ABSTRACT
Herein, we report the synthesis of an alternating copolymer (ACP) with a bio-reducible amphiphilic polydisulfide backbone and highlight the impact of the alternating monomer connectivity on the self-assembly, morphology, chain-exchange dynamics, drug-release kinetics, and enzyme activity inhibition. Condensation polymerization between hydrophobic 1,10-bis(pyridin-2-yldisulfaneyl)decane and hydrophilic 2,3-mercaptosuccinic acid (1.04 : 1.00 ratio) generated amphiphilic ACP P1 (Mw = 8450 g mol-1, D = 1.3), which exhibited self-assembly in water, leading to the formation of an ultra-thin (height <5.0 nm) entangled fibrillar network. In contrast, structurally similar amphiphilic random copolymer P2 exhibited a truncated irregular disc-like morphology under the same conditions. It is postulated that due to the perfect alternating sequence of the hydrophobic and hydrophilic segments in P1, its immiscibility-driven aggregation in water leads to a pleated structure, which further assembles and forms the observed long fibrillar structures, similar to crystallization-driven self-assembly. In fact, wide-angle X-ray diffraction (WXRD) analysis of a lyophilized P1 sample showed sharp peaks, indicating its crystalline nature (approximately 37% crystallinity), and these were completely missing for P2. The effect of such distinct self-assembly on the chain-exchange dynamics was probed by fluorescence resonance energy transfer (FRET) using 3,3'-dioctadecyloxacarbocyanine perchlorate (DiO) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) as the FRET-donor and -acceptor, respectively. For DiI- and DiO-entrapped solutions of P1, when mixed, no prominent FRET appeared even after 24 h. In sharp contrast, for P2, intense FRET emission occurred, and the FRET ratio (approximately 0.9) reached saturation in approximately 15 h, indicating the greatly enhanced kinetic stability of P1 aggregates. Glutathione-induced release of encapsulated Nile red showed much slower kinetics for P1 compared to that of P2, which was corroborated by the observed slow chain-exchange dynamics of the highly stable alternating copolymer assembly. Furthermore, the well-ordered assembly of P1 exhibited an excellent surface-functional group display (zeta potential of -32 mV compared to -14 mV for P2), which resulted in the effective recognition of the α-chymotrypsin (Cht) protein surface by electrostatic interaction. Consequently, P1 significantly (>70%) suppressed the enzymatic activity of Cht, while in the presence of P2, the enzyme was still active with >70% efficacy.
ABSTRACT
This manuscript describes the synthesis, self-assembly, and antibacterial properties of naphthalene-diimide (NDI)-derived cationic π-amphiphiles. Three such asymmetric NDI derivatives with a nonionic hydrophilic wedge and a guanidine group in the two opposite sides of the NDI chromophore were considered. They differ by a single functional group (hydrazide, amide, and ester for NDI-1, NDI-2, and NDI-3, respectively), located in the linker between the NDI and the hydrophilic wedge. For NDI-1, the H-bonding among the hydrazides regulated unilateral stacking and a preferential direction of curvature of the resulting supramolecular polymer, producing an unsymmetric polymersome with the guanidinium groups displayed at the outer surface. NDI-3, lacking any H-bonding group, exhibits π-stacking without any preferential orientation and generates spherical particles with a relatively poor display of the guanidium groups. In sharp contrast to NDI-1, NDI-2 exhibits an entangled one-dimensional (1D) fibrillar morphology, indicating the prominent role of the H-bonding motif of the amide group and flexibility of the linker. The antibacterial activity of these assemblies was probed against Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative). NDI-1 showed the most promising antibacterial activity with a minimum inhibitory concentration (MIC) of â¼7.8 µg/mL against S. aureus and moderate activity (MIC â¼ 125 µg/mL) against E. coli. In sharp contrast, NDI-3 did not show any significant activity against the bacteria, suggesting a strong impact of the H-bonding-regulated directional assembly. NDI-2, forming a fibrillar network, showed moderate activity against S. aureus and negligible activity against E. coli, highlighting a significant impact of the morphology. All of these three molecules were found to be compatible with mammalian cells from the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) and hemolysis assay. The mechanistic investigation by membrane polarization assay, live/dead fluorescence assay, and microscopy studies confirmed the membrane disruption mechanism of cell killing for the lead candidate NDI-1.
