to deliver antitubercular agents selectively in a similar manner to hypoxia activated prodrugs in cancer therapy. Nitroimidazoles have been studied extensively as bioactivated prodrugs of cancer, and their suitability as substrates for mammalian reductases highlight their huge potential. This review will discuss the mechanism of action and resistance mechanisms of the current prodrugs used for the treatment of tuberculosis. It will also highlight the potential advantages and challenges of using hypoxia activated prodrugs as a viable strategy to target latent M.tb in hypoxic regions of granulomas.

In vitro evaluation of novel SN-38 prodrug activated by α-rhamnosidase of exogenous enzyme.

This study introduces the α-rhamnose (Rham)-conjugated prodrug of SN-38 (Rham-SN-38) as a promising alternative to irinotecan. α-rhamnosidase, responsible for SN-38 release from Rham-SN-38, does not express in human cells, minimizing individual variability and side effects. The injection of the α-rhamnosidase into the tumor tissues makes it possible, for the first time, to activate the Rham-SN-38. Furthermore, α-rhamnosidase demonstrates significantly higher activity than carboxylesterase, the specific enzyme activating irinotecan. SN-38 release mediated by α-rhamnosidase completes within 2h, with a kcat/Km value approximately 5.0 × 104-fold higher than that of irinotecan. The 50% inhibition concentration (IC50) of Rham-SN-38 against three types of cancer cells and one normal cell exceeds 4.5 × 103nM. The addition of α-rhamnosidase significantly increases cytotoxicity, with IC50 comparable to free SN-38. The QIC50, an index reflecting the difference in cytotoxicity with and without α-rhamnosidase, exceeds approximately 1.0 × 102-fold. Rham-SN-38, synthesized in this study, demonstrates significant potential as a prodrug for cancer therapy.

The Catalysis Mechanism of E. coli Nitroreductase A, a Candidate for Gene-Directed Prodrug Therapy: Potentiometric and Substrate Specificity Studies.

E. coli nitroreductase A (NfsA) is a candidate for gene-directed prodrug cancer therapy using bioreductively activated nitroaromatic compounds (ArNO2). In this work, we determined the standard redox potential of FMN of NfsA to be -215 ± 5 mV at pH 7.0. FMN semiquinone was not formed during 5-deazaflavin-sensitized NfsA photoreduction. This determines the two-electron character of the reduction of ArNO2 and quinones (Q). In parallel, we characterized the oxidant specificity of NfsA with an emphasis on its structure. Except for negative outliers nitracrine and SN-36506, the reactivity of ArNO2 increases with their electron affinity (single-electron reduction potential, E17) and is unaffected by their lipophilicity and Van der Waals volume up to 386 Å. The reactivity of quinoidal oxidants is not clearly dependent on E17, but 2-hydroxy-1,4-naphthoquinones were identified as positive outliers and a number of compounds with diverse structures as negative outliers. 2-Hydroxy-1,4-naphthoquinones are characterized by the most positive reaction activation entropy and the negative outlier tetramethyl-1,4-benzoquinone by the most negative. Computer modelling data showed that the formation of H bonds with Arg15, Arg133, and Ser40, plays a major role in the binding of oxidants to reduced NfsA, while the role of the π-π interaction of their aromatic structures is less significant. Typically, the calculated hydride-transfer distances during ArNO2 reduction are smallwer than for Q. This explains the lower reactivity of quinones. Another factor that slows down the reduction is the presence of positively charged aliphatic substituents.

Bioengineered chimeric tRNA/pre-miRNAs as prodrugs in cancer therapy.

Today, biologic prodrugs have led to targeting specific tumor markers and have increased specificity and selectivity in cancer therapy. Various studies have shown the role of ncRNAs in cancer pathology and tumorigenesis and have suggested that ncRNAs, especially miRNAs, are valuable molecules in understanding cancer biology and therapeutic processes. Most miRNAs-based research and treatment are limited to chemically synthesized miRNAs. Synthetic alterations in these miRNA mimics may affect their folding, safety profile, and even biological activity. However, despite synthetic miRNA mimics produced by automated systems, various carriers could be used to achieve efficient production of bioengineered miRNAs through economical microbial fermentation. These bioengineered miRNAs as biological prodrugs could provide a new approach for safe therapeutic methods and drug production. In this regard, bioengineered chimeric miRNAs could be selectively processed to mature miRNAs in different types of cancer cells by targeting the desired gene and regulating cancer progression. In this article, we aim to review bioengineered miRNAs and their use in cancer therapy, as well as offering advances in this area, including the use of chimeric tRNA/pre-miRNAs.

