Painting the Target Around the Arrow: Two-Step Prodrug Therapies from a Carbohydrate Chemists Perspective

Houston, Todd Ashley

doi:10.2174/156720107782151278

Cited by 9 publications

(5 citation statements)

References 35 publications

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“…Conventional chemotherapy represents an important treatment option for advanced cancers, but the limited therapeutic index of most antineoplastic drugs can cause normal tissue toxicity and severe side effects. Antibody-directed enzyme prodrug therapy (ADEPT) seeks to increase tumor selectivity and reduce undesirable side effects of chemotherapy by targeting an antibody−enzyme conjugate (immunoenzyme) to cancer cells for preferential activation of nontoxic anticancer prodrugs in the tumor microenvironment. − We previously reported that immunoenzymes formed by chemical linkage of anticancer antibodies and E. coli β-glucuronidase could selectively activate glucuronide prodrugs at antigen-positive cancer cells, enhance antitumor immune responses, and produce long-term tumor regression in syngenic and xenograft cancer models. − However, a major impediment to clinical translation of immunoenzymes containing microbial enzymes is their high immunogenicity in patients, which dramatically hinders tumor targeting and prevents effective therapy. − …”

Section: Introductionmentioning

confidence: 99%

A Humanized Immunoenzyme with Enhanced Activity for Glucuronide Prodrug Activation in the Tumor Microenvironment

Leu

et al. 2011

Bioconjugate Chem.

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Antibody-directed enzyme prodrug therapy (ADEPT) utilizing β-glucuronidase is a promising method to enhance the therapeutic index of cancer chemotherapy. In this approach, an immunoenzyme (antibody-β-glucuronidase fusion protein) is employed to selectively activate anticancer glucuronide prodrugs in the tumor microenvironment. A major roadblock to the clinical translation of this therapeutic strategy, however, is the low enzymatic activity and strong immunogenicity of the current generation of immunoenzymes. To overcome this problem, we fused a humanized single-chain antibody (scFv) of mAb CC49 to S2, a human β-glucuronidase (hβG) variant that displays enhanced catalytic activity for prodrug hydrolysis. Here, we show that hcc49-S2 displayed 100-fold greater binding avidity than hcc49 scFv, possessed greater enzymatic activity than wild-type hβG, and more effectively killed antigen-positive cancer cells exposed to an anticancer glucuronide prodrug as compared to an analogous hβG immunoenzyme. Treatment of tumor-bearing mice with hcc49-S2 followed by prodrug significantly delayed tumor growth as compared to hcc49-hβG. Our study shows that hcc49-S2 is a promising targeted enzyme for cancer treatment and demonstrates that enhancement of human enzyme catalytic activity is a powerful approach to improve immunoenzyme efficacy.

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Section: Introductionmentioning

confidence: 99%

A Humanized Immunoenzyme with Enhanced Activity for Glucuronide Prodrug Activation in the Tumor Microenvironment

Leu

et al. 2011

Bioconjugate Chem.

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“…Drug targeted strategy are being validated to address important requirements for targeted therapy, drug delivery system and improved diagnosis. Tumor targeted drug delivery could be classified into carrier and non-carrier based therapy [40]. Carrier based drug therapies comprise, polymeric based drug carriers (polymeric nanoparticles [41], polymeric micelles [42], polymer-drug bioconjugates [43], dendrimers [44]), lipid based drug carriers (liposomes [45]), viral nanocarriers [46], inorganic nanocarriers (quantum dots [47], silica nanoparticles [48], carbon nanotubes [49]) and these nanomaterials with drug collectively called nanomedicine delivered the drug molecules, recombinant DNA and proteins to the targeted tumor cells/tissues/organs.…”

