Development of a novel albumin-binding prodrug that is cleaved by urokinase-type-plasminogen activator (uPA)

Chung, Daeun; Kratz, Felix

doi:10.1016/j.bmcl.2006.07.023

Cited by 34 publications

(26 citation statements)

References 17 publications

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“…These prodrugs often consist of an anticancer drug, the maleimide group as the thiol-binding moiety and an enzymatically cleavable peptide linker. Examples include doxorubicin prodrugs that are cleaved by matrix metalloproteases 2 and 9, 40 cathepsin B, 70 urokinase plasminogen (uPA) or prostate-specific antigen (PSA), 71,72 methotrexate prodrugs that are cleaved by cathepsin B or plasmin, 73 and camptothecin prodrugs that are cleaved by cathepsin B or unidentified proteases. 74 In addition, maleimide derivatives with 5-fluorouracil analogues and platinum(II) complexes have been developed.…”

Section: General Strategy To Develop Hsa-conjugated Drugsmentioning

confidence: 99%

Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy

2016

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Albumin is the most abundant circulating protein in plasma and has recently emerged as a versatile protein carrier for drug targeting and for improving the pharmacokinetic profile of peptide or protein based drugs. Three drug delivery technologies related to albumin have been developed, which include the coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugating bioactive proteins by albumin fusion technology (AFT), and encapsulation of drugs into albumin nanoparticles. This review article starts with a brief introduction of human serum albumin (HSA), and then summarizes the mainstream chemical strategies of developing HSA binding molecules for coupling with drug molecules. Moreover, we also concisely condense the recent progress of the most important clinical applications of HSA-binding platforms, and specify the current challenges that need to be met for a bright future of HSA-binding.

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Section: General Strategy To Develop Hsa-conjugated Drugsmentioning

confidence: 99%

Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy

2016

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“…In recent work, we discovered that among a spectrum of doxorubicin amino acid derivatives N-(L-arginine)doxorubicin (H-Arg-DOXO) was the only compound that was efficiently cleaved to doxorubicin in tumor homogenates at pH 7.4. 13 We reasoned that replacing Gly by Arg at the C-terminal position could behave in a similar way and also release doxorubicin through the action of other proteases in tumor homogenates. Consequently, we developed the doxorubicin prodrug EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-Arg-DOXO (PSA5) that is shown in Figure 1.…”

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confidence: 99%

Synthesis and biological evaluation of an albumin‐binding prodrug of doxorubicin that is cleaved by prostate‐specific antigen (PSA) in a PSA‐positive orthotopic prostate carcinoma model (LNCaP)

