Improved <i>in vivo</i> Antitumor Efficacy and Reduced Systemic Toxicity of Carboxymethylpullulan‐peptide‐doxorubicin Conjugates

Nogusa, Hideo; Hamana, Hiroshi; Uchida, Naoshige; Maekawa, Ryuji; Yoshioka, Takayuki

doi:10.1111/j.1349-7006.2000.tb00922.x

Cited by 9 publications

(4 citation statements)

References 10 publications

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“…The intrinsic or acquired resistance of tumor cells to Dau also reduces the response to the treatment. Conjugation with different type of carrier (e.g., oligoand polypeptides, 1 proteins, 2 polysaccharides, 3 polymers, 4,5 dextran 6 ) could decrease the side-effects and improve the selectivity of the drug attached by utilization of different cellular uptake mechanism(s).…”

Section: Introductionmentioning

confidence: 99%

New daunomycin–oligoarginine conjugates: Synthesis, characterization, and effect on human leukemia and human hepatoma cells

et al. 2009

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In this article, the synthesis, a novel chromatographic procedure and characteristics of a new class of daunomycin (Dau)-oligoarginine conjugates are described. In these compounds oligoarginine with 6 or 8 residues (Arg(n), n = 6, 8) is attached to Dau by different covalent bond: squaric amide (Dau- square-Arg(n)), oxime (Dau=N-O-CH2-CO-Arg(n)), or hydrazone (H-Glu(Arg(n))-NH-N=Dau). Conjugates were characterized by RP-HPLC and mass spectrometry. We report also on our findings concerning chemical and biological properties of Dau-conjugates as a function of covalent linkage, site of conjugation and length of the oligoarginine moiety. Stability, fluorescent properties as well as cytostatic effect and cellular uptake of these compounds were studied. Dau-conjugates with squaric amide or oxime linkage were stable, but continuous release of free Dau was observed from the hydrazone conjugate in solution. We found that some spectral characteristics (e.g., the amplitude of the emission spectrum) of conjugates could be sensitive for the site of coupling (amino vs. oxo function). Cytostasis and cellular uptake of conjugates were investigated both on human leukemia (HL-60) and human hepatoma (HepG2) cell lines by MTT assay and flow cytometry We found that cytostatic effect and uptake properties of Dau-conjugates were dependent on the acid stability of the linkage (hydrazone vs. oxime/amide) applied and more markedly on the cell line studied.

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Section: Introductionmentioning

confidence: 99%

New daunomycin–oligoarginine conjugates: Synthesis, characterization, and effect on human leukemia and human hepatoma cells

et al. 2009

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“…In the recent years, a large number of databases have been published, revealing discovery of novel peptides with therapeutic properties ranging from antimicrobial 2 3 4 , antimalarial 5 , antiparasitic 6 , anticancer 7 , cell penetrating 8 , tumor homing 9 , antihypertensive 10 etc. Peptides have gained leverage over antibody and small molecule-based drugs as they possess better tissue penetration, high specificity and comparatively low production cost 11 12 . Though hundreds of potential therapeutic peptides have been discovered so far, only limited peptide-based drugs are in the market.…”

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confidence: 99%

A Web Server and Mobile App for Computing Hemolytic Potency of Peptides

Chaudhary

Kumar

Singh

et al. 2016

Sci Rep

175

148

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Numerous therapeutic peptides do not enter the clinical trials just because of their high hemolytic activity. Recently, we developed a database, Hemolytik, for maintaining experimentally validated hemolytic and non-hemolytic peptides. The present study describes a web server and mobile app developed for predicting, and screening of peptides having hemolytic potency. Firstly, we generated a dataset HemoPI-1 that contains 552 hemolytic peptides extracted from Hemolytik database and 552 random non-hemolytic peptides (from Swiss-Prot). The sequence analysis of these peptides revealed that certain residues (e.g., L, K, F, W) and motifs (e.g., “FKK”, “LKL”, “KKLL”, “KWK”, “VLK”, “CYCR”, “CRR”, “RFC”, “RRR”, “LKKL”) are more abundant in hemolytic peptides. Therefore, we developed models for discriminating hemolytic and non-hemolytic peptides using various machine learning techniques and achieved more than 95% accuracy. We also developed models for discriminating peptides having high and low hemolytic potential on different datasets called HemoPI-2 and HemoPI-3. In order to serve the scientific community, we developed a web server, mobile app and JAVA-based standalone software (http://crdd.osdd.net/raghava/hemopi/).

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“…Compared to the free medication, the conjugation was more efficient at decreasing tumor volume and improving survival rates. The compound is solely effective against solid tumors (Nogusa et al., 2000a ). Pullulan exhibited excellent property in increasing the drug release at the tumor site for Epirubicin, Adriamycin, Doxorubicin, Methotrexate, and Combretastatin as mentioned in Table 3.…”

Section: Chemical Modification Of Pullulanmentioning

confidence: 99%

Pullulan based derivatives: synthesis, enhanced physicochemical properties, and applications

Agrawal

Budhwani

Gurjar³

et al. 2022

Drug Delivery

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Drug distribution relies heavily on polymers, which also offer a variety of benefits like controlled release, targeted release, prolonged release, etc. Due to their low toxicity and great safety, biodegradable polymers are highly preferred. The exopolysaccharide known as pullulan is generated from a fungus known as Aureobasidium pullulan . It has many different qualities, including biodegradability, appropriate adhesion, antioxidant, film-forming capacity, blood compatibility, mucosal adhesion, etc. However, its application in the pharmaceutical industry is restricted by its insolubility in organic solvents, mechanical characteristics, and lack of macromolecule-carrying ability groups. This review provides an overview of the modifications made to pullulan, including periodate oxidation, etherification, esterification, sulfation, urethane derivatization, PEG incorporation, and cationization, to enhance its solubility in organic solvents, mechanical properties, pH sensitivity, drug delivery, anticoagulant, and antimicrobial properties. Pullulan has nine active hydroxyl groups in its structure that react chemically that can be used for physicochemical modification to produce pullulan derivatives. A key area of pullulan research has been pullulan modification, which has demonstrated enhanced solubility, pH-sensitive targeting, broadened horizons for delivery systems, anticoagulation, and antibacterial properties.

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Improved in vivo Antitumor Efficacy and Reduced Systemic Toxicity of Carboxymethylpullulan‐peptide‐doxorubicin Conjugates

Abstract: The antitumor efficacy of the conjugate of doxorubicin (DXR) and carboxymethylpullulan (CMPul) with Phe-Gly spacer (CMPul-FG-DXR) was evaluated using murine tumor models and compared with that of DXR. The conjugate exhibited higher antitumor efficacy against Lewis lung carcinoma than DXR.

Cited by 9 publications

References 10 publications

New daunomycin–oligoarginine conjugates: Synthesis, characterization, and effect on human leukemia and human hepatoma cells

New daunomycin–oligoarginine conjugates: Synthesis, characterization, and effect on human leukemia and human hepatoma cells

A Web Server and Mobile App for Computing Hemolytic Potency of Peptides

Pullulan based derivatives: synthesis, enhanced physicochemical properties, and applications

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