Recent Trends in Targeted Anticancer Prodrug and Conjugate Design

Singh, Yashveer; Palombo, Matthew S.; Sinko, Patrick J.

doi:10.2174/092986708785132997

Cited by 205 publications

(142 citation statements)

References 167 publications

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“…Prodrugs can help improve tumor targetability and efficiency by incorporating tumor-targeting ligands, transporter-associated ligands and polymers (83,84,87,95). In addition to overcoming physiochemical or biopharmaceutical problems, prodrugs can help achieve targeted therapy by taking advantage of tumor-specific antigens on tumor cell surfaces, transporter-associated ligands, low extracellular pH inside the tumor core, etc.…”

Section: Prodrugsmentioning

confidence: 99%

Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges

Wen¹,

Jung²,

2015

AAPS J

401

189

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Abstract. Various drug delivery approaches can be used to maximize therapeutic efficacy and minimize side effects, by impacting absorption, distribution, metabolism, and elimination (ADME) of a drug compound. For those drugs with poor water solubility or low permeability, techniques such as amorphous solid dispersion, liposomes, and complexations have been used to improve their oral bioavailability. Modified release (MR) formulations have been widely used to improve patient compliance, as well as to reduce side effects, especially for those drugs with short half-lives or narrow therapeutic windows. More than ten drugs using sterile long-acting release (LAR) formulations with clear clinical benefit have been successfully marketed. Furthermore, drug delivery systems have been used in delaying drug clearance processes. Additionally, modifying the in vivo drug distribution using targeted delivery systems has significantly improved oncology treatments. All the drug delivery approaches have their advantages and limitations. For both brand and generic drugs, the achievement of consistent quality and therapeutic performance using drug delivery systems can also pose serious challenges in developing a drug for the market, which requires close collaboration among industry, academia, and regulatory agencies. With the advent of personalized medicines, there will be great opportunities and challenges in utilizing drug delivery systems to provide better products and services for patients.

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Section: Prodrugsmentioning

confidence: 99%

Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges

Wen¹,

Jung²,

2015

AAPS J

401

189

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“…The details of these advances have been documented in several recent reviews (2)(3)(4)(5)(6). Here, our aim is to present a unified view of the prodrug concept in targeted cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Prodrug Applications for Targeted Cancer Therapy

Giang

Boland

Poon

2014

AAPS J

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Abstract. Prodrugs are widely used in the targeted delivery of cytotoxic compounds to cancer cells. To date, targeted prodrugs for cancer therapy have achieved great diversity in terms of target selection, activation chemistry, as well as size and physicochemical nature of the prodrug. Macromolecular prodrugs such as antibody-drug conjugates, targeted polymer-drug conjugates and other conjugates that self-assemble to form liposomal and micellar nanoparticles currently represent a major trend in prodrug development for cancer therapy. In this review, we explore a unified view of cancer-targeted prodrugs and highlight several examples from recombinant technology that exemplify the prodrug concept but are not identified as such. Recombinant "prodrugs" such as engineered anthrax toxin show promise in biological specificity through the conditionally targeting of multiple cellular markers. Conditional targeting is achieved by structural complementation, the spontaneous assembly of engineered inactive subunits or fragments to reconstitute functional activity. These complementing systems can be readily adapted to achieve conditionally bispecific targeting of enzymes that are used to activate low-molecular weight prodrugs. By leveraging strengths from medicinal chemistry, polymer science, and recombinant technology, prodrugs are poised to remain a core component of highly focused and tailored strategies aimed at conditionally attacking complex molecular phenotypes in clinically relevant cancer.

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“…Singh et al highlighted recent trends in pro-drug and conjugate rationale and a design for cancer treatment, by analyzing comparative accounts of the advantages and disadvantages associated with each approach (10). A variety of receptors related to cellular growth factors or cytokines on tumor cells have been shown to be overexpressed (11), and we believe that targeting these receptors is a promising strategy.…”

Section: Introductionmentioning

confidence: 99%

Orexin 2 receptor as a potential target for immunotoxin and antibody-drug conjugate cancer therapy

et al. 2011

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Abstract. Targeting tumor-specific receptors is a promising approach for cytotoxic agents. The orexin 2 receptor (OX2R) has reportedly been expressed in a few types of cancer, but not in normal, cells. This study aimed to explore and assess the expression levels of OX2R in a wide range of cancer cell lines and clinical samples to identify its localization. To analyze OX2R expression, we developed a polyclonal antibody specific to OX2R by immunizing two rabbits with a peptide cocktail. A total of 36 cancer cell lines were employed for reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis, and 221 samples from various tissue arrays were used for the immunohistochemistry of OX2R expression. OX2R was identified in three cancerous cell lines, from the gallbladder, squamous cell carcinoma of the head and neck (SCCHN) and glioblastoma. With clinical samples of tissue arrays, 69/221 (31.2%) samples reacted positively with the OX2R antibody. We confirmed its presence on the cell membrane. In conclusion, OX2R was identified on several cancer cells as well as clinical samples. Further studies with larger numbers of clinical samples are required to confirm the statistical significance of the presence and relationships of OX2R with tumor histology. Results of the current study suggested that OX2R is a potent target for immunotoxin or antibody-drug conjugate (ADC) cancer therapy on OX2R-positive cancer cells.

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Recent Trends in Targeted Anticancer Prodrug and Conjugate Design

Cited by 205 publications

References 167 publications

Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges

Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges

Prodrug Applications for Targeted Cancer Therapy

Orexin 2 receptor as a potential target for immunotoxin and antibody-drug conjugate cancer therapy

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