Novel Nanoscale Multivalent Platinum Drug Based on a PAMAM Dendrimer

摘要

Recently, there has been considerable interest in hydrophilic, biocompatiable polymeric materials that could serve as drug carriers to achieve site-specific and time-controlled delivery of therapeutics, thus alleviating undesired side effects and enhancing the efficacy of treatment. Traditionally linear hydrophilic polymers have been examined for potential application as drug carriers. The advent of dendrimers, which are highly branched macromolecules with precisely controlled size, shape and end-group functionality, has provided an excellent opportunity to design novel drug carriers. PAMAM dendrimers are the first complete dendrimer family to be synthesized, characterized and commercialized. Biological studies using PAMAM dendrimers have demonstrated that high generation PAMAM dendrimers are non-immunogenic and display low mammalian toxicity, while anionic PAMAM dendrimers (surface groups with carboxylic or hydroxylic functionalities) are non-toxic in vitro. Platinum complexes exhibit strong antitumor activities, especially the well known cis-platin [cis-diamminedichloroplatinum(II)] and carboplatin [cis-diamminecyclobutyldicarboxylate platinum(II)] widely used for the treatment of human testicular, overian, bladder, head and neck carcinomas. However, the side-effects such as nephrotoxicity and myelotoxicity are major drawbacks of these compounds for clinical applications. Molecular simulation studies have suggested that higher generation PAMAM dendrimers (G ≥ 4) are dense-packed spheroids. These observations suggest that a dendrimer of appropriate size should function as a well-behaved carrier for platinum species which display therapeutic properties. Coordination of an appropriate platinum moiety to the dendrimer surface would generate a drug formulation with water solubility, dosage limitations, and response characteristics superior to those of classical platinum drugs.