Increased Enzyme Loading in PICsomes via Controlling Membrane Permeability Improves Enzyme Prodrug Cancer Therapy Outcome.

Mesoscopic-sized polyion complex vesicles (PICsomes) with semi-permeable membranes are promising nanoreactors for enzyme prodrug therapy (EPT), mainly due to their ability to accommodate enzymes in their inner cavity. Increased loading efficacy and retained activity of enzymes in PICsomes are crucial for their practical application. Herein, a novel preparation method for enzyme-loaded PICsomes, the stepwise crosslinking (SWCL) method, was developed to achieve both high feed-to-loading enzyme efficiency and high enzymatic activity under in vivo conditions. Cytosine deaminase (CD), which catalyzes the conversion of the 5-fluorocytosine (5-FC) prodrug to cytotoxic 5-fluorouracil (5-FU), was loaded into PICsomes. The SWCL strategy enabled a substantial increase in CD encapsulation efficiency, up to ~44% of the feeding amount. CD-loaded PICsomes (CD@PICsomes) showed prolonged blood circulation to achieve appreciable tumor accumulation via enhanced permeability and retention effect. The combination of CD@PICsomes and 5-FC produced superior antitumor activity in a subcutaneous model of C26 murine colon adenocarcinoma, even at a lower dose than systemic 5-FU treatment, and showed significantly reduced adverse effects. These results reveal the feasibility of PICsome-based EPT as a novel, highly efficient, and safe cancer treatment modality.

Stimulus-responsive self-assembled prodrugs in cancer therapy.

Small-molecule prodrugs have become the main toolbox to improve the unfavorable physicochemical properties of potential therapeutic compounds in contemporary anti-cancer drug development. Many approved small-molecule prodrugs, however, still face key challenges in their pharmacokinetic (PK) and pharmacodynamic (PD) properties, thus severely restricting their further clinical applications. Self-assembled prodrugs thus emerged as they could take advantage of key benefits in both prodrug design and nanomedicine, so as to maximize drug loading, reduce premature leakage, and improve PK/PD parameters and targeting ability. Notably, temporally and spatially controlled release of drugs at cancerous sites could be achieved by encoding various activable linkers that are sensitive to chemical or biological stimuli in the tumor microenvironment (TME). In this review, we have comprehensively summarized the recent progress made in the development of single/multiple-stimulus-responsive self-assembled prodrugs for mono- and combinatorial therapy. A special focus was placed on various prodrug conjugation strategies (polymer–drug conjugates, drug–drug conjugates, etc.) that facilitated the engineering of self-assembled prodrugs, and various linker chemistries that enabled selective controlled release of active drugs at tumor sites. Furthermore, some polymeric nano-prodrugs that entered clinical trials have also been elaborated here. Finally, we have discussed the bottlenecks in the field of prodrug nanoassembly and offered potential solutions to overcome them. We believe that this review will provide a comprehensive reference for the rational design of effective prodrug nanoassemblies that have clinic translation potential.

Enzyme prodrug therapy: cytotoxic potential of paracetamol turnover with recombinant horseradish peroxidase

Targeted cancer treatment is a promising, less invasive alternative to chemotherapy as it is precisely directed against tumor cells whilst leaving healthy tissue unaffected. The plant-derived enzyme horseradish peroxidase (HRP) can be used for enzyme prodrug cancer therapy with indole-3-acetic acid or the analgesic paracetamol (acetaminophen). Oxidation of paracetamol by HRP in the presence of hydrogen peroxide leads to N-acetyl-p-benzoquinone imine and polymer formation via a radical reaction mechanism. N-acetyl-p-benzoquinone imine binds to DNA and proteins, resulting in severe cytotoxicity. However, plant HRP is not suitable for this application since the foreign glycosylation pattern is recognized by the human immune system, causing rapid clearance from the body. Furthermore, plant-derived HRP is a mixture of isoenzymes with a heterogeneous composition. Here, we investigated the reaction of paracetamol with defined recombinant HRP variants produced in E. coli, as well as plant HRP, and found that they are equally effective in paracetamol oxidation at a concentration ≥ 400 µM. At low paracetamol concentrations, however, recombinant HRP seems to be more efficient in paracetamol oxidation. Yet upon treatment of HCT-116 colon carcinoma and FaDu squamous carcinoma cells with HRP–paracetamol no cytotoxic effect was observed, neither in the presence nor absence of hydrogen peroxide.Graphic abstract

