Dendrimers as potential drug carriers; encapsulation of acidic hydrophobes within water soluble PAMAM derivatives

This paper describes the synthesis of three neutral water soluble poly(amidoamine) (PAMAM) dendrimer derivatives. The ability of the two larger dendrimers to bind small acidic hydrophobic molecules is reported. Spectroscopic data and pH behaviour suggested that the acidic hydrophobes were forming stable ion pairs with the dendrimer's internal, basic tertiary nitrogens. With respect to forming 1:1 and 2:1 substrate/dendrimer complexes, both of the larger dendrimers were equally efficient at binding. All dendrimer/substrate complexes were completely miscible with water in all proportions (i.e. infinitely water soluble). When the bound substrates are drug moieties, then the resulting complexes could be considered as potential drug delivery systems. Flow calorimetry demonstrated that the dendrimers were able to release their hydrophobic guests when in contact with a biological cell.     

铂类抗癌药物的多功能纳米递送体系

以顺铂为代表的小分子铂类抗癌药物是临床应用的一线化疗药物,但其严重的毒副作用和难以克服的耐药性限制了铂类药物的临床应用和研发。运用纳米药物递送技术可以实现药物的靶向递送和可控释放,来提高药物的生物利用度,降低药物的毒副作用以及耐药性,为癌症的治疗带来新的希望。此外,丰富多样的纳米递送体系易于实现药物与具有生物学活性试剂的共运输,从而为各种治疗策略以及诊疗策略的联用提供可能,为最终实现癌症的精准治疗展现广阔前景。本文从靶向递药、药物可控释放、联合治疗、诊疗一体化四个方面对铂类抗癌药物的多功能纳米递送体系在癌症治疗中的最新研究进展进行综述,同时通过列举最新研究成果,展示了新材料、新技术以及新颖设计思想在铂基纳米递送体系中的应用。     

PAMAM Dendrimers for siRNA Delivery: Computational and Experimental Insights

Short double‐stranded RNAs, which are known as short interfering RNA (siRNA), can be used to specifically down‐regulate the expression of the targeted gene in a process known as RNA interference (RNAi). However, the success of gene silencing applications based on the use of synthetic siRNA critically depends on efficient intracellular delivery. Polycationic branched macromolecules such as poly(amidoamine) (PAMAM) dendrimers show a strong binding affinity for RNA molecules and, hence, can provide an effective, reproducible, and relatively nontoxic method for transferring siRNAs into animal cells. Notwithstanding these perspectives, relatively few attempts have been made so far along these lines to study in detail the molecular mechanisms underlying the complexation process between PAMAMs and siRNAs. In this work we combine molecular simulation and experimental approaches to study the molecular requirements of the interaction of RNA‐based therapeutics and PAMAM dendrimers of different generations. The dendrimers and their siRNA complexes were structurally characterized, and the free energy of binding between each dendrimer and a model siRNA was quantified by using the well‐known MM/PBSA approach. DOSY NMR experiments confirmed the structural in silico prediction and yielded further information on both the complex structure and stoichiometry at low N/P ratio values. siRNA/PAMAM complex formation was monitored at different N/P ratios using gel retardation assays, and a simple model was proposed, which related the amount of siRNA complexed to the entropy variation upon complex formation obtained from the computer simulations.     

肽类树状大分子的合成及其在药物传输系统中的应用

树状大分子是近年来蓬勃发展的一类新型高分子材料, 其表面存在大量的官能团, 分子内部存在空腔且分子尺寸可控, 因此, 树状大分子已被广泛应用于众多的领域. 肽类树状大分子是指在树状大分子结构中含有肽键的一类大分子, 因其具有类似蛋白质一样的球状结构, 且具有优异的水溶性、生物相容性、生物降解性和细胞低毒性等特点, 所以, 肽类树状大分子可以作为药物传输的载体. 此外, 肽类树状大分子的疏水空腔可以装载疏水性药物, 对其起到增溶和缓释作用. 综述了肽类树状大分子的合成方法, 并对其与药物分子的结合机制及其在药物传输系统中的应用进行了总结与展望.     

