Cooperative dissolution of peptidomimetic vesicles and amyloid ß fibrils.

The aggregation of amyloid proteins in the brain is a significant neurotoxic event that contributes to neurodegenerative disorders. The aggregation of amyloid beta (Aß), particularly Aß42 monomers, into various forms such as oligomers, protofibrils, fibrils, and amyloid plaques is a key pathological feature in Alzheimer's disease. As a result, Aß42 is a primary target and the development of molecular strategies for the dissolution of Aß42 aggregates is considered a promising approach to mitigating Alzheimer's disease pathology. A set of pyrene-conjugated peptidomimetics derived from Aß14-23 (AkdcPy, AkdmPy, and AkdnPy) by incorporating an unnatural amino acid [kd: cyclo(Lys-Asp)] were studied for their ability to modulate Aß42 aggregation. AkdcPy and AkdmPy formed vesicular structures in aqueous media. The vesicles of AkdmPy loaded with the neuroprotective compound berberine (Ber), dissipated mutually in the presence of preformed Aß42 fibrils. During this process, the active drug Ber was released. This work is expected to inspire the development of drug-loaded peptidomimetic-based therapeutic formulations to modulate disorders associated with amyloid toxicity.

Fabrication of soft-nanocomposites from functional molecules with diversified applications.

With the increasing demand for new soft materials having excellent physical and biological characteristics and functionality, the design of hybrid materials offers a simple, yet versatile platform for the development of materials with specific and tunable properties. By definition a "soft-nanocomposite" is the combination of supramolecular self-assemblies with nanomaterials of different origins (inorganic/metallic nanoparticles and carbonaceous allotropes like carbon nanotubes and graphene) through covalent/non-covalent interactions. Dynamic supramolecular self-assemblies can serve as excellent hosts for the incorporation of these dimensionally different nanomaterials. Nanomaterials within the matrix of supramolecular self-assemblies can give rise to new characteristics due to the synergistic contribution of both materials. Although the very initial work intended to use molecular gels as media for the preparation and stabilization of nanoparticles, recent reports have suggested that amalgamation of different supramolecular self-assemblies with nanoparticles is advantageous for both constituents. These newly developed soft-nanocomposites have interesting properties including electrical conductivity, viscoelasticity, thermal robustness, magnetic, phase-selective, redox and near-infrared radiation sensitive properties and so on. This review will focus on some of the most recent advancements in the development of novel soft-nanocomposites. In particular, we intend to correlate various design strategies for synthesis as well as composite preparation from functional molecules with interesting applications in the area of supercapacitors, nanoelectronics, photovoltaic devices, chemical and biosensors, biomedicine and so on. We expect that this article will be a general and conceptual demonstration of various approaches to develop different soft-nanocomposites and will highlight their applications across disciplines.

Self-assembly of surface functionalized amphiphilic carbon dots: tuning in morphological manifestations.

Despite the continuous surge of interest in supramolecular chemistry, the design and synthesis of building blocks to develop diverse examples of self-assemblies is still challenging. During the past decades, formation of self-assemblies such as micelles, vesicles, and gels with a fibril network using amphiphiles has been investigated at length. Considering the increasing applications of these self-aggregates across the scientific domain, it is crucial to adopt an alternative strategy for the preparation of self-aggregates using a new building block that has been applied in diverse domains. With this aim, surface functionalized carbon dots (CDs) with varying aliphatic/aromatic (cholesteryl, palmitoyl, naphthyl) substitutions linked with spacers such as ethylenediamine, p-phenylenediamine, 2,2'-(ethylenedioxy)bis(ethylamine) were developed. The surface passivated CDs formed self-assemblies in dimethylsulfoxide-water (DMSO-H2O, 2 : 1, v/v). The roles of surface functionalities and spacer units in the formation of self-assemblies using the synthesized CDs were investigated by microscopic and spectroscopic studies. Progressive morphological transition was found from vesicle-to-fiber in DMSO-H2O (2 : 1, v/v) which was dependent on surface passivating substitutions of the CDs from cholesteryl to naphthyl to palmitoyl. Together with the exclusive formation of self-assemblies using amphiphilic CDs, the present study enabled the tuning of self-organization behaviour of the CD by alteration of its surface functionality.

Morphological transformation of self-assemblies by tuning hydrophobic segment of small amphiphiles.

HYPOTHESIS: With increasing surge in the development of supramolecular self-assemblies, it is crucial to predict the influence of amphiphilic segment in dictating the morphology of self-aggregates. This article reports the design and synthesis of low molecular weight amphiphiles with varying hydrophobicity both in the spacer unit and at the terminal moiety. EXPERIMENTS: Hydrophobicity at the spacer moiety was modulated by altering alkyl chain length and by inclusion of aromatic ring and the same was changed at hydrophobic terminal using pyrene, naphthalene, n-hexadecane having 2-aminopyridine as polar head. Microscopy and spectroscopy were used to investigate the morphologies of self-aggregated amphiphiles. FINDINGS: Variation of hydrophobicity of the spacer moiety either by changing the alkyl chain length (C0, C2, C6, C11 and phenyl ring) having pyrene as terminal hydrophobic unit led to the formation of only spherical vesicles in respective solvent system. Morphological transformation of self-aggregates from vesicle to fused-vesicle to gel was observed in DMSO-water upon alteration in the hydrophobic end of amphiphile from pyrene to naphthyl to C16 alkyl chain having C6 alkyl chain as spacer. Hence, the hydrophobicity at the terminal of the amphiphile has the predominant role in tuning the morphology of self-aggregates through modulation in the hydrophobic-lipophilic balance (HLB) of amphiphiles.