Potential of unglycosylated horseradish peroxidase variants for enzyme prodrug cancer therapy

Fighting cancer still relies on chemo- and radiation therapy, which is a trade-off between effective clearance of malignant cells and severe side effects on healthy tissue. Targeted cancer treatment on the other hand is a promising and refined strategy with less systemic interference. The enzyme horseradish peroxidase (HRP) exhibits cytotoxic effects on cancer cells in combination with indole-3-acetic acid (IAA). However, the plant-derived enzyme is out of bounds for medical purposes due to its foreign glycosylation pattern and resulting rapid clearance and immunogenicity. In this study, we generated recombinant, unglycosylated HRP variants in Escherichia coli using random mutagenesis and investigated their biochemical properties and suitability for cancer treatment. The cytotoxicity of the HRP-IAA enzyme prodrug system was assessed in vitro with HCT-116 human colon, FaDu human nasopharyngeal squamous cell carcinoma and murine colon adenocarcinoma cells (MC38). Extensive cytotoxicity was shown in all three cancer cell lines: the cell viability of HCT-116 and MC38 cells treated with HRP-IAA was below 1% after 24 h incubation and the surviving fraction of FaDu cells was ≤ 10% after 72 h. However, no cytotoxic effect was observed upon in vivo intratumoral application of HRP-IAA on a MC38 tumor model in C57BL/6J mice. However, we expect that targeting of HRP to the tumor by conjugation to specific antibodies or antibody fragments will reduce HRP clearance and thereby enhance therapy efficacy.

Recent advances in the synthesis, stability, and activation of platinum(IV) anticancer prodrugs

• The interplay between platinum(II) drugs and platinum(IV) prodrugs is summarized. • The oxidation reactions of platinum(II) drugs are reviewed. • The hydrolytic stability of platinum(IV) prodrugs is discussed. • Recent progress in the activation of platinum(IV) prodrugs is outlined. Platinum-based anticancer drugs have been widely applied in clinical settings for more than 40 years. The remarkable breakthroughs that have come from the use of these complexes in cancer therapy have stimulated a continual search for new platinum anticancer drugs. The most promising result of these efforts is a prodrug strategy based on the use of platinum(IV) versions of the traditional platinum(II) anticancer drugs. Hence, the design of synthetic methods for platinum(IV) prodrugs and an understanding of their hydrolytic stability and intracellular activation processes are critical for the development of platinum(IV) prodrugs for cancer therapy. In this review, we summarize recent progress in this field from a comprehensive viewpoint, with an emphasis first on the oxidation processes in chemical environments where platinum(II) compounds are converted to their platinum(IV) species, followed by the reduction processes in biological environments where platinum(IV) species are converted back to platinum(II) forms. First, recent approaches that use new oxidizing reagents to synthesize platinum(IV) prodrugs are summarized, and the oxidation mechanisms and outer-sphere functionalization of platinum(IV) prodrugs are examined. Second, the hydrolysis of platinum(IV) complexes, which has sometimes been underexplored, is discussed, and the factors associated with the hydrolytic stability of platinum(IV) complexes are reviewed. Last, we focus on the reduction of platinum(IV) prodrugs, from the perspectives of reduction potential, rate of reduction, reducing agents, and reduction products. The need for new strategies to achieve controllable intracellular reduction of platinum(IV) prodrugs is emphasized. This review aims to help researchers to improve their understanding of platinum(IV) anticancer prodrugs and hopefully to generate new ideas, strategies, and applications in the area of metal-based drugs.

Delivery of Natural Agents by Means of Mesoporous Silica Nanospheres as a Promising Anticancer Strategy.