Graeser¹,

Chung

Esser³

et al. 2007

Intl Journal of Cancer

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The prostate-specific antigen (PSA) is a serine protease that is over-expressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. We have recently investigated a macromolecular prodrug strategy for improved cancer chemotherapy based on 2 features: (i) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration, and (ii) enzymatic release of the albuminbound drug at the tumor site (Mansour et al., Cancer Res 2003, 63, 4062-4066). In this work, we describe an albumin-binding prodrug, EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-Arg-DOXO [EMC: e-Maleimidocaproic acid; DOXO 5 doxorubicin; X 5 amino acid] that is cleaved by PSA. Because of the incorporation of 2 arginine residues, the prodrug exhibited excellent water-solubility and was rapidly and selectively bound to endogenous albumin. Incubation studies with PSA and tumor homogenates from PSA-positive tumors (LNCaP) demonstrated that the albumin-bound form of the prodrug was efficiently cleaved by PSA at the P 1 -P 0 1 scissile bond releasing the doxorubicin dipeptide H-Ser-Arg-DOXO, which was further degraded to doxorubicin as the final cleavage product. In cell culture experiments, the prodrug was 100-fold less active against LNCaP cells than the free drug. In contrast, in a mouse model of human prostate cancer using luciferase transduced LNCaP cells orthotopically implanted in SCID mice, the prodrug showed enhanced antitumor efficacy when compared to doxorubicin. Doxorubicin treatment at a dose of 2 3 4 mg/kg caused significant weight loss and mortality (225%), and did not result in a significant antitumor response at the end of the experiment. The prodrug at 3 3 12 mg/kg doxorubicin equivalents, however, was well tolerated and induced a significant reduction in tumor size of 62% (625%, **p 5 0.003) as well as a decrease of the metastatic burden in the lungs as detected in luciferase assays (250%, SD 6 115%, *p 5 0.038). ' 2007 Wiley-Liss, Inc.Key words: doxorubicin; macromolecular prodrug; human serum albumin; PSA; orthotopic animal model; LNCaP; luciferase; in vivo bioluminescence Hormone refractory prostate cancer responds unfavorably to chemotherapy. The best results to date are achieved with Taxotere. 1 To improve prostate cancer therapy, tumor-specific delivery of anticancer agents to the primary tumor and metastases is a goal worth pursuing.For selectively releasing anticancer agents, the prostate-specific antigen (PSA) is especially attractive as a target protease because it is solely expressed in prostate tissue and prostate carcinoma in prostate cancer patients with high levels up to mg/g present in human prostate carcinoma. 2,3 PSA is a serine protease that belongs to the kallikrein gene family with chymotrypsin-like activity that is involved in the hydrolytic processing of semenogelins (cleavage of the semenal fluid proteins semenogelin I and II), which is required for liquefaction of seminal fluids. 2,3 Over...

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“…Therefore, it has been identified as a target to specifically release cytotoxic agents. The first uPA-sensitive prodrug was reported by Chung and Kratz (22). It consisted of an albumin-bound doxorubicin containing a uPA substrate.…”

Section: Discussionmentioning

confidence: 99%

Selective Photodetection and Photodynamic Therapy for Prostate Cancer through Targeting of Proteolytic Activity

Zuluaga

Sekkat

Gabriel

et al. 2013

Molecular Cancer Therapeutics

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Frequent side effects of radical treatment modalities and the availability of novel diagnostics have raised the interest in focal therapies for localized prostate cancer. To improve the selectivity and therapeutic efficacy of such therapies, we developed a minimally invasive procedure based on a novel polymeric photosensitizer prodrug sensitive to urokinase-type plasminogen activator (uPA). The compound is inactive in its prodrug form and accumulates passively at the tumor site by the enhanced permeability and retention effect. There, the prodrug is selectively converted to its photoactive form by uPA, which is overexpressed by prostate cancer cells. Irradiation of the activated photosensitizer exerts a tumor-selective phototoxic effect. The prodrug alone (8 mmol/L) showed no toxic effect on PC-3 cells, but upon irradiation the cell viability was reduced by 90%. In vivo, after systemic administration of the prodrug, PC-3 xenografts became selectively fluorescent. This is indicative of the prodrug accumulation in the tumor and selective local enzymatic activation. Qualitative analysis of the activated compound confirmed that the enzymatic cleavage occurred selectively in the tumor, with only trace amounts in the neighboring skin or muscle. Subsequent photodynamic therapy studies showed complete tumor eradication of animals treated with light (150 J/cm 2 at 665 nm) 16 hours after the injection of the prodrug (7.5 mg/kg). These promising results evidence the excellent selectivity of our prodrug with the potential to be used for both imaging and therapy for localized prostate cancer. Mol Cancer Ther; 12(3); 306-13. Ó2012 AACR.

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Development of a novel albumin-binding prodrug that is cleaved by urokinase-type-plasminogen activator (uPA)

Cited by 34 publications

References 17 publications

Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy

Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy

Synthesis and biological evaluation of an albumin‐binding prodrug of doxorubicin that is cleaved by prostate‐specific antigen (PSA) in a PSA‐positive orthotopic prostate carcinoma model (LNCaP)

Selective Photodetection and Photodynamic Therapy for Prostate Cancer through Targeting of Proteolytic Activity

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