pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogels via aza‐michael addition for anticancer drug delivery

A pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogel containing “acetals” as pH‐sensitive groups and “disulfides” as reducible linkages was designed and synthesized via aza‐Michael addition reaction between PAMAM and PEGDA diacrylates. The pore size and swelling ratio of hydrogels was varied from 14 ± 3 to 19 ± 4 μm and 214 ± 13 to 300 ± 19 μm, respectively, with varying ethylene glycol repeating units in diacrylates. The swelling ratio of PEGDA/PAMAM network hydrogel increased with increase in the molecular weight of PEG and with decrease in pH. The presence of different cationizable amino‐functionalities in PEGDA/PAMAM network hydrogel helped to enhance the swelling ability of hydrogel under the acidic conditions. The continuous increase in metabolically active live HeLa cells with time in MTT assay implied biocompatibility/noncytotoxicity of the synthesized PEGDA/PAMAM injectable network hydrogel. Furthermore, the prepared PEGDA/PAMAM hydrogel showed higher degradation at lower pH and at higher concentration of DTT. The burst release of doxorubicin from PEGDA/PAMAM hydrogel under the environment of the lower pH and in presence of DTT compared to the release at normal physiological pH and in absence of DTT suggested the potential ability of this model hydrogel system for targeted and selective anticancer drug release at tumor tissues. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 2080–2095     

A NOVEL NANOFILTRATION MEMBRANE PREPARED WITH PAMAM AND TMC (I)

A series of nanofiltration (NF) membranes were prepared with poly(amido-amine) (PAMAM) and trimesoyl chloride (TMC) viu in situ interfacial polymerization.The effects of the generation number and concentration of PAMAM on the properties of NF membranes were discussed.Fourier transform infrared spectroscopy (FTIR-ATR),atomic force microscopy (AFM),scanning electron microscopy (SEM) and contact angle measurements were employed to characterize the resulting membranes.The nanofiltration performances were evaluated with solutions of NaCl,Na2SO4,MgCl2 and MgSO4,respectively.FTIR-ATR spectra indicated that TMC reacted more sufficiently with the higher generation PAMAM.The salts rejection of the resulting membranes increased with increasing the generation number of PAMAM,which was mainly attributed to the concentration difference of terminal amino-groups among the different generation PAMAM.The MgCl2 (2000 mg/L) rejection of NF-G5 reached 90.3% under the pressure of 0.6 Mpa in a cross-flow method measurement.The rejection of MgCl2 increased with increasing concentration of PAMAM.The salts rejection order of NF membranes with high rejection is MgCl2>MgSO4>Na2SO4>NaCI.It was also found that the NF-Gx (x=4,5,6,7) membranes became more hydrophilic with increasing the generation number of PAMAM.     

Inverse Polyamidoamine (i-PAMAM) Dendrimer Antimicrobials

Here we redesigned the branches of polyamidoamine (PAMAM) dendrimers by moving the amide carbonyl group on the other side of the amide nitrogen atom, transforming the β-alaninyl-amidoethylamine branch, which easily undergoes retro-Michael reactions and renders PAMAMs intrinsically unstable, into a more stable glycyl-amidopropylamine branch. The resulting inverse PAMAM (i-PAMAM) dendrimers have the same carbon framework as PAMAMs and only differ by the position of the carbonyl group. In contrast to PAMAMs which are prepared in solution and are difficult to purify, we synthesize i-PAMAMs using high-temperature solid-phase peptide synthesis by iterative coupling and deprotection of the commercially available N,N-bis(N′-Fmoc-3-aminopropyl)glycine and purify them preparative reverse phase HPLC. Our i-PAMAM dendrimers show no detectable degradation over time. We demonstrate this new class of dendrimers with the synthesis of antimicrobial dendrimers with potent yet non-membrane disruptive activities against both Gram-negative and Gram-positive bacteria.     

Liquid membranes for gas/vapor separations

A review on developments of liquid membranes (LMs) in the field of gas and vapor separation of the last 16 years is presented. Liquid membrane configurations employing supports, i.e. immobilized, supported and contained liquid membranes are focussed and detailed information on the respective materials, i.e. supports (supplier, type, thickness, pore width, porosity, tortuosity), liquids and carriers, are presented together with their specific separation tasks. Performance of different LMs in terms of permeability and selectivity as well as stability (duration of testing, applied differential pressures) are compared and discussed. Finally, different preparation methods of LMs are illustrated.     

Elastic Light Tunable Tissue Adhesive Dendrimers

Development of bioadhesive formulations for tissue fixation remains a challenge. The major drawbacks of available bioadhesives are low adhesion strength, toxic byproducts, and complexity of application onto affected tissues. In order to address these problems, this study has developed a hydrogel bioadhesive system based on poly amido amine (PAMAM) dendrimer, grafted (conjugated) with UV‐sensitive, 4‐[3‐(trifluoromethyl)‐3H‐diazirin‐3‐yl] benzyl bromide (PAMAM‐g‐diazirine). This particular diazirine molecule can be grafted to the surface amine groups of PAMAM in a one‐pot synthesis. Diazirine functionalities are carbene precursors that form covalent crosslinks with hydrated tissues after low‐power UV activation without necessity of free‐radical initiators. The rheological properties and adhesion strength to ex vivo tissues are highly controllable depending on diazirine grafting, hydrogel concentration, and UV dose intensity fitting variety types of tissues. Covalent bonds at the tissue/bioadhesive interface provide robust adhesive and mechanical strength in a highly hydrated environment. The free flowing hydrogel conversion to elastic adhesive after UV activation allows intimate contact with the ex vivo swine tissue surfaces with low in vitro cytotoxicity observed, making it a promising bioadhesive formulation toward clinical applications.