Natural prodrugs derived from different natural origins (e.g., medicinal plants, microbes, animals) have a long history in traditional medicine. They exhibit a broad range of pharmacological activities, including anticancer effects in vitro and in vivo. They have potential as safe, cost-effective treatments with few side effects, but are lacking in solubility, bioavailability, specific targeting and have short half-lives. These are barriers to clinical application. Nanomedicine has the potential to offer solutions to circumvent these limitations and allow the use of natural pro-drugs in cancer therapy. Mesoporous silica nanoparticles (MSNs) of various morphology have attracted considerable attention in the search for targeted drug delivery systems. MSNs are characterized by chemical stability, easy synthesis and functionalization, large surface area, tunable pore sizes and volumes, good biocompatibility, controlled drug release under different conditions, and high drug-loading capacity, enabling multifunctional purposes. In vivo pre-clinical evaluations, a significant majority of results indicate the safety profile of MSNs if they are synthesized in an optimized way. Here, we present an overview of synthesis methods, possible surface functionalization, cellular uptake, biodistribution, toxicity, loading strategies, delivery designs with controlled release, and cancer targeting and discuss the future of anticancer nanotechnology-based natural prodrug delivery systems.

Use of prodrugs in cancer therapy - A Review

A prodrug is a medicine that is primarily used after administration, that is metabolized into a pharmacologically active drug. A prodrug is generally a precursor form of a drug. A prodrug is used to selectively improve the drug that directly interacts with cells used in any form of treatment like chemotherapy. The drug, when taken separately, does not have much effect, whereas, a drug taken in after the administration of prodrug acts very effectively. Prodrugs are often used in the pharmaceutical field. Prodrug alters certain properties of prodrugs, such as physicochemical properties to enhance their efficacy and reduce their toxicity. The cancer cells are first injected with a gene that expresses an enzyme that has the ability to convert a non-toxic prodrug into its active cytotoxic form. Various applications of prodrugs include improving drug penetration through biological membranes, increasing site-specificity of a drug; it mainly improves patient's acceptance. Prodrugs stabilize the active drug and prevent drug metabolism. This review was written with an aim to highlight the important aspects of prodrugs and its use in cancer therapy.

Synthetic Tuning of Domain Stoichiometry in Nanobody-Enzyme Megamolecules.

This paper presents a method to synthetically tune atomically precise megamolecule nanobody-enzyme conjugates for prodrug cancer therapy. Previous efforts to create heterobifunctional protein conjugates suffered from heterogeneity in domain stoichiometry, which in part led to the failure of antibody-enzyme conjugates in clinical trials. We used the megamolecule approach to synthesize anti-HER2 nanobody-cytosine deaminase conjugates with tunable numbers of nanobody and enzyme domains in a single, covalent molecule. Linking two nanobody domains to one enzyme domain improved avidity to a human cancer cell line by 4-fold but did not increase cytotoxicity significantly due to lowered enzyme activity. In contrast, a megamolecule composed of one nanobody and two enzyme domains resulted in an 8-fold improvement in the catalytic efficiency and increased the cytotoxic effect by over 5-fold in spheroid culture, indicating that the multimeric structure allowed for an increase in local drug activation. Our work demonstrates that the megamolecule strategy can be used to study structure-function relationships of protein conjugate therapeutics with synthetic control of protein domain stoichiometry.

A highly efficient non-viral process for programming mesenchymal stem cells for gene directed enzyme prodrug cancer therapy

Mesenchymal stem cells (MSCs) driven gene-directed enzyme prodrug therapy has emerged as a potential strategy for cancer treatment. The tumour-nesting properties of MSCs enable these vehicles to target tumours and metastases with effective therapies. A crucial step in engineering MSCs is the delivery of genetic material with low toxicity and high efficiency. Due to the low efficiency of current transfection methods, viral vectors are used widely to modify MSCs in preclinical and clinical studies. We show, for the first time, the high transfection efficiency (> 80%) of human adipose tissue derived-MSCs (AT-MSCs) using a cost-effective and off-the-shelf Polyethylenimine, in the presence of histone deacetylase 6 inhibitor and fusogenic lipids. Notably, the phenotypes of MSCs remained unchanged post-modification. AT-MSCs engineered with a fused transgene, yeast cytosine deaminase::uracil phosphoribosyltransferase (CDy::UPRT) displayed potent cytotoxic effects against breast, glioma, gastric cancer cells in vitro. The efficiency of eliminating gastric cell lines were effective even when using 7-day post-transfected AT-MSCs, indicative of the sustained expression and function of the therapeutic gene. In addition, significant inhibition of temozolomide resistant glioma tumour growth in vivo was observed with a single dose of therapeutic MSC. This study demonstrated an efficient non-viral modification process for MSC-based prodrug therapy.

