bis-MPA Dendrons Research Articles

Enzyme and pH dual responsive linear-dendritic block copolymer micelles based on a phenylalanyl-lysine motif and peripherally ketal-functionalized dendron as potential drug carriers.

Stimuli-responsive linear-dendritic block copolymers (LDBCs) have attracted significant research attention as novel drug carriers. We report here three generations of new enzyme and pH dual responsive linear-dendritic block copolymers (LDBCs) with a phenylalanyl-lysine (Phe-Lys) dipeptide linking hydrophilic linear poly(N-vinylpyrrolidone) (PNVP) and a hydrophobic peripherally ketal-functionalized dendron derived from 2,2'-bis(hydroxymethyl)propionic acid (bis-MPA). The LDBCs are synthesized via a combination of interchange of xanthates/reversible addition-fragmentation chain transfer (MADIX/RAFT) polymerization of N-vinylpyrrolidone (NVP) and "chain-first" strategy. Their structures are confirmed by 1H NMR spectra. The gel permeation chromatograph (GPC) analysis revealed that the LDBCs have a narrow molecular weight distribution (PDI ≤ 1.25). The amphiphilic LDBCs can self-assemble into spherical nanomicelles in aqueous solution. The presence of enzyme or/and the change of pH cause disassembly of micelles to release encapsulated cargos. The release rates of the guest molecules are faster in buffer solution at pH 5.0 than those upon the addition of the activating enzyme and can be fine-tuned by changing the generation of bis-MPA dendrons. The combination of enzyme and pH dual stimuli results in significantly accelerated and more complete release of the loaded hydrophobic guests. The cell viability assay confirmed the favorable biocompatibility until the LDBC micelle concentration reached 800 μg mL-1. These results indicate that the LDBCs can be considered as a good candidate for targeting drug delivery.

Divergent Synthesis of Ultrabright and Dendritic Xanthenes for Enhanced Click-Chemistry-Based Bioimaging.

Biorthogonal labelling with fluorescent small molecules is an indispensable tool for diagnostic and biomedical applications. In dye-based 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assays, augmentation of the fluorescent signal entails an overall enhancement in the sensitivity and quality of the method. To this end, a rapid, divergent synthetic procedure that provides ready-to-click pH-insensitive rhodamine dyes exhibiting outstanding brightness was established. Compared to the shortest available synthesis of related high quantum-yielding rhodamines, two fewer synthetic steps are required. In a head-to-head imaging comparison involving copper(I)-catalyzed azide alkyne cycloaddition reactions with in vitro administered EdU, our new 3,3-difluoroazetidine rhodamine azide outperformed the popular 5-TAMRA-azide, making it among the best available choices when it comes to fluorescent imaging of DNA. In a further exploration of the fluorescence properties of these dyes, a set of bis-MPA dendrons carrying multiple fluorescein or rhodamine units was prepared by branching click chemistry. Fluorescence self-quenching of fluorescein- and rhodamine-functionalized dendrons limited the suitability of the dyes as labels in EdU-based experiments but provided new insights into these effects.

Neopentyl Esters as Robust Linkers for Introducing Functionality to Bis-MPA Dendrimers

A series of neopentyl carboxylic acids bearing functionality amenable to click chemistry were prepared and then appended to high-generation bis-MPA dendrons via fluoride-promoted esterification. The nucleophilic stability of neopentyl and non-neopentyl dendrons in acidic to basic phosphate buffers was compared by monitoring degradation via quantitative 1H nuclear magnetic resonance (NMR). The neopentyl periphery dendrons were found to be highly resistant to hydrolysis under all experimental conditions. The neopentyl groups also did not impede click functionalization onto the dendrons.

