Stabilization of mitomycins on complexation with cyclodextrins in aqueous acidic media

Bekers, Otto; Beijnen, Jos H.; Bramel, E. H. Groot; Otagiri, Masaki; Bult, A.; Underberg, W.J.M.

doi:10.1016/0378-5173(89)90226-3

Cited by 16 publications

(5 citation statements)

References 14 publications

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“…Cyclodextrins are carbohydrate macrocycles which, by virtue of their ability to form molecular inclusion complexes with a wide range of hydrophobic molecules, are interesting for exploitation as a new class of conjugates for drug delivery ( , ). Actually, cyclodextrins have been investigated to optimize the solubility, stability, and bioavailability of many drugs ( − ). Nevertheless, the parenteral administration of natural cyclodextrins, namely β-cyclodextrins, causes undesirable toxic effects such as hemolysis ().…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Physicochemical Characterization of Folate−Cyclodextrin Bioconjugate for Active Drug Delivery

et al. 2003

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beta-Cyclodextrin-poly(ethylene glycol)-folic acid conjugate (CD-PEG-FA) was synthesized according to a two-step procedure: (1). synthesis of CD-PEG-NH(2) by reaction of monotosyl-activated beta-cyclodextrin with excess of 700 Da diamino-PEG; (2). synthesis of CD-PEG-FA by reaction of CD-PEG-NH(2) with succinimidyl ester-activated folic acid. The CD-PEG-NH(2) intermediate was purified by precipitation in acetone, and the CD-PEG-FA by gel permeation and C-18 reversed-phase chromatography. Both CD-PEG-NH(2) and CD-PEG-FA were analyzed by mass spectrometry, (1)H NMR, and UV-vis spectroscopy. All analytical methods confirmed the theoretical composition of the conjugates: the CD-PEG-NH(2) intermediate was composed of CD and PEG in the molar ratio of 1:1, and the CD-PEG-FA was composed of beta-cyclodextrin, PEG, and folic acid in the molar ratio of 1:1:1. The CD-PEG-FA conjugate was highly soluble in buffer (>42 mM) as compared to the unmodified beta-cyclodextrin (16.3 mM). Phase solubility diagrams of beta-estradiol revealed that drug solubility increases from 11 microM in buffer to 600 microM in the presence of beta-cyclodextrins and 5900 microM with CD-PEG-FA. However, the affinity of beta-estradiol for beta-cyclodextrins decreased about 4 times with PEG and folic acid conjugation. Stability studies carried out using chlorambucil confirmed that the conjugate partially prevents drug degradation in buffer, although this effect was considerably lower than that obtained with beta-cyclodextrin. Computer modeling studies showed that the folic acid linked to the beta-cyclodextrins through a PEG spacer could partially interact with the cyclodextrin cavity. Finally, CD-PEG-FA displayed reduced hemolytic effect as compared to unmodified beta-cyclodextrin.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Physicochemical Characterization of Folate−Cyclodextrin Bioconjugate for Active Drug Delivery

et al. 2003

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“…Pharmaceutical scientists have utilized this property of CDs to address solubility-and stability-related formulation problems. [1][2][3][4][5][6][7][8][9][10] Unmodified CDs, however, cannot be used in parenteral formulations because they exhibit nephrotoxicity and hemolytic activity. On parenteral administration, the nephrotoxicity exhibited by CDs is believed to result from their reabsorption by renal epithelial cells where their accumulation results in increased lysosomal activity and subsequent necrosis.…”

Section: Introductionmentioning

confidence: 99%

Effect of Alkyl Chain Length and Degree of Substitution on the Complexation of Sulfoalkyl Ether β-Cyclodextrins with Steroids

