The loading rate determines tumor targeting properties of methotrexate albumin conjugates in rats

Stehle, Gerd; Sinn, H.; Wunder, Andreas; Schrenk, H. H.; Schütt, Sandra; Maier‐Borst, W.; Heene, D. L.

doi:10.1097/00001813-199708000-00006

Cited by 79 publications

(59 citation statements)

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“…Like many clinical cancers, they are resistant to native methotrexate due to transport deficiencies caused by an epigenetic alteration that down-regulates the expression of the reduced folate carrier (22,23). Hence, in this study, MDA-MB-231 cells were treated with methotrexate bound to albumin (17,24,25), which enters the cells by albuminmediated endocytosis (25) and circumvents the methotrexate transport deficiency of MDA-MB-231 cells. The other cell lines were treated with free methotrexate.…”

Section: Resultsmentioning

confidence: 99%

Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside

Beckers

Organe

Timmermans

et al. 2006

Molecular Cancer Therapeutics

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Because of its ability to mimic a low energy status of the cell, the cell-permeable nucleoside 5-aminoimidazole-4-carboxamide (AICA) riboside was proposed as an antineoplastic agent switching off major energy-consuming processes associated with the malignant phenotype (lipid production, DNA synthesis, cell proliferation, cell migration, etc.). Key to the antineoplastic action of AICA riboside is its conversion to ZMP, an AMP mimetic that at high concentrations activates the AMP-activated protein kinase (AMPK). Here, in an attempt to increase the efficacy of AICA riboside, we pretreated cancer cells with methotrexate, an antimetabolite blocking the metabolism of ZMP. Methotrexate enhanced the AICA ribosideinduced accumulation of ZMP and led to a decrease in the levels of ATP, which functions as an intrasteric inhibitor of AMPK. Consequently, methotrexate markedly sensitized AMPK for activation by AICA riboside and potentiated the inhibitory effects of AICA riboside on tumor-associated processes. As cotreatment elicited antiproliferative effects already at concentrations of compounds that were only marginally effective when used alone, our findings on the cooperation between methotrexate and AICA riboside provide new opportunities both for the application of classic antimetabolic chemotherapeutics, such as methotrexate, and for the exploitation of the energy-sensing machinery as a target for cancer intervention. [Mol Cancer Ther 2006;5(9):2211 -7]

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Section: Resultsmentioning

confidence: 99%

Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside

Beckers

Organe

Timmermans

et al. 2006

Molecular Cancer Therapeutics

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“…Using the coupling procedure developed in our laboratory and exerting a 1:1 molar loading ratio, the distribution pattern of the conjugate in vivo is identical with underivated albumin, demonstrating that the native character of the protein is not affected (21,22). Preclinical studies have shown antitumor activity of MTX-HSA in rat tumor models (23,24) and in a variety of human xenograft tumors in nude mice (25).…”

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confidence: 88%

“…This resulted in high immunogenicity and in a considerable uptake of the conjugates by the reticuloendothelial system. Subsequently, these conjugates were removed rapidly from the circulation and were taken up in large amounts by the liver, resulting in low concentrations in the tumor (21,22).…”

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confidence: 99%

Albumin-Based Drug Delivery as Novel Therapeutic Approach for Rheumatoid Arthritis

Wunder

Müller‐Ladner

Stelzer

et al. 2003

The Journal of Immunology

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201

136

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We reported recently that albumin is a suitable drug carrier for targeted delivery of methotrexate (MTX) to tumors. Due to pathophysiological conditions in neoplastic tissue, high amounts of albumin accumulate in tumors and are metabolized by malignant cells. MTX, covalently coupled to human serum albumin (MTX-HSA) for cancer treatment, is currently being evaluated in phase II clinical trials. Because synovium of patients with rheumatoid arthritis (RA) shares various features observed also in tumors, albumin-based drug targeting of inflamed joints might be an attractive therapeutic approach. Therefore, the pharmacokinetics of albumin and MTX in a mouse model of arthritis was examined. Additionally, uptake of albumin by synovial fibroblasts of RA patients and the efficacy of MTX and MTX-HSA in arthritic mice were studied. The results show that when compared with MTX, significantly higher amounts of albumin accumulate in inflamed paws, and significantly lower amounts of albumin are found in the liver and the kidneys. The protein is metabolized by human synovial fibroblasts in vitro and in vivo. MTX-HSA was significantly more effective in suppression of the onset of arthritis in mice than was MTX. In conclusion, albumin appears to be a suitable drug carrier in RA, most likely due to effects on synovial fibroblasts, which might increase therapeutic efficacy and reduce side effects of MTX.