Subject(s)
Anti-Bacterial Agents , Escherichia coli , Hydrogen Bonding , Staphylococcus aureus , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Staphylococcus aureus/drug effects , Escherichia coli/drug effects , Microbial Sensitivity Tests , Naphthalenes/chemistry , Naphthalenes/pharmacology , Imides/chemistry , Imides/pharmacology , Cations/chemistry , Cations/pharmacology , HumansABSTRACT
This paper reports synthesis of a bioreducible hyperbranched (HB) polymer by A2+B3 approach from commercially available dithiothreitol (DTT) (A2) and an easily accessible trifunctional monomer (B3) containing three reactive pyridyl-disulfide groups. Highly efficient thiol-activated disulfide exchange reaction leads to the formation of the HB polymer (Mw = 21000; D = 2.3) with bioreducible disulfide linkages in the backbone and two different functional groups, namely, hydroxyl and pyridyl-disulfide in the core and periphery, respectively, of the HB-polymer. Postpolymerization functionalization of the hydroxyl-groups with camptothecin (CPT), a topoisomerase inhibitor and known anticancer drug, followed by replacing the terminal pyridyl-disulfide groups with oligo-oxyethylene-thiol resulted in easy access to an amphiphilic HB polydisulfide-CPT conjugate (P1) with a very high drug loading content of â¼40%. P1 aggregated in water (above â¼10 µg/mL) producing drug-loaded nanoparticles (Dh â¼ 135 nm), which showed highly efficient glutathione (GSH)-triggered release of the active CPT. Mass spectrometry analysis of the GSH-treated P1 showed the presence of the active CPT drug as well as a cyclic monothiocarbonate product, which underpins the cascade-degradation mechanism involving GSH-triggered cleavage of the labile disulfide linkage, followed by intramolecular nucleophilic attack by the in situ generated thiol to the neighboring carbonate linkage, resulting in release of the active CPT drug. The P1 nanoparticle showed excellent cellular uptake as tested by confocal fluorescence microscopy in HeLa cells by predominantly endocytosis mechanism, resulting in highly efficient cell killing (IC50 â¼ 0.6 µg/mL) as evident from the results of the MTT assay, as well as the apoptosis assay. Comparative studies with an analogous linear polymer-CPT conjugate showed much superior intracellular drug delivery potency of the hyperbranched polymer.
Subject(s)
Nanoparticles , Polymers , Humans , Polymers/chemistry , HeLa Cells , Drug Carriers/chemistry , Nanoparticles/chemistry , Disulfides/chemistry , Sulfhydryl Compounds , Camptothecin/pharmacology , Drug LiberationABSTRACT
Organic ferroelectric (FE) materials, though known for more than a century, are yet to reach close to the benchmark of inorganic or hybrid materials in terms of the magnitude of polarization. Amongst the different classes of organic systems, donor (D)-acceptor (A) charge-transfer (CT) complexes are recognized as promising for ferroelectricity owing to their neutral-to-ionic phase transition at low temperature. This review presents an overview of different supramolecular D-A systems that have been explored for FE phase transitions. The discussion begins with a general introduction of ferroelectricity and its different associated parameters. Then it moves on to show early examples of CT cocrystals that have shown FE properties at sub-ambient temperature. Subsequently, recent developments in the field of room temperature (RT) ferroelectricity, exhibited by H-bond-stabilized lock-arm supramolecular-ordering (LASO) in D-A co-crystals or other FE CT-crystals devoid of neutral-ionic phase transition are discussed. Then the discussion moves on to emerging reports on other D-A soft materials such as gel and foldable polymers; finally it shows very recent developments in ferroelectricity in supramolecular assemblies of single-component dipolar or ambipolar π-systems, exhibiting intra-molecular charge transfer. The effects of structural nuances such as H-bonding, balanced charge transfer and chirality on the observed ferroelectricity is described with the available examples. Finally, piezoelectricity in recently reported ambipolar ADA-type systems are discussed to highlight the future potential of these soft materials in micropower energy harvesting.