以聚酰胺-胺树形分子为模板制备AgI纳米簇

本文以聚酰胺-胺(PAMAM)树形分子为模板,原位制备AgI纳米簇.系统地研究了AgI纳米簇制备过程中各种反应条件如树形分子端基、反应时间、Ag⁺与PAMAM摩尔比等对AgI纳米簇粒径的影响,分别用紫外-可见光谱、荧光光谱、透射电镜等对所制备的纳米簇进行表征.在相同的条件下,以G4.5-COOH₃为模板较以G5.0-NH₂为模板制备的AgI纳米簇粒径小、分布均匀,这主要取决于G4.5-COOCH₃PAMAM树形分子所起的“内模板”作用.G4.5-COOH₃树形分子浓度为1×10^-5mol/L,Ag⁺与树形分子摩尔比为30:1时所制备的AgI纳米簇的粒径分布均匀、稳定性好,室温避光可稳定存在两个月以上.     

Peptide‐Decorated Dendrimers and Their Bioapplications

Peptide‐decorated dendrimers (PDDs) are a class of spherical, regular, branched polymers that are modified by peptides covalently attached to their surface. PDDs have been used as protein mimetics, novel biomaterials, and in a wide range of biomedical applications. Since their design and development in the late eighties, poly‐l ‐lysine has been a preferred core structure for PDDs. However, numerous recent innovations in polymer synthesis and ligation chemistry have re‐energized the field and led to the emergence of well‐defined peptide dendrimers with more diverse core structures and functions. This Minireview highlights the development of PDDs driven by significantly improved ligation chemistry incorporating structurally well‐defined peptides and the emerging use of PDDs in imaging and drug development.     

AgBr纳米簇：PAMAM树形分子模板法制备及光催化性能研究

以酯端基聚酰胺-胺(PAMAM)树形分子为模板，原位制备了AgBr纳米簇。由于酯端基的半代PAMAM树形分子起到“内模板”作用，制得的AgBr纳米簇粒径小、尺寸分布窄、稳定性好，并通过改变Ag⁺∶PAMAM树形分子的物质的量的比可以精确控制纳米簇的尺寸。AgBr纳米簇/树形分子纳米复合材料在光催化降解甲基橙方面具有很好的催化能力，且随纳米簇的尺寸减小，其催化能力增强。     

银离子与聚酰胺-胺型树形高分子配位作用的研究

The complexation between poly(amidoamine) (PAMAM) dendrimers and silver ion was studied in this paper. The results showed that generations and surface groups of dendrimers， reaction time， pH value， mole ratio of Ag⁺/PAMAM dendrimers， as well as reaction temperature strongly influence complexation between Ag⁺ and PAMAM dendrimers. The maximum complexing number of Ag⁺ that amino-， hydroxyl- and carboxylate- terminated PAMAM dendrimers could bind has been obtained. It has been found that the measured value of amino- and hydroxyl- ter-minated PAMAM is almost similar to the theory value， but to carboxylate- terminated PAMAM， there is a dis-crepancy between the measured value and theory value because of the electrostatic interaction between the silver ion and carboxyl group.     

Reaction of Amino-Terminated PAMAM Dendrimers with Carbon Dioxide in Aqueous and Methanol Solutions

Polyamines have been used as active materials to capture carbon dioxide gas based on its well-known reaction with amines to form carbamates. This work investigates the reactions between three amino-terminated poly(amidoamine) (PAMAM) dendrimers (G1, G3 and G5) and CO₂(g) in aqueous (D₂O) and methanolic (CD₃OD) solutions. The reactions were monitored using ¹H NMR spectroscopy, and yielded dendrimers with a combination of terminal carbamate and terminal ammonium groups. In aqueous media the reaction was complicated by the generation of soluble carbonate and bicarbonate ions. The reaction was cleaner in CD₃OD, where the larger G5 dendrimer solution formed a gel upon exposure to CO₂(g). All reactions were reversible, and the trapped CO₂ could be released by treatment with N₂(g) and mild heating. These results highlight the importance of the polyamine dendrimer size in terms of driving changes to the solution’s physical properties (viscosity, gel formation) generated by exposure to CO₂(g).     

Dendrimers as Non-Viral Vectors in Gene-Directed Enzyme Prodrug Therapy

Gene-directed enzyme prodrug therapy (GDEPT) has been intensively studied as a promising new strategy of prodrug delivery, with its main advantages being represented by an enhanced efficacy and a reduced off-target toxicity of the active drug. In recent years, numerous therapeutic systems based on GDEPT strategy have entered clinical trials. In order to deliver the desired gene at a specific site of action, this therapeutic approach uses vectors divided in two major categories, viral vectors and non-viral vectors, with the latter being represented by chemical delivery agents. There is considerable interest in the development of non-viral vectors due to their decreased immunogenicity, higher specificity, ease of synthesis and greater flexibility for subsequent modulations. Dendrimers used as delivery vehicles offer many advantages, such as: nanoscale size, precise molecular weight, increased solubility, high load capacity, high bioavailability and low immunogenicity. The aim of the present work was to provide a comprehensive overview of the recent advances regarding the use of dendrimers as non-viral carriers in the GDEPT therapy.     

