Malik, Navid; (1999) Dendrimer Conjugates: Evaluation as Novel Anticancer Therapeutics. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Dendrimers are novel highly branched polymers. Theoretically they have a polydispersity close to one, and offer the opportunity of either attaching bioactive molecules to their functionalised surface or entrapment of bioactive molecules within the dendrimer core. This can facilitate drug targeting and controlled release. To be useful as drug carriers dendrimers must be biocompatible. Three families of dendrimer, polyamidoamine starburst™ (PAMAM), poly(propyleneimine) (DAB), and carbosilane were screened using haematotoxicity and cell cytotoxicity (biocompatibility) assays. Dendrimers bearing a cationic surface (NH2) were generally found to be haemolytic and cytotoxic, whereas dendrimers bearing anionic surface functionality (COO- Na+) and the carbosilane dendrimers were found to be biocompatible. The anionic PAMAM dendrimer generation 3.5 was selected as a carrier for the anti-tumour drugs cisplatin and in preliminary studies doxorubicin. A highly water soluble dendrimer-platinate with 23 wt% platinum loading was synthesised. The dendrimer-platinate was stable at physiological pH and in vitro cytotoxicity testing showed it to be less active than cisplatin, probably due to its slow capture by endocytosis. In vivo, the dendrimer- platinate was equi-active compared to cisplatin in intraperitoneal tumour models (L1210 and B16F10) when administered intraperitoneally and had a maximum tolerated dose (MTD) of 15 mg/kg platinum-equivalent. When administered intravenously to treat a subcutaneous solid tumour (B16F10), the dendrimer-platinate was active whereas cisplatin was inactive at its MTD (1 mg/kg). As the dendrimer-platinate accumulates passively in the solid tumour, displaying a platinum AUC 50 fold higher than that seen for cisplatin, dendrimers have the ability to show tumour targeting. Hence a second conjugate was synthesised having a doxorubicin loading of 3 wt %.

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