Facile Synthesis And Innate Anticancer Effects Of Novel Dendrimers

Dendrimers are a class of artificial macromolecules with tree-like topological structures. Different from traditional linear polymers, dendrimers are characteristic of structural perfection, highly molecular symmetry, multivalence, internal cavity, controllable nano-scale sizes and molecular weights, ae well as excellent solubility. The properties have endowed dendrimers wide application prospects in many fields. Especially in biomedical applications, dendrimers have been increasingly employed as nanocarriers of drugs and genes as well as diagnostic agents. However, the relatively low delivery or transfection efficacy and high toxicity of dendrimer-based nanocarriers prevent them from clinical translation. Moreover, dendrimer synthesis is generally very time-consuming, and the dendrimers that can be efficiently synthesized are still very rare, which also limits their application.Aiming at these problems, the research in this thesis focuses on facile synthesis of dendrimers for nanomedicines. Based on several novel click chemistries, several orthogonal monomer pairs were designed, and novel dendrimers were efficiently synthesized. The structure-property relationship of dendrimers were preliminarily discussed. Meanwhile, the therapeutic effects of the dendrimers per se, especially the anticancer effect, were investigated. Furthermore, the in vitro cytotoxicity and in vivo acute and subacute toxicity of the dendriemrs were extensively evaluated. And the pharmacological behaviors of the dendrimer were preliminarily studied.Chapter 1 in this thesis briefly introduces the dendrimer history, structure and physicochemical properties, and emphatically expounds the development of dendrimer synthesis methods and the biomedical applications. Then the effect of copper on cancer development and the several copper-related therapies for cancer treatment are introduced. Based on these two aspects, the design philosophy and main research projects of this thesis are proposed.In Chapter 2, based on two click reactions, namely isothiocyanate-amine coupling and thiol-Michael addition, three orthogonal monomer pairs (BMAITC/cysteamine, BMITC/cysteamine and BMTU-ITC/cysteamine) were designed, and polyacylthiourea (PATU), polythiourea (PTU) and polydithiourea (PDTU) were readily prepared. Various techniques including 1H-NMR,13C-NMR, FT-IR, MALDI-TOF MS and GPC were employed to characterize the structures of dendrimers. The properties of dendrimers such as fluorescence emission, copper chelation were studied, and the structure-property relationship was discussed.In Chapter 3, the innate therapeutic effects of PATU and PTU dendrimers, especially the PEGylated G4 PATU dendrimer (PATU-PEG), were evaluated. The in vitro and in vivo toxicity behaviors of PATU-PEG, and its natural anticancer and anti-metastatic activities were extensively investigated. And the pharmacological behaviors of PATU-PEG, including pharmacokinetics, biodistribution and the potential anticancer mechanisms, were preliminarily studied. The results indicated that PATU-PEG had no cytotoxicity and ultra-low in vivo acute and subacute toxicities with an intravenous LD50 greater than 1 g/kg in mice, but potently inhibited tumor growth and metastasis. Such anticancer activity arises from its capability in depleting in vivo bioavailable copper and intracellular reactive oxygen species and thereby inducing anti-angiogenesis and cell proliferation inhibition. Compared with the reported cytotoxicity-based anticancer polymers, this dendrimer is the first synthetic polymer exerting inherent anticancer activity via non-cytotoxic pathways and giving efficacy even higher than some clinically used cytotoxin-drugs yet without cytotoxin-induced side effects.In Chapter 4, isothiocyanate-amine coupling and thiol-Michael addition were ultilized again for dendrimer synthesis. Unlike the monomer design in Chapter 2, the dithiocarbamate group was introduced into the design of isothiocyanate monomers, affording BMDTC-Et-ITC, BMDTC-Bu-ITC and BMTU-Bu-ITC. Pairing with cysteamine, two classes of polydithiocarbamate-hybrid-polythiourea dendrimers (PDTCETU and PDTCBTU) and a class of polydithiourea dendrimers (PTUBTU) were constructed, respectively, and then characterized using various techniques including’H-NMR and GPC. The properties of dendrimers such as fluorescence emission, copper chelation were studied, and the structure-property relationship was discussed. Furthermore, the effect of copper on the in vitro cytotoxicities of these dendrimers was accessed.In Chapter 5, a kinetically chemoselective monomer pair, BMAVS and cysteamine, was designed. Based on two clickable Michael additions, namely vinyl sulfonate-amine addition and methacrylate-thiol addtion, poly(vinyl sulfonate) dendrimers were facilely synthesized by a one-pot per generation method from BMAVS and cysteamine. Various techniques including 1H-NMR, MALDI-TOF MS and GPC were employed to characterize the structures of the dendrimers.In Chapter 6, a brief summary of the whole thesis was made and an individual opinion about the future development of dendrimer chemistry were proposed.