ABSTRACT
Aggregation of amphiphilic polymers in block-selective solvents produces different nanostructures, which have been studied extensively for wide-ranging applications. Nevertheless, such immiscibility-driven aggregation does not endow them with the desired structural precision, predictability or surface functional group exposure, which significantly impact their functional applications. More recently, biomimetic folded structures of synthetic macromolecules (mostly oligomers) have come to the fore, but such studies have been limited to probe the secondary structures. In this article, we have collated hierarchical structures of foldamers, especially highlighting our recent contribution to the field of chain-folding regulated assembly of segmented polyurethanes (PUs) and their functional applications. A series of such PUs have been discussed, which contain a segmented hydrocarbon backbone and alternately placed pendant solvophilic groups. In either water or highly non-polar solvents (TCE, MCH), depending on the nature of the pendant group, they exhibit folded structures stabilized by intra-chain H-bonding. Hierarchical assembly of such folded chains by inter-chain H-bonding and/or π-stacking leads to the formation of well-defined nanostructures with functional applications ranging from organic optoelectronics to biomaterials. For example, a segmented PU with appended naphthalene-diimide (NDI) chromophores showed a pleated structure in MCH, which helped in organization of the NDI chromophores within π-stacking distance. Such folded polymer chains eventually produced nanotubular structures with excellent electron mobility. They also showed efficient intercalation of the pyrene (Py) donor by NDI-Py charge-transfer interaction and in this case the mixed nanotubular structure exhibited prominent room-temperature ferroelectricity. On the other hand, having cationic functionalities as the pendant groups such chain-folding regulated assembly produced unilamellar polymersomes with excellent antibacterial activity with very low minimum inhibitory concentrations (<10 µg mL-1). Replacing the pendant amine functionality with sulphate groups made these polyurethanes highly potent antiviral materials. In the absence of the alternating connectivity of the solvophobic and solvophilic segments or rigid hydrocarbon backbone, such folding propensity is destroyed, leading to structural collapse. While significant efforts have been made in correlating primary structures of wide-ranging polymers with their functional applications, this article demonstrates the direct correlation between the secondary structures of polymers and their functional properties.
Subject(s)
Polymers , Polyurethanes , Humans , Polymers/chemistry , Solvents/chemistry , Naphthalenes/chemistry , Anti-Bacterial Agents/pharmacology , Antiviral Agents/pharmacology , SuppurationABSTRACT
This article reports alternating supramolecular copolymerization of two naphthalene-diimide (NDI)-derived building blocks (NDI-1 and NDI-2) under thermodynamic control. Both monomers contain a central NDI chromophore, attached to a hydrocarbon-chain and a carboxylic-acid group. The NDI core in NDI-2 is symmetrically substituted with two butane-thiol groups, which makes it distinct from NDI-1. In decane, a 1 : 1 mixture of NDI-1 and NDI-2 shows spontaneous gelation and a typical fibrillar network, unlike the behavior of either of the components individually. The solvent-dependent UV/vis spectrum of the mixed sample in decane shows bathochromically shifted sharp absorption bands and a sharp emission band (holds a mirror-image relationship) with a significantly small Stokes shift compared to those in CHCl3, indicating J-aggregation. In contrast, the aggregated spectra of the individual monomers show broad structureless features, suggesting ill-defined aggregates. Cooling curves derived from the temperature-dependent UV/vis spectroscopy studies revealed early nucleation and a signature of well-defined cooperative polymerization for the mixed sample, unlike either of the individual components. Molecular dynamics simulations predicted the greatest dimer formation tendency for the NDI-1 + NDI-2 (1 : 1), followed by pure NDI-1 and NDI-2. Theoretical studies further revealed a partial positive charge in the NDI ring of NDI-1 when compared to NDI-2, promoting the alternating stacking propensity, which is also favored by the steric factor as NDI-2 is core-substituted with alkyl thiols. Such theoretical predictions fully corroborate with the experimental results showing 1 : 1 stoichiometry (from Job's plot) of the two monomers, indicating alternate stacking sequences in the H-bonded (syn-syn catemer type) supramolecular copolymer. Such alternating supramolecular copolymers showed highly efficient (>93%) fluorescence resonance energy transfer (FRET).