Microvesicle-Mediated Delivery of Minicircle DNA Results in Effective Gene-Directed Enzyme Prodrug Cancer Therapy.

An emerging approach for cancer treatment employs the use of extracellular vesicles, specifically exosomes and microvesicles, as delivery vehicles. We previously demonstrated that microvesicles can functionally deliver plasmid DNA to cells and showed that plasmid size and sequence, in part, determine the delivery efficiency. In this study, delivery vehicles comprised of microvesicles loaded with engineered minicircle (MC) DNA that encodes prodrug converting enzymes developed as a cancer therapy in mammary carcinoma models. We demonstrated that MCs can be loaded into shed microvesicles with greater efficiency than their parental plasmid counterparts and that microvesicle-mediated MC delivery led to significantly higher and more prolonged transgene expression in recipient cells than microvesicles loaded with the parental plasmid. Microvesicles loaded with MCs encoding a thymidine kinase (TK)/nitroreductase (NTR) fusion protein produced prolonged TK-NTR expression in mammary carcinoma cells. In vivo delivery of TK-NTR and administration of prodrugs led to the effective killing of both targeted cells and surrounding tumor cells via TK-NTR-mediated conversion of codelivered prodrugs into active cytotoxic agents. In vivo evaluation of the bystander effect in mouse models demonstrated that for effective therapy, at least 1% of tumor cells need to be delivered with TK-NTR-encoding MCs. These results suggest that MC delivery via microvesicles can mediate gene transfer to an extent that enables effective prodrug conversion and tumor cell death such that it comprises a promising approach to cancer therapy.

Revisiting Bromohexitols as a Novel Class of Microenvironment-Activated Prodrugs for Cancer Therapy.

Bromohexitols represent a potent class of DNA-alkylating carbohydrate chemotherapeutics that has been largely ignored over the last decades due to safety concerns. The limited structure-activity relationship data available reveals significant changes in cytotoxicity with even subtle changes in stereochemistry. However, no attempts have been made to improve the therapeutic window by rational drug design or by using a prodrug approach to exploit differences between tumour physiology and healthy tissue, such as acidic extracellular pH and hypoxia. Herein, we report the photochemical synthesis of highly substituted endoperoxides as key precursors for dibromohexitol derivatives and investigate their use as microenvironment-activated prodrugs for targeting cancer cells. One endoperoxide was identified to have a marked increased activity under hypoxic and low pH conditions, indicating that endoperoxides may serve as microenvironment-activated prodrugs.

A highly efficient non-viral process for engineering theranostic mesenchymal stem cells for gene directed enzyme prodrug cancer therapy

Background & Aim Mesenchymal stem cells (MSC) are emerging as promising vehicles for Gene-directed enzyme prodrug therapy (GDEPT). The inherent tumor-trophic migratory properties of MSC enable these vehicles to deliver effective, targeted therapy to tumors and metastatic diseases. A critical step in modifying MSC is the delivery of genes with high efficiency and low cytotoxicity. Due to the poor efficiency of transfection approaches, viral methods are used extensively to transduce MSC in preclinical and clinical studies. This study aims to develop a scalable non viral gene delivery method to efficiently modify MSC. Methods, Results & Conclusion Methods TrafEn (Trafficking Enhancer), to enhance transfection using off-the-shelf, cost-effective polymers. TrafEn was rationally developed to facilitate efficient trafficking of the genetic material inside cells. Polyplex transfection was enhanced by including a simultaneous treatment with DOPE/CHEMS lipid suspension and a microtubule stabilizer, a histone deacetylase-6 inhibitor. Result We demonstrate, for the first time, the efficient transfection (>90%) of human adipose tissue derived MSCs (AT-MSCs) using an off-the shelf and cost-effective cationic polymer, polyethylenimine, in the presence of fusogenic lipids and histone deacetylase 6 inhibitor (HDAC6i) (Figure 1). Importantly, the cell phenotypes of MSCs remained unchanged after modification, a key requisite for clinical application of MSCs. AT-MSCs modified with a fused transgene, yeast cytosine deaminase::uracil phosphoribosyltransferase (CDy::UPRT), exhibited strong cytotoxic effects towards glioma, breast and gastric cancer cells in vitro. The efficiency of killing of gastric MKN1 and MKN28 cell lines were greater than 80% even with 7 days post-transfected AT-MSCs, indicative that the expression period of the therapeutic gene was sustainable. Conclusion This study describes a useful tool for polymer based ex vivo MSC modification which is highly scalable and cost-effective. The proposed workflow bypasses the restriction in viral vector supply and expedites MSC modification, without compromising the quality and anti-cancer efficacy of the theranostic MSCs.