Metal Ion (Fe2+ and Co2+) Induced Morphological Transformation of Self-Aggregates of Cholesterol-Tethered Bipyridine Amphiphiles: Selective Cancer Cell Killing by Pro-Drug Activation.

Design and development of diverse supramolecular self-assemblies from a single amphiphilic molecule has always been challenging, and it can have prospects in different task-specific applications. The present study reports the formation of different morphologies of self-aggregates by the inclusion of transition metals that are biologically more relevant due to their participation in biochemical reactions. A cholesterol-tethered bipyridine-appended amphiphile (CBB) has been synthesized that spontaneously formed vesicles in a 2:1 DMSO-water (v/v) solvent mixture. This vesicle undergoes metal-ion-induced transition from the vesicle to associated vesicles or sheets. The formation of the associated vesicular structure was observed in the presence of a transition metal ion, Fe2+, while morphological transformation from the vesicle to sheet took place in the presence of Co2+. Different spectroscopic and microscopic investigations showed that both the morphological transformations took place via the alteration of the molecular-level aggregation pattern from H-type (for vesicle formed by only CBB) to J-type (for the associated vesicle or sheet formed by metal ion included CBB). Moreover, the Fe2+-containing self-aggregate successfully produced reactive oxygen species (ROS, i.e., hydroxyl/superoxide radicals) from H2O2 through Fenton reactions. This unique characteristic of Fe2+ including a self-aggregate was utilized for oxidative DNA damage in the presence of H2O2. Consequently, this Fe(II)-CBB complex self-aggregate was exploited in selective and efficient killing of cancer cells owing to its high H2O2 content. Thus, Fe(II)-included self-assembly (associated vesicular aggregate) of CBB becomes the unique pro-drug activator which can selectively destroy the cancer cells through Fenton reaction even in the absence of any anticancer drug.

Glucose oxidase mediated targeted cancer-starving therapy by biotinylated self-assembled vesicles.

Herein, we demonstrate glucose oxidase (GOx) mediated targeted cancer-starving therapy by self-assembled vesicle of trimesic acid based biotinylated amphiphile (TMB). The TMB vesicles entrapped GOx and selectively killed cancer cells (HeLa, B16F10), with ∼6-fold higher efficiency compared to non-cancer cells (CHO, NIH3T3), by blocking the energy supply to tumors through the oxidation of intracellular glucose.

Vesicle formation by cholesterol based hydrazone tethered amphiphiles: Stimuli responsive dissipation of self-assembly.

Stimuli are one of the key parameters to achieve a control over the association/dissociation of molecular tectons in self-assemblies. In this present article, we synthesized cholesterol based pH-sensitive hydrazone-tailored low molecular mass amphiphiles (CBH-1-3). The hydrazone residue was modified by varying the carbonyl moieties from aldehyde (benzaldehyde (CBH-1), p-dimethylaminobenzaldehyde (CBH-2)) to ketone (benzophenone (CBH-3)). Microscopic and spectroscopic characterizations were carried out to investigate the pattern of self-aggregation and its morphology. Among these amphiphiles, CBH-1 and CBH-2 were found to form vesicular aggregates through H-type aggregation in 1:3 v/v, DMSO-water having dimension of around 50-120 nm in the case of CBH-1 and ∼150-250 nm for CBH-2. Moreover, low angle X-ray diffraction (XRD) pattern of the self-aggregates confirmed the formation of bilayer vesicles through highly ordered lamellar like structure for the hydrazone-tailored amphiphiles. These vesicles are stable at pH 7.0 and above, however get disassembled at acidic pH (pH < 5.0). This dissipation of the vesicular self-aggregates because of the cleavage of the hydrazone bond under acidic environment was investigated by UV-visible, FTIR and mass spectrometric studies. Moreover, absence of any spherical aggregate in the transmission electron microscopic (TEM) images of the acid treated vesicles confirmed its disintegration in acidic medium. Furthermore, dye encapsulation and its pH-responsive release from the CBH-1 vesicles were tested using doxorubicin as drug.

Tailor-Made Self-Assemblies from Functionalized Amphiphiles: Diversity and Applications.

The objective of this feature article is to coalesce our recent advancements on different expressions of tailor-made supramolecular self-assemblies and to explore them as a function of molecular architecture. In the last decade, we have developed a library of elegant and simple functional amphiphilic small molecules, which have very interesting abilities to form diverse manifestations of supramolecular self-assemblies such as micelles, reverse micelles, vesicles, fibers, supramolecular gels, and so on. Each of the expressions of the self-aggregated structures has its individual prominence and finds important applications in the fields of chemistry, physics, biology, and others. In this feature article, the major emphasis is mostly on how to attain precise control over the development of various well-defined supramolecular self-assemblies through the judicious design of low-molecular-weight amphiphiles. By tuning only the functional moieties of the amphiphilic structure, diverse supramolecular architectures can be constructed with task-specific applications. We expect that this article will provide a general and conceptual demonstration of various approaches to the development of different functional supramolecular systems and their prospective applications in numerous domains.