ABSTRACT
A strategy for a redox-activatable heavy-atom-free photosensitizer (PS) based on thiolated naphthalimide has been demonstrated. The PS exhibits excellent reactive oxygen species (ROS) generation in the monomeric state. However, when encapsulated in a disulfide containing bioreducible amphiphilic triblock copolymer aggregate (polymersome), the PS exhibits aggregation in the confined hydrophobic environment, which results in a smaller exciton exchange rate between the singlet and triplet excited states (TDDFT studies), and consequently, the ROS generation ability of the PS was almost fully diminished. Such a PS (in the dormant state)-loaded redox-responsive polymersome showed excellent cellular uptake and intracellular release of the PS in its active form, which enabled cell killing upon light irradiation due to ROS generation. In a control experiment involving aggregates of a similar block copolymer, but lacking the bioreducible disulfide linkage, no intracellular reactivation of the PS was noticed, highlighting the importance of stimuli-responsive polymer assemblies in the area of targeted photodynamic therapy.
Subject(s)
Photochemotherapy , Photosensitizing Agents , Photosensitizing Agents/pharmacology , Reactive Oxygen Species , Polymers/chemistry , Disulfides/chemistry , Oxidation-ReductionABSTRACT
This paper describes the synthesis of a polymer-prodrug conjugate, its aqueous self-assembly, noncovalent encapsulation of a second drug, and stimuli-responsive intracellular dual drug delivery. Condensation polymerization between a functionalized diol and a commercially available diisocyanate in the presence of poly(ethylene glycol) hydroxide (PEG-OH) as the chain stopper produces an ABA-type amphiphilic block copolymer (PU-1) in one pot, with the middle hydrophobic block being a polyurethane containing a pendant tert-butyloxycarbonyl (Boc)-protected amine in every repeating unit. Deprotection of the Boc group, followed by covalent attachment of the Pt(IV) prodrug using the pendant amine groups, produces the polymer-prodrug conjugate PU-Pt-1, which aggregates to nanocapsule-like structures in water with a hydrophilic interior. In the presence of sodium ascorbate, the Pt(IV) prodrug can be detached from the polymer backbone, producing the active Pt(II) drug. Cell culture studies show appreciable cell viability by the parent polymer. However, the polymer-prodrug conjugate nanocapsules exhibit cellular uptake and intracellular release of the active drug under a reducing environment. The capsule-like aggregates of the polymer-prodrug conjugate were used for noncovalent encapsulation of a second drug, doxorubicin (Dox), and Dox-loaded PU-Pt-1 aggregate showed a significantly superior cell killing efficiency compared to either of the individual drugs, highlighting the promising application of such a dual-drug-delivery approach.
Subject(s)
Neoplasms , Prodrugs , Cisplatin , Prodrugs/pharmacology , Polyurethanes , Drug Delivery Systems , Polyethylene Glycols/chemistry , Polymers/chemistry , Doxorubicin/pharmacology , Doxorubicin/chemistry , Micelles , Amines , Drug Carriers/chemistryABSTRACT
An amphiphilic segmented polyurethane (F-PU-S), with pendant sulfate groups and a flexible hydrocarbon backbone, exhibits intrachain H-bonding-reinforced folding and hierarchical assembly, producing an anionic polymersome with efficient display of sulfate groups at the surface. It shows an excellent antiviral activity against Sendai virus (SV) by inhibiting its entry to the cells. Mechanistic investigation suggests fusion of the SV and the polymersome to produce larger particles in which neither the folded structure of the polymer nor the fusogenic property of the SV exists anymore. In sharp contrast, a structurally similar polymer R-PU-S, in which the chain folding pathway is blocked by replacing the flexible C6 chain with a rigid cyclohexane chain in the backbone, cannot form a similar polymersome structure and hence does not exhibit any antiviral activity. On the other hand, the third polymer (F-PU-C), which is similar to F-PU-S except for the pendant anionic groups (carboxylate instead of sulfate), also fails to exhibit any antiviral activity against SV, confirming the essential role of the chain folding as well as the pendant sulfate groups for the fusion-induced antiviral activity of F-PU-S, which provides an important structural guideline for developing new antiviral polymers.
