Polymers containing enzymatically degradable bonds, 4. Preliminary experiments in vivo

Kopeček, Jindřich; Cífková, I.; Rejmanová, Pavla; Strohalm, J.; Obereigner, B.; Ulbrich, Karel

doi:10.1002/macp.1981.021821102

Cited by 65 publications

(19 citation statements)

References 14 publications

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“…8) In recent years the use of soluble synthetic polymers as drug delivery systems has been received increasing attention. N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers containing a tetrapeptide side chain (Gly-Phe-Leu-Gly) terminated in DOX and, optionally, galactosamine, as a targeting moiety, 9) were recently approved in the United Kingdom for phase I/phase II clinical trials to treat primary hepatoma. HPMA copolymer prodrugs produced increased life spans and an increased number of long-term survivors [10][11][12][13] depending on the structure of the conjugate, timing of administration, and number of doses.…”

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confidence: 99%

Synthesis of Poly(vinyl alcohol)-Doxorubicin Conjugates Containing cis-Aconityl Acid-Cleavable Bond and Its Isomer Dependent Doxorubicin Release

Kakinoki

Kaneo

Ikeda

et al. 2008

Biological & Pharmaceutical Bulletin

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Aconityl-doxorubicin (ADOX) was synthesized by the modified method of Shen and Ryser. Two isomers of cis-ADOX (cis-configuration) and trans-ADOX (trans-configuration) were generated in the reaction of DOX and cis-aconitic anhydride. These products were separated completely by using HPLC and analyzed by TOF-MS spectroscopy and 1 H-and 13 C-NMR experiments. The yields of cis-ADOX and trans-ADOX were 36.3 and 44.8%, respectively. The free g g-carboxylic group of ADOX molecule was coupled to poly(vinyl alcohol) (PVA) via ethylenediamine spacer, resulting the macromolecular conjugates of PVA-cis-ADOX and PVA-trans-ADOX, respectively. The DOX content of the conjugates estimated by the hydrolysis method detected the aglycone of DOX which can be estimated as the PVA-bound DOX selectively was 4.4 w/w% which was similar to 4.6 w/w% by the ordinary UV method. Both PVA-cis-ADOX and PVA-trans-ADOX were very stable at neutral pH, but the release of DOX was increased markedly under acidic conditions. Half-life of the release of DOX from PVA-cis-ADOX at pH 5.0 was 3 h which was 4.7-fold shorter than that from PVA-trans-ADOX (14 h). The cytotoxicities of PVA-cis-ADOX and PVA-trans-ADOX were evaluated by using J774.1 cells employing a [ 3 H]uridine incorporation assay as a measure of RNA synthesis. A significant difference in antitumor activity between PVA-cis-ADOX and PVA-trans-ADOX was observed where the former was much active than the later. It was suggested that the conjugate enters the cells and reaches the lysosomal/endosomal compartment, and that the aconityl spacer releases DOX from the conjugate in the acidic compartment of lysosomes/endosomes due to the participation of a free carboxylic group.

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Synthesis of Poly(vinyl alcohol)-Doxorubicin Conjugates Containing cis-Aconityl Acid-Cleavable Bond and Its Isomer Dependent Doxorubicin Release

Kakinoki

Kaneo

Ikeda

et al. 2008

Biological & Pharmaceutical Bulletin

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“…enzymatically cleavable crosslinks were incorporated in the architecture of the polymer since similarly constructed polymers undergo hydrolytic breakdown upon i.v. administration to rats to form water-soluble lower molecular weight polymer chains that were excreted into the urine [225]. Kopecek evaluated the body distribution of four branched HPMA copolymer-doxorubicin conjugates [224].…”

Section: Anthracyclines Conjugates With Hpma Copolymersmentioning

confidence: 99%

Prodrugs of Anthracyclines in Cancer Chemotherapy

Kratz¹,

Warnecke²,

Schmid³

et al. 2006

CMC

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Designing and developing truly tumor-specific prodrugs remains a challenge in the field of cancer chemotherapy. Active targeting strategies, on the one hand, aim at exploiting membrane-associated receptors or antigens for drug delivery; on the other hand, the enhanced vascular permeability and retention of macromolecules in tumor tissue substantiates the concept of passive targeting. Consequently, research efforts have concentrated on conjugating anticancer agents with a wide spectrum of carriers including antibodies, peptides, serum proteins, and synthetic polymers. Conversely, low-molecular weight prodrugs of anticancer agents have been developed that do not bear an active or passive targeting moiety, but are activated by tumor-associated enzymes at the tumor site. Anthracyclines probably represent the class of anticancer agents that has been most widely used for the development of prodrugs. This overview gives an update of the various low- and high-molecular weight prodrugs of anthracyclines, e.g. with antibodies, peptides, carbohydrates, serum proteins or synthetic polymers, that have been developed over the past 20 years and that exemplify the salient features of a respective drug delivery system. A detailed description will be dedicated to anthracycline prodrugs that have reached an advanced stage of preclinical testing or that have entered clinical trials.

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“…Their study showed that the rate of Dox release from these different conjugate systems was pH-dependent with the highest release rate obtained at pH 5, while only a very small amount of Dox release was observed at physiological pH. The cytotoxicity of various pH-sensitive conjugates was tested and compared with that of other conjugates such as the enzymatically degradable conjugate PK1 (HPMA–Dox copolymer conjugate, linked via Gly-Phe-Leu-Gly peptidyl spacer) 61. The cytotoxicity of the hydrazone-based conjugates was the highest and comparable to that of the free drug, Dox.…”

Section: Polymer–drug Conjugatesmentioning

confidence: 99%

Polymer-Based Therapeutics

2009

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Polymeric materials have been applied in therapeutic applications, such as drug delivery and tissue regeneration, for decades owing to their biocompatibility and suitable mechanical properties. In addition, select polymer-drug conjugates have been used as bioactive pharmaceuticals owing to their increased drug efficacy, solubility, and target specificity compared with small-molecule drugs. Increased synthetic control of polymer properties has permitted the production of polymer assemblies for the targeted and controlled delivery of drugs, and polymeric sequestrants take advantage of their lack of solubility for the sequestration of target molecules in vivo. In more recent studies reviewed in greater detail here, the properties of polymers that distinguish them from small-molecule drugs, such as their high molecular weight and their ability to display multiple pendant moieties, have been specifically exploited for activating cellular targets or inhibiting the binding of pathogens. The elucidation of relevant structure-function relationships in investigations of this kind has relied on the combination of living polymerization methods with chemical conjugation methods, and protein engineering methods have shown increasing potential in the manipulation of architectural features of such polymer therapeutics. Garnering a detailed understanding of the various mechanisms by which multivalent polymers engage biological targets is certain to expand the role of polymers as therapeutics, by enabling highly specific activities of designed polymers in the biological environment.

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Polymers containing enzymatically degradable bonds, 4. Preliminary experiments in vivo

Cited by 65 publications

References 14 publications

Synthesis of Poly(vinyl alcohol)-Doxorubicin Conjugates Containing cis-Aconityl Acid-Cleavable Bond and Its Isomer Dependent Doxorubicin Release

Synthesis of Poly(vinyl alcohol)-Doxorubicin Conjugates Containing cis-Aconityl Acid-Cleavable Bond and Its Isomer Dependent Doxorubicin Release

Prodrugs of Anthracyclines in Cancer Chemotherapy

Polymer-Based Therapeutics

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