Self-Assembled Vesicle-Carbon Nanotube Conjugate Formation through a Boronate-Diol Covalent Linkage.

A vesicle-single walled carbon nanotube (CNT) conjugate was developed by a boronic acid-diol covalent linkage between a self-assembled vesicle and dispersed CNT. Trimesic acid based phenylboronic acid appended triple-tailed amphiphiles (T1 and T1S) were synthesized that formed monolayered vesicles through H-aggregation in DMSO-water (2:1 v/v) and pure water, respectively. Aqueous CNT dispersion was prepared with cholesterol-based glucose-functionalized amphiphile (D1). These two supramolecular self-assemblies were covalently linked by using a boronic acid-diol interaction between a phenylboronic acid based T1S vesicle and 1,2-diol moieties of glucose tethered dispersing agent (D1) to develop a vesicle-CNT conjugate. Lewis acid-base chemistry was exploited to form this boronate-diol adduct between two supramolecular self-assemblies. The formation of vesicles, CNT dispersion, and the vesicle-CNT conjugate was characterized by microscopic and spectroscopic techniques. Anticancer drug doxorubicin was encapsulated within this T1S-vesicle-D1-CNT conjugate with a higher loading capacity compared to the individual cargo carrier (vesicle or CNT). This cytocompatible T1S-vesicle-D1-CNT conjugate successfully delivered loaded doxorubicin within a B16F10 melanoma cell and also exhibited better cellular transportation ability compared to the drug-loaded vesicle or CNT. This was further reflected in an enhanced killing efficiency of the cancer cells by the vesicle-CNT conjugate compared to the drug-loaded vesicle or CNT.

Solvent Induced Morphological Evolution of Cholesterol Based Glucose Tailored Amphiphiles: Transformation from Vesicles to Nanoribbons.

Supramolecular self-assembly of low molecular mass amphiphiles is of topical interest with the urge to achieve precise control over the formation of various self-aggregated structures. Particularly, fabrication of multifarious nanostructures from single molecular backbone would be highly advantageous for task specific applications of the self-aggregates. To this end, the present study reports the solvent triggered evolution of hierarchical self-assembled structures of cholesterol based glucose appended amphiphiles and the pathway of structural transition. The amphiphiles formed bilayered vesicles in water and gels in different organic solvents. In DMSO-water solvent mixture, it showed gradual transition in the morphology of self-aggregates from vesicle-to-fiber and intermediate morphologies depending on the solvent compositions. Microscopic and spectroscopic investigations showed that morphological transformation took place through fusion, elongation and twisting of self-aggregates owing to the reorganization of the amphiphiles (H-type to J-type) in varied solvent polarity. Moreover, sheetlike molecular organization originating from hydrogen bonding and solvophobic interaction played a vital role in the formation of nanoribbons that led to the formation of gel fibril network. This study endows a new strategy to develop solvent induced multistructured self-aggregates from a single molecular scaffold, unraveling the route of forming hierarchical self-assembly.

Spontaneous Formation of a Vesicular Assembly by a Trimesic Acid Based Triple Tailed Amphiphile.

Trimesic acid based amino acid functionalized triple tailed amphiphiles (TMA-1 and TMA-2) were synthesized. The triskelion amphiphile TMA-1 with a neutral side chain self-assembled into a vesicle in 2:1 (v/v) DMSO-water, while the ammonium side chain decorated TMA-2 formed vesicles in pure water. Microscopic and spectroscopic characterizations were carried out to confirm the self-aggregated vesicular morphology and its size which is around 250-300 nm in the case of TMA-1 and around 100-150 nm for TMA-2 vesicles. The unique structure of these amphiphiles with an aromatic core and three hydrophilic side chains led to an interlamellar orientation of their hydrophobic (aromatic) domain, while hydrophilic terminals were directed toward the aqueous domain. These amphiphiles formed monolayered vesicles possibly through H-aggregation during the process of self-assembly, which is different from conventional bilayered vesicles formed by twin-chain lipid molecules. The time resolved decay curve of hydrophobic dye entrapped within these vesicles indicated that the hydrophobicity within the microenvironment of TMA-1 and TMA-2 vesicles is higher than that in pure water; however, at the same time, it is comparatively lower than that observed in bilayered phosphocholine vesicles. Furthermore, calcein dye was entrapped within these vesicles to ensure their encapsulation efficiency (65-85%). The ability to entrap dye molecules by these synthesized vesicles was utilized to encapsulate and deliver anticancer drug doxorubicin inside the mammalian cells. A simple synthetic procedure and facile aggregation to vesicular self-assembly with superior dye/drug encapsulation proficiency made these vesicles a potential cellular transporter.