Zia

Rajewski

Bornancini

et al. 1997

Journal of Pharmaceutical Sciences

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This study was designed to test how the sulfoalkyl ether (SAE) modification of beta-cyclodextrin (beta-CD) affects the binding capacity of testosterone and progesterone, thereby enhancing their solubility. The SAE-beta-CD derivatives contain either sulfopropyl ether (SPE) or sulfobutyl ether (SBE) groups on the 2-, 3-, and 6-hydroxyl positions of the dextrose moieties. SAE-beta-CDs are a mixture of positional and regional isomers containing from one to as many as 12 SAE groups per CD. The effect of chain length and the degree of substitution on complexation behavior was investigated by the phase-solubility method. The results were compared with those obtained with beta-CD, where possible, and with hydroxypropyl-beta-CD (HP-beta-CD). To determine the effect of degree of substitution (DS) on the binding, mixtures of SAE-beta-CDs with multiple substitution levels and varying average degrees of substitution were studied as well as mixtures of SAE-beta-CDs that contained the same degree of substitution. Mixtures that contained SAE-beta-CDs of the same degree of substitution were isolated from the multiple substitution level mixtures by ion-exchange chromatography and purified for investigation. Unlike the parent beta-CD, linear increases in the apparent solubilities of testosterone and progesterone were observed, and the binding potentials were comparable to those of beta-CD or better. The results demonstrate that the binding potentials of the SAE-beta-CD derivatives were dependent on the guest molecule, the degree of substitution, and the alkyl ether chain length. Our previous study showed the inhibition of complexation by direct sulfonation of the beta-CD. However, in the present work, interferences with the charged sulfonate groups were avoided by repositioning them away from the cavity. Increasing the degree of substitution assisted in complex formation; however, its effects were limited. Reduction of the alkyl chain length, as in the case of SPE-beta-CD compared with SBE-beta-CD, decreased the complexation potential. This decrease in complexation potential was further suppressed with an increase in the number of substituents placed on the CD torus. Generally, the binding potential of SAE-beta-CD derivatives increased with increasing alkyl chain length. However, placement of more than an optimum number of SAE groups on the CD torus resulted in inhibition of complexation.

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“…However, DOX is also well-known because it interacts with the hydrophobic cavities of βCD through supramolecular hydrophobic interactions. 13,42 This property was used to confer specificity to the antitumoral through the covalent linking of the βCD moiety to diverse director molecules, including BPs. 43,44 For this reason, the tandem DOX-βCD was considered a proof of concept for the proposed PEI-BP-CD ternary supramolecular systems.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Polyethylenimine–Bisphosphonate–Cyclodextrin Ternary Conjugates: Supramolecular Systems for the Delivery of Antineoplastic Drugs

et al. 2021

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Bisphosphonates (BPs) are bone-binding molecules that provide targeting capabilities to bone cancer cells when conjugated with drug-carrying polymers. This work reports the design, synthesis, and biological evaluation of polyethyleneimine–BP–cyclodextrin (PEI-BP-CD) ternary conjugates with supramolecular capabilities for the loading of antineoplastic drugs. A straightforward, modular, and versatile strategy based on the click aza-Michael addition reaction of vinyl sulfones (VSs) allows the grafting of BPs targeting ligands and βCD carrier appendages to the PEI polymeric scaffold. The in vitro evaluation (cytotoxicity, cellular uptake, internalization routes, and subcellular distribution) for the ternary conjugates and their doxorubicin inclusion complexes in different bone-related cancer cell lines (MC3T3-E1 osteoblasts, MG-63 sarcoma cells, and MDA-MB-231 breast cancer cells) confirmed specificity, mitochondrial targeting, and overall capability to mediate a targeted drug transport to those cells. The in vivo evaluation using xenografts of MG-63 and MDA-MB-231 cells on mice also confirmed the targeting of the conjugates.

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Stabilization of mitomycins on complexation with cyclodextrins in aqueous acidic media

Cited by 16 publications

References 14 publications

Synthesis and Physicochemical Characterization of Folate−Cyclodextrin Bioconjugate for Active Drug Delivery

Synthesis and Physicochemical Characterization of Folate−Cyclodextrin Bioconjugate for Active Drug Delivery

Effect of Alkyl Chain Length and Degree of Substitution on the Complexation of Sulfoalkyl Ether β-Cyclodextrins with Steroids

Polyethylenimine–Bisphosphonate–Cyclodextrin Ternary Conjugates: Supramolecular Systems for the Delivery of Antineoplastic Drugs

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