Synthesis and Characterization of Cationic Dendrimer‐PDMS Hybrids

A modular strategy for the synthesis of dendron-linear polymer hybrids comprised of a flexible polydimethylsiloxane (PDMS) midblock with cationic 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) dendron end groups is developed. The invention of a scalable methodology to access quaternary ammonium carboxylate building blocks and their direct use in esterification chemistry enables rapid access to cationic bis-MPA dendrons. The convergent click coupling of highly charged dendrons to hydrophobic PDMS chain-ends gives a 12-membered family of hybrids that are comprised of different dendron generations (G1-3) and quaternary ammonium alkyl chain lengths (C4 , C8 , C12 , C16 ). This provides a library of materials with variable hydrophobicity, charge density, and chain-end valency. The physical behavior of the dendron-linear PDMS hybrid copolymers significantly changes after introduction of the cationic dendron end-groups and leads to soft-solid materials as a result of inhibited chain mobility. These PDMS-dendron hybrids are expected to behave as surface-active antimicrobial additives in bulk cross-linked silicone systems.

Micellar Nanocarriers from Dendritic Macromolecules Containing Fluorescent Coumarin Moieties.

The design of efficient drug-delivery vehicles remains a big challenge in materials science. Herein, we describe a novel class of amphiphilic hybrid dendrimers that consist of a poly(amidoamine) (PAMAM) dendritic core functionalized with bisMPA dendrons bearing cholesterol and coumarin moieties. Their self-assembly behavior both in bulk and in water was investigated. All dendrimers exhibited smectic A or hexagonal columnar liquid crystal organizations, depending on the generation of the dendrimer. In water, these dendrimers self-assembled to form stable spherical micelles that could encapsulate Nile Red, a hydrophobic model compound. The cell viability in vitro of the micelles was studied in HeLa cell line, and proved to be non-toxic up to 72 h of incubation. Therefore, these spherical micelles allow the encapsulation of hydrophobic molecules, and at the same time provided fluorescent traceability due to the presence of coumarin units in their chemical structure, demonstrating the potential of these dendrimers as nanocarriers for drug-delivery applications.

Globular Polymer Grafts Require a Critical Size for Efficient Molecular Sieving of Enzyme Substrates.

A series of 2,2-bis(hydroxymethyl)propionic acid dendrons of generation 2 through 8 having a strained cyclooctyne at the core and hydroxy groups at the periphery were prepared by a divergent method and used to functionalize azide-decorated α-chymotrypsin. The ability of the appended dendrons to selectively block enzyme activity (through a molecular sieving effect) was investigated using a small molecule substrate (benzoyl-l-tyrosine p-nitroanilide), as well as two proteins of different size (casein and bovine serum albumin). Additionally, the ability of dendrons to block complexation with a chymotrypsin antagonist, α-antichymotrypsin, was investigated, and it was found that the dendron coating effectively prevented inhibition by this antagonist. We found that a critical generation is required to achieve efficient sieving with bis-MPA dendrons, which illustrates the importance of macromolecular architecture and size in the shielding of proteins.

Convergent dendrimer synthesis by olefin metathesis and studies toward glycoconjugation

The synthesis of novel hyperbranched monodisperse linear dendrimers, based on 2,2-bis-(hydroxymethyl)-propionic acid (bis-MPA), has been achieved by convergent metathesis-mediated coupling between the alkene-terminated focal point of bis-MPA dendrons. On their surface, dendrimers present 4, 8 and 16 functional groups. Glycodendrimers exposing multiple saccharide moieties have also been obtained. To the best of our knowledge, this is the first example of the use of metathesis for focal point coupling.

DNA Transfection to Mesenchymal Stem Cells Using a Novel Type of Pseudodendrimer Based on 2,2-Bis(hydroxymethyl)propionic Acid

In the search for effective vehicles to carry genetic material into cells, we present here new pseudodendrimers that consist of a hyperbranched polyester core surrounded by amino-terminated 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) dendrons. The pseudodendrimers are readily synthesized from commercial hyperbranched bis-MPA polyesters of the second, third, and fourth generations and third-generation bis-MPA dendrons, bearing eight peripheral glycine moieties, coupled by the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). This approach provides globular macromolecular structures bearing 128, 256, and 512 terminal amino groups, and these can complex pDNA. The toxicity of the three pseudodendrimers was studied on two cell lines, mesenchymal stem cells, and HeLa, and it was demonstrated that these compounds do not affect negatively cell viability up to 72 h. The complexation with DNA was investigated in terms of N-to-P ratio and dendriplex stability. The three generations were found to promote internalizing of pDNA into mesenchymal stem cells (MSCs), and their transfection capacity was compared with two nonviral commercial transfection agents, Lipofectamine and TransIT-X2. The highest generations were able to transfect these cells at levels comparable to both commercial reagents.