Use of Half-Generation PAMAM Dendrimers (G0.5–G3.5) with Carboxylate End-Groups to Improve the DACHPtCl2 and 5-FU Efficacy as Anticancer Drugs

The DACHPtCl₂ compound (trans-(R,R)-1,2-diaminocyclohexanedichloroplatinum(II)) is a potent anticancer drug with a broad spectrum of activity and is less toxic than oxaliplatin (trans-l-diaminocyclohexane oxalate platinum II), with which it shares the active metal fragment DACHPt. Nevertheless, due to poor water solubility, its use as a chemotherapeutic drug is limited. Here, DACHPtCl₂ was conjugated, in a bidentate form, with half-generation PAMAM dendrimers (G0.5–G3.5) with carboxylate end-groups, and the resulting conjugates were evaluated against various types of cancer cell lines. In this way, we aimed at increasing the solubility and availability at the target site of DACHPt while potentially reducing the adverse side effects. DNA binding assays showed a hyperchromic effect compatible with DNA helix’s disruption upon the interaction of the metallodendrimers and/or the released active metallic fragments with DNA. Furthermore, the prepared DACHPt metallodendrimers presented cytotoxicity in a wide set of cancer cell lines used (the relative potency regarding oxaliplatin was in general high) and were not hemotoxic. Importantly, their selectivity for A2780 and CACO-2 cancer cells with respect to non-cancer cells was particularly high. Subsequently, the anticancer drug 5-FU was loaded in a selected metallodendrimer (the G2.5COO(DACHPt)₁₆) to investigate a possible synergistic effect between the two drugs carried by the same dendrimer scaffold and tested for cytotoxicity in A2780cisR and CACO-2 cancer cell lines. This combination resulted in IC₅₀ values much lower than the IC₅₀ for 5-FU but higher than those found for the metallodendrimers without 5-FU. It seems, thus, that the metallic fragment-induced cytotoxicity dominates over the cytotoxicity of 5-FU in the set of considered cell lines.     

Photoresponsive nanocarriers based on PAMAM dendrimers with a o‐nitrobenzyl shell

Gn (n = 3, 4, and 5) poly(amidoamine) (PAMAM) dendrimers were synthesized and peripherally modified with photocleavable o‐nitrobenzyl (NB) groups by reacting o‐nitrobenzaldehyde with the terminal amine groups of PAMAM dendrimers, followed by reducing the imine to amine groups with NaBH₄. The NB‐modified dendrimers, Gn‐NB (n = 3, 4, and 5), were characterized by nuclear magnetic resonance and fourier transform infrared spectroscopy. The results showed that the NB groups were successfully attached on the periphery of the dendrimers with near 100% grafting efficiency. Such a photosensitive NB shell could be cut off on irradiation with 365 nm ultraviolet (UV) light. The encapsulation and release of guest molecules, that is, salicylic acid (SA) and adriamycin (ADR), by Gn‐NB were explored. The encapsulation capability of these dendrimers was found to increase as the guest molecular size was decreased and have dependence on the generation of dendrimers as well. For both of SA and ADR, the average encapsulation numbers per dendrimer decreased in the order of G4‐NB > G5‐NB > G3‐NB, indicating that the fourth generation dendrimer was a better container for the guest molecules. The rate of SA release was found to be greater with UV irradiation than that without, suggesting that the NB‐shelled PAMMAM dendrimers could function as a molecular container/box with photoresponsive characteristics. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 551–557, 2010     

聚酰胺-胺树形分子对胶带上油潜指纹的显现研究

研究了不同pH值和光源波长条件下,荧光性聚酰胺-胺树形分子(PAMAM)水溶液对胶带粘面上油潜指纹的显现效果.结果显示:PAMAM树形分子水溶液pH值大于7时,指纹残留物被不同程度地溶解,因此显现效果不佳;pH值为4—7时,显现效果较好,处理过的指纹发出明亮的蓝色荧光,指纹纹路完整、特征明显,且与基底的对比度较高;但由于用365 nm紫外光激发时,PAMAM树形分子的蓝色荧光容易受胶带中杂质蓝色荧光的影响,因此对比度仅为28.8%左右;采用其它波段的可见光或者复合白光作为光源后,有效规避了胶带中杂质的同色系荧光干扰,指纹对比度可提高至90%,并且避免了紫外光使用过程中对人体的伤害.PAMAM树形分子水溶液是一种环保的、具有潜在应用价值的识别胶带粘面上油潜指纹的优良显现材料.     