Subject(s)
Polymers , Polymers/pharmacology , Protein Structure, SecondaryABSTRACT
This manuscript reports the effect of hydrogen-bonding functionality on the supramolecular assembly of naphthalene-diimide (NDI)-derived amphiphilic building blocks in water. All the molecules contain a central NDI chromophore, functionalized with a hydrophilic oligo-oxyethylene (OE) wedge in one arm and a phenyl group on the opposite arm. They differ by a single H-bonding functionality, which links the NDI chromophore and the phenyl moiety. The H-bonding functionalities are amide, thioamide, urea, and urethane in NDI-A, NDI-TA, NDI-U, and NDI-UT, respectively. All of these molecules exhibit π-stacking in water, as evident from their distinct UV/vis absorption spectra when compared to that of the monomeric dye in THF. However, among these four, only NDI-A and NDI-TA show hydrogelation, while the other two precipitate out of the medium. The NDI-A hydrogel also exhibits transient stability and leads to a crystalline precipitate within â¼5 h. Only NDI-TA produces stable transparent hydrogel with the entangled fibrillar morphology that is typical for gelators. Both NDI-A and NDI-TA showed a thermoresponsive property with a lower critical solution temperature of about 41-42 °C. Powder XRD studies show a parallel orientation for NDI-A and an antiparallel orientation for NDI-TA. Computational studies support this experimental observation and indicate that the NDI-A assembly is highly stabilized by strong H-bonding among the amide groups and π-stacking interaction in the parallel orientation. On the other hand, due to weak H-bonding among the thioamide groups, the binding energy of the parallelly oriented NDI-TA was significantly lower and the optimized structure was disordered. Instead, its antiparallel orientation was more stable, with criss-cross aligned H-bonding interactions and π-π interactions between adjacent aromatic rings. The NDI-TA hydrogel with less ordered OE chains on the surface showed prominent adsorption of serum protein BSA. In sharp contrast, NDI-A did not exhibit any notable interaction with BSA, as evident from the ITC studies.
Subject(s)
Hydrogels , Naphthalenes , Adsorption , Naphthalenes/chemistry , Hydrogels/chemistry , Water/chemistry , Thioamides , Amides , HydrogenABSTRACT
This communication reports synergistic H-bonding and charge-transfer (CT) interaction-promoted alternating supramolecular copolymerization of amide-functionalized pyrene (Py) and naphthalene-diimide (NDI) building blocks and the emergence of ferroelectricity with saturation polarization â¼3.2 µC cm-2, Curie temperature â¼304 K, and coercive field â¼8.5 kV cm-1 at 100 Hz. The Py or NDI molecules on their own do not exhibit any ferroelectric hysteresis, indicating an essential role of both CT-interaction and H-bonding in ferroelectricity. Computational studies provide insight into the origin of the polarization and the importance of the NDI/Py ratio. This study, showing room temperature ferroelectricity in purely organic systems, is of high relevance for flexible electronics and sensors. It opens up new opportunities for soft FE-materials with ample scope for further structural optimization.
ABSTRACT
This article reports supramolecular polymerization of two bis-amide functionalized naphthalene-diimide (NDI) building blocks (NDI-L and NDI-C) in two solvents, namely n-heptane (Hep) and methylcyclohexane (MCH). NDI-L and NDI-C differ only by the peripheral hydrocarbon wedges, consisting of linear C7 chains or cyclic methylcyclohexane rings, respectively. UV/Vis and FTIR spectroscopy studies reveal distinct internal order and H-bonding pattern for NDI-L and NDI-C aggregates irrespective of the solvent system, indicating the dominant role of the intrinsic packing parameters of the individual building block, possibly influenced by the peripheral steric crowding. However, NDI-L produces a significantly stronger gel in Hep compared to MCH as evident from the rheological and thermal properties. In contrast, NDI-C exhibits a clear preference for MCH, producing gel with moderate strength but in Hep it fails to produce 1D morphology or gelation. All-atom molecular dynamics (MD) simulation studies corroborate with the experimental observation and provide the rationale for the observed solvent-shape effect by revealing a quantitative estimate regarding the thermodynamics of self-assembly in these four combinations. Such clear-cut shape-matching effect (between the peripheral hydrocarbon wedge and the solvent system) unambiguously support a direct participation of the solvent molecules during supramolecular polymerization and presence of a closely-adhered solvent shell around the supramolecular polymers, similar to the first layer of water molecules around the protein surface. Solvent induced CD experiments support this hypothesis as induced CD band was observed only from a chiral co-solvent of matching shape. This is reconfirmed by the higher de-solvation temperature of the shape-matching NDI/solvent system combination compared to the shape mis-match combination in variable temperature UV/Vis experiments, revealing transformation to a different aggregate at higher temperatures rather than disassembly to the monomer for all four combinations.