Activation of Prodrugs by NIR‐Triggered Release of Exogenous Enzymes for Locoregional Chemo‐photothermal Therapy

AbstractEnzymes have been used to direct the conversion of prodrugs in cancer therapy. However, non‐specific distribution of endogenous enzymes seriously hinders their bioapplications. Herein, we developed a near‐infrared‐triggered locoregional chemo‐photothermal therapy based on the exogenous enzyme delivery and remolded tumor mivroenvironment. The catalytic efficiency of enzymes was enhanced by the hyperthermia, and the therapeutic efficacy of photothermal therapy (PTT) was improved owing to the inhibition of heat shock protein 90 by chemotherapeutics. The locoregional chemo‐phototherapy achieved a one‐time successful cure in 4T1 tumor‐bearing mice model. Thus, a mutually reinforcing feedback loop between PTT and chemotherapy can be initiated by the irradiation, which holds a promising future in cancer therapy.

Activation of Prodrugs by NIR-Triggered Release of Exogenous Enzymes for Locoregional Chemo-photothermal Therapy.

Enzymes have been used to direct the conversion of prodrugs in cancer therapy. However, non-specific distribution of endogenous enzymes seriously hinders their bioapplications. Herein, we developed a near-infrared-triggered locoregional chemo-photothermal therapy based on the exogenous enzyme delivery and remolded tumor mivroenvironment. The catalytic efficiency of enzymes was enhanced by the hyperthermia, and the therapeutic efficacy of photothermal therapy (PTT) was improved owing to the inhibition of heat shock protein 90 by chemotherapeutics. The locoregional chemo-phototherapy achieved a one-time successful cure in 4T1 tumor-bearing mice model. Thus, a mutually reinforcing feedback loop between PTT and chemotherapy can be initiated by the irradiation, which holds a promising future in cancer therapy.

Isocytosine deaminase Vcz as a novel tool for the prodrug cancer therapy

BackgroundThe cytosine deaminase (CD)/5-fluorocytosine (5-FC) system is among the best explored enzyme/prodrug systems in the field of the suicide gene therapy. Recently, by the screening of the environmental metagenomic libraries we identified a novel isocytosine deaminase (ICD), termed Vcz, which is able of specifically converting a prodrug 5-fluoroisocytosine (5-FIC) into toxic drug 5-fluorouracil (5-FU). The aim of this study is to test the applicability of the ICD Vcz / 5-FIC pair as a potential suicide gene therapy tool.MethodsVcz-expressing human glioblastoma U87 and epithelial colorectal adenocarcinoma Caco-2 cells were treated with 5-FIC, and the Vcz-mediated cytotoxicity was evaluated by performing an MTT assay. In order to examine anti-tumor effects of the Vcz/5-FIC system in vivo, murine bone marrow-derived mesenchymal stem cells (MSC) were transduced with the Vcz-coding lentivirus and co-injected with 5-FIC or control reagents into subcutaneous GL261 tumors evoked in C57/BL6 mice.Results5-FIC alone showed no significant toxic effects on U87 and Caco-2 cells at 100 μM concentration, whereas the number of cells of both cell lines that express Vcz cytosine deaminase gene decreased by approximately 60% in the presence of 5-FIC. The cytotoxic effects on cells were also induced by media collected from Vcz-expressing cells pre-treated with 5-FIC. The co-injection of the Vcz-transduced mesenchymal stem cells and 5-FIC have been shown to augment tumor necrosis and increase longevity of tumorized mice by 50% in comparison with control group animals.ConclusionsWe have confirmed that the novel ICD Vcz together with the non-toxic prodrug 5-FIC has a potential of being a new enzyme/prodrug system for suicide gene therapy.

Cancer Therapy: Biotransporting Self-Assembled Nanofactories Using Polymer Vesicles with Molecular Permeability for Enzyme Prodrug Cancer Therapy (Adv. Mater. 36/2017)

Cancer Therapy: Biotransporting Self-Assembled Nanofactories Using Polymer Vesicles with Molecular Permeability for Enzyme Prodrug Cancer Therapy (Adv. Mater. 36/2017)