     

Biocompatible Size‐Defined Dendrimer–Albumin Binding Protein Hybrid Materials as a Versatile Platform for Biomedical Applications

For the design of a biohybrid structure as a ligand‐tailored drug delivery system (DDS), it is highly sophisticated to fabricate a DDS based on smoothly controllable conjugation steps. This article reports on the synthesis and the characterization of biohybrid conjugates based on noncovalent conjugation between a multivalent biotinylated and PEGylated poly(amido amine) (PAMAM) dendrimer and a tetrameric streptavidin‐small protein binding scaffold. This protein binding scaffold (SA‐ABDwt) possesses nM affinity toward human serum albumin (HSA). Thus, well‐defined biohybrid structures, finalized by binding of one or two HSA molecules, are available at each conjugation step in a controlled molar ratio. Overall, these biohybrid assemblies can be used for (i) a controlled modification of dendrimers with the HSA molecules to increase their blood‐circulation half‐life and passive accumulation in tumor; (ii) rendering dendrimers a specific affinity to various ligands based on mutated ABD domain, thus replacing tedious dendrimer–antibody covalent coupling and purification procedures.

     

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.     

Advanced polymeric dendrimers in the management of Alzheimer's disease

In recent years, advanced polymeric dendrimers have emerged as a promising avenue for AD management. Dendrimers are highly branched, three-dimensional macromolecules with precise nanoarchitectures, making them ideal candidates for the delivery of therapeutic agents and diagnostic tools. Their unique properties, such as well-defined size, multifunctionality, and controlled surface chemistry, allow for the design of targeted and highly efficient drug delivery systems and diagnostic probes. This review aims to provide a comprehensive overview of the potential applications of advanced polymeric dendrimers in the management of Alzheimer's disease. We explored their role in drug delivery, diagnostics, and other therapeutic interventions for AD. Additionally, we will delve into the challenges and opportunities in utilizing dendrimers as a key player in the battle against this devastating disease. The review will begin by discussing the current state of Alzheimer's disease, including its pathological features, clinical manifestations, and existing treatment strategies. It will then transition to an in-depth examination of polymeric dendrimers, highlighting their structural characteristics, synthesis methods, and biocompatibility. Subsequently, the review will delve into the various ways in which dendrimers can be tailored for AD management, including drug encapsulation and delivery, enhanced blood–brain barrier penetration, and targeted diagnostic imaging. Furthermore, we explored the potential benefits of dendrimer-based therapies, such as improved drug efficacy, reduced side effects, and enhanced patient compliance. The review will also address the challenges associated with dendrimer-based approaches, including toxicity concerns, regulatory hurdles, and the need for rigorous clinical evaluation.     

Effect of solvent-controlled aggregation on the intrinsic emission properties of PAMAM dendrimers

Solvent-induced aggregation and its effect on the intrinsic emission properties of amine, hydroxy and carboxylate terminated, poly(amidoamine) (PAMAM) dendrimers have been investigated in glycerol, ethylene glycol, methanol, ethylene diamine and water. Altering the solvent medium induces remarkable changes in the intrinsic emission properties of the PAMAM dendrimers at identical concentration. Upon excitation at 370 nm, amine terminated PAMAM dendrimer exhibits an intense emission at 470 nm in glycerol, ethylene glycol as well as glycerol-water mixtures. Conversely, weak luminescence is observed for hydroxy and carboxylate terminated PAMAM dendrimers in the same solvent systems. When the solvent is changed to ethylene diamine, hydroxy terminated PAMAM exhibits intense blue emission at 425 nm. While the emission intensity is varied when the solvent milieu is changed, excited state lifetime values of PAMAM dendrimers remain independent of the solvent used. UV-visible absorption and dynamic light scattering (DLS) experiments confirm the formation of solvent-controlled dendrimer aggregates in the systems. Comparison of the fluorescence and DLS data reveals that the size distribution of the dendrimer aggregates in each solvent system is distinct, which control the intrinsic emission intensity from PAMAM dendrimers. The experimental results suggest that intrinsic emission intensity from PAMAM dendrimers can be regulated by proper selection of solvents at neutral conditions and room temperature.     

功能化硅壳荧光纳米粒的细胞吞噬研究

合成了氨基聚酰胺-胺(PAMAM(G1.0))和酯基(PAMAM(G1.5))功能化的两种硅壳荧光纳米粒,通过透射电镜(TEM)、纳米粒度及动电位测定仪(zeta电势)、傅立叶红外光谱仪(FTIR)和热失重分析仪(TGA)进行表征;通过透射电镜(TEM)、共聚焦显微镜(CLSM)、细胞计数试剂盒(CCK-8)实验、流式细胞计数法评价两种硅壳荧光纳米粒进入9L细胞能力的大小、在细胞内的分布情况以及细胞毒性.TEM分析表明,修饰的硅壳纳米粒大小约为60 nm左右,pH=7.4,氨基功能化的纳米粒zeta电势为+19.08,酯基功能化的为-9.01;FTIR和TGA实验进一步证明两种纳米粒被氨基和酯基的功能化.TEM和CLSM结果表明纳米粒主要存在细胞浆中,且能被溶酶体吞噬.CCK-8结果显示两种纳米粒的浓度高达1 mg/mL时仍无明显的毒性作用,且有促细胞增殖作用.流式细胞计数结果表明,细胞摄取纳米粒呈浓度和时间依赖性,氨基比酯基修饰的纳米粒更易进入细胞.