Self‐Assembly of Amphiphilic Janus Dendrimers into Mechanically Robust Supramolecular Hydrogels for Sustained Drug Release

Compounds that can gelate aqueous solutions offer an intriguing toolbox to create functional hydrogel materials for biomedical applications. Amphiphilic Janus dendrimers with low molecular weights can readily form self‐assembled fibers at very low mass proportion (0.2 wt %) to create supramolecular hydrogels (G′?G′′) with outstanding mechanical properties and storage modulus of G′>1000 Pa. The G′ value and gel melting temperature can be tuned by modulating the position or number of hydrophobic alkyl chains in the dendrimer structure; thus enabling exquisite control over the mesoscale material properties in these molecular assemblies. The gels are formed within seconds by simple injection of ethanol‐solvated dendrimers into an aqueous solution. Cryogenic TEM, small‐angle X‐ray scattering, and SEM were used to confirm the fibrous structure morphology of the gels. Furthermore, the gels can be efficiently loaded with different bioactive cargo, such as active enzymes, peptides, or small‐molecule drugs, to be used for sustained release in drug delivery.     

Polymeric Micelles for Multidrug Delivery and Combination Therapy

The use of conventional therapy based on a single therapeutic agent is not optimal to treat human diseases. The concept called “combination therapy”, based on simultaneous administration of multiple therapeutics is recognized as a more efficient solution. Interestingly, this concept has been in use since ancient times in traditional herbal remedies with drug combinations, despite mechanisms of these therapeutics not fully comprehended by scientists. This idea has been recently re‐enacted in modern scenarios with the introduction of polymeric micelles loaded with several drugs as multidrug nanocarriers. This Concept article presents current research and developments on the application of polymeric micelles for multidrug delivery and combination therapy. The principles of micelle formation, their structure, and the developments and concept of multidrug delivery are introduced, followed by discussion on recent advances of multidrug delivery concepts directed towards targeted drug delivery and cancer, gene, and RNA therapies. The advantages of various polymeric micelles designed for different applications, and new developments combined with diagnostics and imaging are elucidated. A compilation work from our group based on multidrug‐loaded micelles as carriers in drug‐releasing implants for local delivery systems based on titania nanotubes is summarized. Finally, an overview of recent developments and prospective outlook for future trends in this field is given.     

聚酰胺-胺树状大分子的应用

聚酰胺-胺(PAMAM)树状大分子是目前树状大分子化学中研究较为成熟的一类，是三种已经商品化的树状大分子之一，其功能化和应用是目前树状大分子领域的热点。PAMAM已在多个领域显示出良好的应用前景。本文主要对PAMAM在表面活性剂、催化剂、纳米复合材料、金属纳米材料、膜材料、导电材料等方面的应用进行评述。     

Curcumin Loaded Dendrimers Specifically Reduce Viability of Glioblastoma Cell Lines

Glioblastoma (GB) is a deadly and aggressive cancer of the CNS. Even with extensive resection and chemoradiotherapy, patient survival is still only 15 months. To maintain growth and proliferation, cancer cells require a high oxidative state. Curcumin, a well-known anti-inflammatory antioxidant, is a potential candidate for treatment of GB. To facilitate efficient delivery of therapeutic doses of curcumin into cells, we encapsulated the drug in surface-modified polyamidoamine (PAMAM) dendrimers. We studied the in vitro effectiveness of a traditional PAMAM dendrimer (100% amine surface, G4 NH₂), surface-modified dendrimer (10% amine and 90% hydroxyl-G4 90/10-Cys), and curcumin (Cur)-encapsulated dendrimer (G4 90/10-Cys-Cur) on three species of glioblastoma cell lines: mouse-GL261, rat-F98, and human-U87. Using an MTT assay for cell viability, we found that G4 90/10-Cys-Cur reduced viability of all three glioblastoma cell lines compared to non-cancerous control cells. Under similar conditions, unencapsulated curcumin was not effective, while the non-modified dendrimer (G4 NH₂) caused significant death of both cancerous and normal cells. By harnessing and optimizing the components of PAMAM dendrimers, we are providing a promising new route for delivering cancer therapeutics. Our results with curcumin suggest that antioxidants are good candidates for treating glioblastoma.