Section: Endocytosis Of Nanomedicinesmentioning

confidence: 99%

SMART Drug Based Targeted Delivery: A New Paradigm for Nanomedicine Strategies

Dhanasekaran¹

2015

Int J Immunother Cancer Res

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Introduction: Targeted drug delivery systems are nanoscale drug carrier molecules designed for improving the communication of cellular and molecular components and biodistribution of tumour targeted drug (chemo) therapeutics. Nanomaterials are generally clusters of molecules, atoms and molecular fragments into extremely small size particles (1-100 nm) in nature. Nanomaterials engineered as self-assembled biodegradable particles were used for targeted drug delivery system. Nanocarriers/ particles should be-capable of transporting high doses of chemotherapeutic drugs/nanomedicines into the targeted tumor cells without disturbing the normal healthy cells. It is also used for construction of novel targeted drug delivery system and future application in nanovaccination and nanotechnology. Conclusion:Multifunctional smart nanoparticles or carries hold out the possibility of effective drug targeted therapeutics in molecular and cellular levels at the earliest stage. Here, we briefly discuss the significance of targeting strategies and drug delivery system and outline the current approaches and future directions in the improvement of tumor targeting nanomedicines.liposomes, micelles, nanoparticulate system (polymer, carbon, drug nanoparticles, ceramic-based, biological, metal, and magnetic) and dendrimers are used for imaging and targeted drug delivery [9]. Freitas Jr. [4] and Flynn and Wei [10] reported the importance of commercialization of nanomedicine including gated nanosieves, immunoisolation, ultrafast DNA sequencing, nanoshells, fullerenebased pharmaceuticals, single-virus detectors, tecto-dendrimers, biologic robots and radio-controlled biomolecules [4]. This review deals with the practical application of nanomedicines and provides an overview of approaches in targeted drug delivery system. Discussion Ideal design for smart drug (Nanomedicine)Smart drug which are ideally designed to satisfy the requirements will pave the way for targeted drug delivery. These requirements includes: a) high stability (longevity) and not easily degraded or cleared by the reticuloendothelial system (RES) during blood circulation, b) accumulation of high concentration of drug at the tumor targeted sites or area, c) effective intracellular drug delivery at the tumour targeted area or site that matches drug pharmacodynamics of kinetics and spatial control and d) tolerability. The blood circulation stability and self-life of the drug (size, morphology, low degree of lipid hydrolysis and drug retention) are influenced by the physical and chemical nature of the encapsulated drug and encapsulation techniques. The design of tumor drug targeted delivery system based on: passive drug targeted delivery as a significance of enhanced permeability and retention effect (EPR) (without ligand targets and active drug release mechanisms) [11,12], targeted drug release based on recognition of receptor molecules [13][14][15][16], triggered drug release or stimuli -responsive release (pH, redox potential, temperature, light intensity, ROS response magnet...

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“…Later studies using antitumor agents (e.g., methyldithio-maytasinoid) that were 100 -1000-fold more potent than the previous drug received some improvement, as a measurable tumor regression was observed in the tested animals [55] . A general review of prodrug strategies in cancer therapy appeared elsewhere [56] , including two-step prodrug strategies involving carbohydrate moiety [57] .…”

Section: Expert Opinionmentioning

confidence: 99%

The ATTEMPTS delivery systems for macromolecular drugs

Kwon

Naik

et al. 2008

Expert Opinion on Drug Delivery

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Aiming at successful targeted drug delivery -a system that possesses both targeting and prodrug features that can be activated once the system reaches the target site upon systemic administration -would be desired to reduce systemic toxicity. Previously we proposed a heparin/protamine-based system for delivery of protease drugs such as tissue-specific plasminogen activator (t-PA). This approach, termed 'antibody targeted, triggered, electrically modified prodrug-type strategy' (ATTEMPTS), would permit antibody-directed administration of inactive t-PA and allow a subsequent triggered release of the active t-PA at the target site. This system can be adapted to target tumor tissues when protein transduction domain (PTD) peptide such as TAT is incorporated in the ATTEMPTS construct. Both in vitro and preliminary in vivo studies using TAT-gelonin (TAT-Gel) and TATasparaginase (TAT-ASNase) conjugates have demonstrated that the on/off regulation of the membrane translocation activity of PTD at tumor target, followed by intracellular delivery of cytotoxic macromolecular drug, can be accomplished. Hence, the PTD-mediated delivery system derived from our previous ATTEMPTS approach is a system that incorporates all of the targeting function, prodrug feature, release mechanism and cell entry mechanism and could become a generic system for delivery of macromolecular drugs.

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Painting the Target Around the Arrow: Two-Step Prodrug Therapies from a Carbohydrate Chemists Perspective

Cited by 9 publications

References 35 publications

A Humanized Immunoenzyme with Enhanced Activity for Glucuronide Prodrug Activation in the Tumor Microenvironment

A Humanized Immunoenzyme with Enhanced Activity for Glucuronide Prodrug Activation in the Tumor Microenvironment

SMART Drug Based Targeted Delivery: A New Paradigm for Nanomedicine Strategies

The ATTEMPTS delivery systems for macromolecular drugs

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