Subject(s)
Polymers , Polymerization , Polymers/chemistry , Solvents/chemistry , Temperature , ThermodynamicsABSTRACT
This communication reveals co-assembly of an electron-deficient naphthalene-diimide (NDI)-appended polyurethane (P1) and electron-rich pyrene (Py), forming an organogel with prominent room-temperature ferroelectricity. In a non-polar medium, intra-chain hydrogen-bonding among the urethane groups of P1 produces a folded structure with an array of the NDIs in the periphery, which intercalate Py by charge-transfer (CT)-interaction. Such CT-complexation enables slow crystallization of the peripheral hydrocarbons, causing gelation with nanotubular morphology, in which the wall consists of the alternating NDI-Py stack. Such D-A assembly exhibits ferroelectricity (saturation polarization Ps ≈0.8â µC cm-2 and coercive field Ec ≈8â kV cm-1 at 500â V and 10â Hz frequency) with Curie temperature (Tc ) of ≈350â K, which can be related to the disassembly of the CT-complex. In the absence of Py, P1 forms spherical aggregates, showing dielectric behaviour.
ABSTRACT
This article reports H-bonding driven supramolecular polymerization of naphthalimide (A)-thiophene (D)-naphthalimide (A) (AD n A, n = 1-4) conjugated ambipolar π-systems and its remarkable impact on room temperature ferroelectricity. Electrochemical studies confirm the ambipolar nature of these AD n A molecules with the HOMO-LUMO gap varying between 2.05 and 2.29 eV. Electron density mapping from ESP calculations reveals intra-molecular charge separation as typically observed in ambipolar systems. In the aggregated state, AD1A and AD2A exhibit bathochromically shifted absorption bands while AD3A and AD4A show typical H-aggregation with a hypsochromic shift. Polarization vs. electric field (P-E) measurements reveal stable room temperature ferroelectricity for these supramolecular assemblies, most prominent for the AD2A system, with a Curie temperature (T c) ≈ 361 K and saturation polarization (P s) of â¼2 µC cm-2 at a rather low coercive field of â¼2 kV cm-1. Control molecules, lacking either the ambipolar chromophore or the amide functionality, do not show any ferroelectricity, vindicating the present molecular and supramolecular design. Computational studies enable structural optimization of the stacked oligomer(s) of AD2A molecules and reveal a significant increase in the macro-dipole moment (in the range of 10-12 Debye) going from the monomer to the oligomer(s), which provides the rationale for the origin of ferroelectricity in these supramolecular polymers.
ABSTRACT
Herein, we report the rich morphological and conformational versatility of a biologically active peptide (PEP-1), which follows diverse self-assembly pathways to form up to six distinct nanostructures and up to four different secondary structures through subtle modulation in pH, concentration and temperature. PEP-1 forms twisted ß-sheet secondary structures and nanofibers at pHâ 7.4, which transform into fractal-like structures with strong ß-sheet conformations at pHâ 13.0 or short disorganized elliptical aggregates at pHâ 5.5. Upon dilution at pHâ 7.4, the nanofibers with twisted ß-sheet secondary structural elements convert into nanoparticles with random coil conformations. Interestingly, these two self-assembled states at pHâ 7.4 and room temperature are kinetically controlled and undergo a further transformation into thermodynamically stable states upon thermal annealing: whereas the twisted ß-sheet structures and corresponding nanofibers transform into 2D sheets with well-defined ß-sheet domains, the nanoparticles with random coil structures convert into short nanorods with α-helix conformations. Notably, PEP-1 also showed high biocompatibility, low hemolytic activity and marked antibacterial activity, rendering our system a promising candidate for multiple bio-applications.
