Abstract
Macromolecular prodrugs are very useful systems for achieving controlled drug release and drug targeting. In particular, various macromolecule-antitumor drug conjugates enhance the effectiveness and improve the toxic side effects. Also, polymeric micro- and nanoparticles have been actively examined and their in vivo behaviors elucidated, and it has been realized that their particle characteristics are very useful to control drug behavior. Recently, researches based on the combination of the concepts of macromolecular prodrugs and micro- or nanoparticles have been reported, although they are limited. Macromolecular prodrugs enable drugs to be released at a certain controlled release rate based on the features of the macromolecule-drug linkage. Micro- and nanoparticles can control in vivo behavior based on their size, surface charge and surface structure. These merits are expected for systems produced by the combination of each concept. In this review, several micro- or nanoparticles composed of macromolecule-drug conjugates are described for their preparation, in vitro properties and/or in vivo behavior.
Highlights
A lot of macromolecular prodrugs have been developed using various kinds of polymeric carriers, mainly in the field of cancer chemotherapy [1, 2], and found to be useful to control drug release, modify biodistribution or excretion and achieve drug targeting
Ch-SPMS and enteric-coated Chitosan-prednisolone conjugate (Ch-SP)-MS were described for their useful features [54], which were realized by transition properties in the grastro-intestinal tract based on the particle characteristics and their drug release profiles [55]
The histological features of the lung, liver and kidney after i.v. injection of these conjugate particles showed that they did not exhibit significant abnormalities in those tissues for one month. This suggested that the carriers, SucCh and CM-Ch, would be biocompatible. These conjugate particles enabled gradual drug release based on hydrolysis of the amide bond, and the tissue-specific delivery of mitomycin C (MMC) based on biodistribution features dependent on particle size
Summary
A lot of macromolecular prodrugs have been developed using various kinds of polymeric carriers, mainly in the field of cancer chemotherapy [1, 2], and found to be useful to control drug release, modify biodistribution or excretion and achieve drug targeting. Neutral and weakly anionic macromolecules are not subject to interactions with biomacromolecules or cells in the body as compared with cationic or strong anionic macromolecules [11, 13]; neutral and weakly anionic macromolecules of more than 4 nm have been examined as carriers exhibiting a long systemic circulation, and these macromolecules receive an enhanced permeability retention (EPR) effect at inflammatory sites such as solid tumor tissues [14,15,16,17], leading to the localization of a carried drug at diseased sites In addition to such drug targeting, the drug release properties are important to achieve effectiveness. Conjugates of DOX with HPMA and carboxymethyl-dextran (CM-Dextran) linked via biodegradable peptide spacers exhibited a high antitumor effect as compared with DOX itself, and improved the toxic side effects [19,20,21,22] These were achieved by drug targeting based on the EPR effect and adequate drug release patterns at the tumor site. Ch-SPMS and enteric-coated Ch-SP-MS were described for their useful features [54], which were realized by transition properties in the grastro-intestinal tract based on the particle characteristics and their drug release profiles [55]
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