Protease-Activated Drug Development

Choi, Ki Young; Swierczewska, Magdalena; Lee, Seulki; Chen, Xiaoyuan

doi:10.7150/thno.4068

Cited by 209 publications

(190 citation statements)

References 235 publications

(180 reference statements)

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“…Both compounds 4a and 5a described in this article feature a linker containing a valine-citrulline moiety, which was previously believed to be particularly suited for the intracellular release of drug payloads, due to the action of lysosomal cathepsin B [41]. This protein is a primarily intracellular protease that can be secreted extracellularly by dying cells, but also by living tumor cells to initiate extracellular proteolytic cascades and to enable tumor cell proliferation [42]. Our therapy data suggest that the presence of cathepsin B in the extracellular tumor environment is sufficient for the efficient liberation of cytotoxic drug moieties, which can then diffuse into surrounding tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Cazzamalli

Corso

Neri

2016

Molecular Cancer Therapeutics

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In most cases, cytotoxic drugs do not preferentially accumulate at the tumor site, causing unwanted toxicities and preventing dose escalation to therapeutically active regimens. Here, we show that acetazolamide derivatives, which bind to carbonic anhydrase IX (CAIX) on the surface of kidney cancer cells, selectively deliver payloads at the site of disease, sparing normal organs. Biodistribution studies, performed in tumor-bearing mice with acetazolamide derivatives bearing a technetium-99m chelator complex or a red fluorophore as payload, revealed a preferential tumor accumulation of the compound at doses up to 560 nmol/Kg. The percentage of injected dose per gram in the tumor was dose-dependent and revealed optimal tumor:organ ratios at 140 nmol/Kg, with a tumor:blood ratio of 80:1 at 6 h. Acetazolamide, coupled to potent cytotoxic drugs via a dipeptide linker, exhibited a potent antitumor activity in nude mice bearing SKRC-52 renal cell carcinomas, while drug derivatives devoid of the acetazolamide moiety did not exhibit any detectable anticancer activity at the same doses. The observation of tumor regression with a noninternalizing ligand and with different cytotoxic moieties (MMAE and PNU-159682) indicates a general mechanism of action, based on the selective accumulation of the product on tumor cells, followed by the extracellular proteolytic release of the cytotoxic payload at the neoplastic site and the subsequent drug internalization into tumor cells. Acetazolamide-based drug conjugates may represent a promising class of targeted agents for the treatment of metastatic kidney cancer, as the majority of human clear cell renal cell carcinomas are strongly positive for CAIX.

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Section: Discussionmentioning

confidence: 99%

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Cazzamalli

Corso

Neri

2016

Molecular Cancer Therapeutics

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“…In order to achieve targeted release of the antigen from the adjuvant inside the cell, an intracellular trigger such as reduction-oxidation (redox) potential, pH, or a specific enzyme can be used. [13][14][15][16][17][18][19] These triggers have been used in a number of devices to enhance the targeted delivery of a drug. 20,21 Triggerable formulations for immunotherapy have been investigated for intracellular targeting to APCs.…”

Section: Introductionmentioning

confidence: 99%

Intracellular Cleavable CpG Oligodeoxynucleotide-Antigen Conjugate Enhances Anti-tumor Immunity

et al. 2017

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“…Thus, we explored taking advantage of the increased activities of HDACs and CTSL as a selective modality for delivering therapeutics to cancer cells instead of using inhibitors. Although many peptide-based prodrugs activated by tumour-associated proteases have been developed 24 , stability and nonspecific activation of parental drugs due to ubiquitous proteases are key factors limiting their clinical efficacy. By introducing an e-acetylated lysine as the first requirement, the resulting prodrug is expected to be wellprotected from proteolytic cleavage until it is deacetylated by the intracellular HDAC, and thus enables highly selective activation in tumour tissues.…”

mentioning

confidence: 99%

Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

et al. 2013

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Eradication of cancer cells while minimizing damage to healthy cells is a primary goal of cancer therapy. Highly selective drugs are urgently needed. Here we demonstrate a new prodrug strategy for selective cancer therapy that utilizes increased histone deacetylase (HDAC) and tumour-associated protease activities produced in malignant cancer cells. By coupling an acetylated lysine group to puromycin, a masked cytotoxic agent is created, which is serially activated by HDAC and an endogenous protease cathepsin L (CTSL) that remove the acetyl group first and then the unacetylated lysine group liberating puromycin. The agent selectively kills human cancer cell lines with high HDAC and CTSL activities. In vivo studies confirm tumour growth inhibition in prodrug-treated mice bearing human cancer xenografts. This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development that could be applied to many other cytotoxic agents.

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Protease-Activated Drug Development

Cited by 209 publications

References 235 publications

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Intracellular Cleavable CpG Oligodeoxynucleotide-Antigen Conjugate Enhances Anti-tumor Immunity

Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

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