Subject(s)
PeptidesABSTRACT
Nonspecific adsorption of proteins on the surface of nanocarriers plays a critical role in their cellular uptake and other biological functions. This article reports vesicular assemblies of two π-amphiphiles (NDI-1 and NDI-2) and thermodynamic aspects of their interaction with bovine serum albumin (BSA). Both contain a hydrophobic naphthalene-diimide (NDI) core and two oligo-oxyethylene (OE) wedges but differ by the presence of the hydrazide group in NDI-1. NDI-2 exhibits a constricted π-stacking and enthalpy-driven adsorption of BSA. In contrast, NDI-1 exhibits a stronger interaction due to enhanced entropy contribution. It is postulated that a tight packing of NDI chromophores in NDI-2 results in an inadequate space in the corona, leading to the dehydration of OE chains, which contributes to the observed enthalpy-driven binding. On the other hand, due to H-bonding along the direction of π-stacking in NDI-1, an enhanced interchromophoric distance provides more space in the shell, resulting in less dehydration of the OE chains, which results in an entropy gain from the BSA binding-induced release of water from the OE chains. Intercalation of an electron-rich pyrene in the electron-deficient NDI-1 stack further reduces the grafting density of the OE chains, resulting in negligible BSA adsorption, similar to a stealth polymer. A correlation can be seen between the thermodynamic landscape of the protein adsorption and the trend of their lower critical solution temperature (LCST), which follows the order NDI-1 + Py < NDI-1 < NDI-2.
Subject(s)
Polymers , Serum Albumin, Bovine , Adsorption , Hydrophobic and Hydrophilic Interactions , ThermodynamicsABSTRACT
This article reveals 4-dimethylaminopyridine (DMAP) regulated pathway selectivity in the supramolecular polymerization of a naphthalene-diimide derivative (NDI-1), appended with a carboxylic acid group. In decane, NDI-1 produces ill-defined aggregate (Agg-1) due to different H-bonding motifs of the -COOH group. With one mole equivalent DMAP, the NDI-1/DMAP complex introduces new nucleation condition and exhibits a cooperative supramolecular polymerization producing J-aggregated fibrillar nanostructure (Agg-2). With 10 % DMAP and fast cooling (10â K/min), similar nucleation and open chain H-bonding with the free monomer in an anti-parallel arrangement produces identical J-aggregate (Agg-2a). With 2.5 % DMAP and slow cooling (1â K/min), a distinct nucleation and supramolecular polymerization pathway emerge leading to the thermodynamically controlled Agg-3 with face-to-face stacking and 2D-morphology. Slow cooling with 5-10 % DMAP produces a mixture of Agg-2a and Agg-3. Computational modelling studies provide valuable insights into the internal order and the pathway complexity.
ABSTRACT
Bioinspired self-assembly has been explored with diverse synthetic scaffolds, among which amphiphiles are perhaps the most extensively studied systems. Classical surfactants or amphiphilic block copolymers, depending on the hydrophobic-hydrophilic balance, produce distinct nanostructures, which hold promise for applications ranging from biology to materials sciences. Nevertheless, their immiscibility-driven aggregation does not provide the opportunity to precisely regulate the internal order, morphology, or functional group display, which is highly desirable, especially in the context of biological applications.A new class of amphiphiles have emerged in the recent past in which the hydrophilic segment(s) is appended with a hydrophobic supramolecular-structure-directing-unit (SSDU), consisting of a π-conjugated chromophore and a H-bonding group. Self-recognition of the SSDU by attractive directional interactions governs the supramolecular assembly, which is fundamentally different than the repulsive solvent-immiscibility driven aggregation of traditional amphiphiles. Such SSDU-appended hydrophilic polymers exhibit entropy-driven highly stable self-assembly producing distinct nanostructures depending on the H-bonding functional group. For example, polymers with the hydrazide-functionalized SSDU attached form a polymersome, while in a sharp contrast, the same polymers when connected to an amide containing SSDU produce a cylindrical micelle via a spherical-micelle intermediate. This relationship holds true for a series of SSDU-attached hydrophilic polymers irrespective of the hydrophobic/hydrophilic balance or chemical structure, indicating that the supramolecular-assembly is primarily controlled by the specific molecular-recognition motif of the SSDU, instead of the packing parameter-based norms. Beyond synthetic polymers, SSDU-attached proteins also exhibit similar molecular-recognition driven self-assembly as well as coassembly with SSDU-attached polymers or hydrophilic wedges, producing multi-stimuli-responsive nanostructures in which the protein gains remarkable protection from thermal denaturation or enzymatic hydrolysis and exhibits