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“…Therefore, the linkage site in both albumin and peptide has to be selected carefully so that the final peptide-albumin conjugate retains its biological activities. Second, the molar ratio of peptide to albumin in a conjugate can affect both activity and half-life (20). A chemical modification of peptide that allows a 1:1 molar ratio was used to assure the minimum structural alteration of albumin after peptide linkage.…”

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confidence: 99%

An Albumin-Conjugated Peptide Exhibits Potent Anti-HIV Activity and LongIn VivoHalf-Life

Xie¹,

Cheng

Wang

et al. 2010

Antimicrob Agents Chemother

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The clinical application of conventional peptide drugs often is limited by their short in vivo half-life and potential immunogenicity. Frequent injection presents challenges to the treatment of chronic diseases, such as HIV infection. We chemically modified a peptide HIV fusion inhibitor with 3-maleimidopropionic acid (MPA), which allows rapid and irreversible conjugation with serum albumin at a 1:1 molar ratio. FB006M, with an MPA modification at the 13th amino acid, rapidly formed conjugate with albumin upon intravenous injection, and it exhibited a remarkably extended in vivo half-life. The albumin conjugate of FB006M displayed potent inhibitory activity against a number of laboratory and clinical isolates of HIV-1 in vitro and in vivo. No immunogenicity or antibody formation was detected after repeated dosing. The clinical application of FB006M may decrease the cost of treatment and improve treatment compliance and patient quality of life.The current treatment of HIV infection and AIDS faces the challenge of the widespread emergence of drug-resistant HIV-1 variants in both newly infected and drug-experienced patients (17). This emphasizes the need for therapeutics with new mechanisms of action. Enfuvirtide, the first and only FDA-approved HIV-1 fusion inhibitor, showed potent activity against both wild-type and drug-resistant HIV-1 (11,12). Being a peptide of 36 amino acid residues, however, it suffers from a short in vivo half-life of 3.46 to 4.35 h and requires twice-daily injection (16). To reduce the cost of treatment and improve patient quality of life, we were interested in developing a peptide-based and long-acting HIV fusion inhibitor by covalently linking an anti-HIV fusion peptide to serum albumin at a 1:1 molar ratio.Albumin is the most abundant protein in plasma. It is well distributed in different tissues and exhibits a half-life of 15 to 19 days in humans. Because of these properties, albumin has been used as a drug carrier (1,6,7). This approach has been applied to small-molecule drugs (9), peptides (10), and protein therapeutics (2). These albumin-drug conjugates demonstrated prolonged in vivo half-life, excellent safety profiles, and therapeutic efficacy. To apply this approach to peptide-based HIV-1 fusion inhibitors, we recognized three important questions that had to be addressed. First, albumin is one magnitude greater in molecular weight than the anti-fusion peptides. The linkage of albumin to peptide may prevent the peptide from accessing its target by steric hindrance (8). Therefore, the linkage site in both albumin and peptide has to be selected carefully so that the final peptide-albumin conjugate retains its biological activities. Second, the molar ratio of peptide to albumin in a conjugate can affect both activity and half-life (20). A chemical modification of peptide that allows a 1:1 molar ratio was used to assure the minimum structural alteration of albumin after peptide linkage. Third, an albumin conjugate in circulation with a long half-life may be immunogenic. It could, ther...

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The loading rate determines tumor targeting properties of methotrexate albumin conjugates in rats

Cited by 79 publications

References 0 publications

Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside

Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside

Albumin-Based Drug Delivery as Novel Therapeutic Approach for Rheumatoid Arthritis

An Albumin-Conjugated Peptide Exhibits Potent Anti-HIV Activity and LongIn VivoHalf-Life

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