Nanostructures based on ammonium-terminated amphiphilic Janus dendrimers as camptothecin carriers with antiviral activity

The self-assembly in water of amphiphilic Janus dendrimers leads to micelles suitable to encapsulate camptothecin and act as therapy against the hepatitis C virus, HCV. Dendrimers consist of bis-MPA dendrons linked by their focal point through a CuAAC reaction. The hydrophilic dendron wears ammonium groups in its periphery whereas the lipophilic dendrons contain stearic acid chains. The morphology of the aggregates is controlled through the chemical structure of the dendrimers, particularly their molecular weight and the adequate combination of the lipophilic and hydrophilic blocks. Camptothecin-loaded dendrimer aggregates constitute effective systems to inhibit HCV replication and show low toxicity working at low drug concentrations.

Fluoride-Promoted Esterification (FPE) Chemistry: A Robust Route to Bis-MPA Dendrons and Their Postfunctionalization.

Bifunctional dendrons based on 2,2-bis(methylol)propionic acid (bis-MPA) are highly desirable scaffolds for biomedical applications. This is due to their flawless nature and large and exact number of functional groups as well as being biodegradable and biocompatible. Herein, we describe a facile divergent growth approach to their synthesis from monobenzylated tetraethylene glycol and post functionalization utilizing fluoride-promoted esterification (FPE) chemistry protocols. The scaffolds, presenting selectively deprotectable hydroxyls in the periphery and at the focal point, were isolated on a multigram scale with excellent purity up to the fourth generation dendron with a molecular weight of 2346 Da in seven reactions with a total yield of 50%. The third generation dendron was used as a model compound to demonstrate its functionalizability. Selective deprotection of the dendron’s focal point was achieved with an outstanding yield of 94%, and biotin as well as azido functionalities were introduced to its focal point and periphery, respectively, through FPE chemistry. Bulky disperse red dyes were clicked through CuAAC to the dendron’s azido groups, giving a biotinylated dendron with multivalent dyes with a molecular weight of 6252 Da in a total yield of 37% in five reactions with an average yield of 82% starting from the third generation focally and peripherally protected dendron. FPE chemistry proved to be a superb improvement over previous protocols towards bis-MPA dendrons as high purity and yields were obtained with less toxic solvents and greatly improved monomer utilization.

Dendritic hydrogels: From exploring various crosslinking chemistries to introducing functions and naturally abundant resources

Dendritic hydrogels from dendritic-linear-dendritic (DLD) block copolymers based on PEG and bis-MPA dendrons were constructed via UV-initiated thiol-ene, thiol-yne, CuAAC, and amine-NHS crosslinkin ...

Shell Cross‐Linked Polymeric Micelles as Camptothecin Nanocarriers for Anti‐HCV Therapy

A suitable carrier for camptothecin to act as therapy against the hepatitis C virus is presented. The carrier relies on an amphiphilic hybrid dendritic-linear-dendritic block copolymer, derived from pluronic F127 and bis-MPA dendrons, that forms micelles in aqueous solution. The dendrons admit the incorporation of multiple photoreactive groups that allow the clean and effective preparation of covalently cross-linked polymeric micelles (CLPM), susceptible of loading hydrophilic and lipophilic molecules. Cell-uptake experiments using a newly designed fluorophore, derived from rhodamine B, demonstrate that the carrier favors the accumulation of its cargo within the cell. Furthermore, loaded with camptothecin, it is efficient in fighting against the hepatitis C virus while shows lower cytotoxicity than the free drug.