redox-responsive enzymatic activity.Furthermore, SSDU-derived bola-shape π-amphiphiles have been recognized as a useful scaffold for the synthesis of unsymmetric polymersomes, rarely reported in the literature. The building block consists of a hydrophobic naphthalene-diimide (NDI) π-system attached to a hydrophilic functional group (ionic or nonionic) and a nonionic wedge on its two opposite arms. Extended H-bonding among the hydrazide groups, placed only on one side of the central chromophore by design, ensures stacking of the NDIs with parallel orientation and induces a preferred direction of curvature so that the H-bonded chain and consequently the functional groups attached to the same side remain at the inner-wall of the supramolecular polymersome. Automatically, the functional groups, located on the other side, are displayed at the outer surface. This design works for different amphiphiles, which by virtue of efficient and predictable functional group display, strongly influences the multivalent binding with different biological targets resulting in efficient enzyme inhibition, glycocluster effect, or antibacterial activity, depending on the nature of the functional group. By taking advantage of the electron accepting nature of the NDI, electron rich pyrene-containing amphiphiles can be costacked in alternating sequence, producing temperature and redox-responsive supramolecular polymers with NDI/pyrene stoichiometry-dependent morphology, lower critical solution temperature (LCST), functional group display, and antibacterial activity.
Subject(s)
Proteins/chemical synthesis , Surface-Active Agents/chemical synthesis , Macromolecular Substances/chemical synthesis , Macromolecular Substances/chemistry , Molecular Structure , Proteins/chemistry , Surface-Active Agents/chemistry , TemperatureABSTRACT
Cellular uptake is an important event in drug delivery and other biomedical applications. Amphiphilic polymers produce aggregates of different size and shape depending on the intrinsic structural differences and the packing parameter. Although they have been explored for various biomedical applications with immense interest, the relationship between the shape of the aggregate and cellular uptake has been studied only in limited examples. This work reports two polymers (P1 and P2), both of which contain a hydrophobic supramolecular structure-directing unit (SSDU) at the chain-end of a fluorescence dye-labeled hydrophilic polymer. Depending on the difference in the structure of the single H-bonding functional group (hydrazide or amide) of the SSDU, P1 and P2 produce polymersomes (NS1) and spherical micelles (NS2), respectively. An aged solution of P2 produces cylindrical micelles (NS3). Confocal microscopy studies reveal that the uptake of these nanostructures in HeLa cells greatly depends on the shape of the aggregate. Spherical NS1 and NS2 show appreciable uptake at 1 or 4 h of incubation, whereas NS3 shows negligible uptake. Temperature-dependent cellular uptake studies reveal an energy-dependent endocytosis pathway. Kinetic studies show gradual increase in the cellular uptake with time, and at 24 h the relative uptake ratio (NS1:NS2:NS3) is 1.0:0.2:<0.1, implying the polymersome morphology (NS1) is most efficient for cellular uptake compared to the spherical or cylindrical micelles. The same trend was also noticed for MDA-MB 231 cells. Confocal microscopy studies further reveal cellular internalization and intracellular location of NS1, which showed maximum cellular uptake. As the intrinsic difference in the chemical structure of the two polymers is negligible, the observed difference can be explicitly assigned to their difference in shape.
Subject(s)
Micelles , Nanostructures , Aged , HeLa Cells , Humans , Kinetics , Nanostructures/chemistry , Polymers/chemistryABSTRACT
Most of the supramolecular structures lack accuracy at the macroscopic scale because of their spontaneous uncontrolled self-assembly. Although significant progress has been made in understanding the pros and cons of various directional noncovalent interactions and their specific molecular recognition ability, it is only in the recent past that the focus has been shifted toward controlling the dimension, dispersity, and other macroscopic properties of supramolecular assemblies. In this context, recent examples encompass various external stimuli to gain the structural precision in supramolecular assembly, among which light-triggered supramolecular assembly has gained significant interest as it is reagent free and endows the possibility of the controlled synthesis of supramolecular assemblies via manipulation of the light energy, irradiation time, or spatial control. This mini-review highlights representative recent examples of phototriggered supramolecular assemblies (from the monomer or another type of assembly) by removal of a photolabile protecting group, photoisomerization, or other methods of photoactivation of a dormant building block.