Degradable Polymeric Bio(nano)materials and Their Biomedical Applications: A Comprehensive Overview and Recent Updates.

Degradable polymers (both biomacromolecules and several synthetic polymers) for biomedical applications have been promising very much in the recent past due to their low cost, biocompatibility, flexibility, and minimal side effects. Here, we present an overview with updated information on natural and synthetic degradable polymers where a brief account on different polysaccharides, proteins, and synthetic polymers viz. polyesters/polyamino acids/polyanhydrides/polyphosphazenes/polyurethanes relevant to biomedical applications has been provided. The various approaches for the transformation of these polymers by physical/chemical means viz. cross-linking, as polyblends, nanocomposites/hybrid composites, interpenetrating complexes, interpolymer/polyion complexes, functionalization, polymer conjugates, and block and graft copolymers, are described. The degradation mechanism, drug loading profiles, and toxicological aspects of polymeric nanoparticles formed are also defined. Biomedical applications of these degradable polymer-based biomaterials in and as wound dressing/healing, biosensors, drug delivery systems, tissue engineering, and regenerative medicine, etc., are highlighted. In addition, the use of such nano systems to solve current drug delivery problems is briefly reviewed.

Profound implication of histological alterations, haematological responses and biocidal assessment of cationic amphiphiles unified with their molecular architecture.

The interfacial properties depicting the micellization behaviour of the cationic amphiphiles (surfactants) belonging to the class of quaternary ammonium salts varying in degree of hydrophobicity were evaluated using tensiometry, conductivity and fluorescence spectrophotometric methods at 303.15 K. The impact of the amphiphilic nature of these amphiphiles as a function of their concentration is accounted against the selective microbial strains using the well-diffusion approach. Also, its influence on the histological (shrinkage/curling of lamellae, necrosis, haemorrhage, hyperplasia of villi in gills and intestine) alterations and haematological (blood parameters) changes in fingerling of Cirrhinus mrigala (C. mrigala) offers an insight into the stern damages reported as aquatic toxicity. The lesions exhibited moderate to severe alterations that are further correlated with the semi-quantitative mean alteration value (MAV). The in vitro and in vivo findings are explained significantly in terms of amphiphilic hydrophobicity which followed the order: C16TAB > C12TAB. All the observed outcomes are rationalized by the structural assessment of the selected amphiphiles as specified by the computational simulation approach using density functional theory (DFT) with B3LYP method and 3-21G basis source set. This work also portrays the biodegradability of these cationic amphiphiles and their fate on the environment. Graphical abstract Molecular architecture of cationic amphiphiles integrated with their in vitro and in vivo rejoinders.

Validating interfacial behaviour of surface-active ionic liquids (SAILs) with computational study integrated with biocidal and cytotoxic assessment.

Surface-active ionic liquids (SAILs) belonging to the series of N-alkylmethylimidazolium halides [C8mimX] (X = Br, Cl, and BF4) and [CnmimBr] (n = 10, 12, 14, and 16) were employed to understand the influence of hydrophobicity of alkyl chain length and the chaotropicity of counter-ions of SAILs on the micellization, antimicrobial action and cytotoxicity properties. The micellization phenomenon of SAILs in an aqueous environment was examined employing tensiometry and steady-state fluorescence spectrophotometry. The corresponding interfacial parameters viz., critical micelle concentration (CMC), effectiveness (γCMC), surface pressure (ПCMC), maximum surface excess concentration (Гmax), and the minimum area engaged per molecule (Amin) at the air-water interface were evaluated at 303.15 K. These experimental findings were monitored and geometrically optimized theoretically using Gaussian software to highlight the recent advances in this field of theoretical calculations for putative structure. The simulation descriptors correlated the micellization behavior as a function of hydrophobicity which may contribute to obtaining awareness on their ecological behavior and fate. In addition, the biological screening of all the examined SAILs was undertaken with a combined experimental and theoretical (optimized) method against bacteria and fungus. Results revealed that SAILs with the alkyl chain-length greater than C8- act as a fair antimicrobial agent against the selected microbial strain which is attributed to the enhanced degree of SAILs hydrophobicity. The cytotoxicity of these imidazolium-based SAILs was also assessed on the cervical human cell line (HeLa) using the MTT cell viability assay and the data thus obtained were subjected to statistical analysis.

Biotoxicity and tissue-specific oxidative stress induced by Gemini surfactant as a protocol on fingerlings of Cirrhinus mrigala (Ham.): An integrated experimental and theoretical methodology.

An increasing concern for Gemini surfactants (GS) based on the class alkanediyl-α-ω-bis (dimethylalkylammonium bromide) has been reported in ecotoxicological researchbecause of their estrogenic properties causing an alarm to aquatic life. In this study, we analyzed the toxic effects of the synthesized GS (12-2-12 and 16-2-16) leading to histological changes in fingerlings (kidney, gills, intestine, and liver) of Cirrhinusmrigala. Damage in the tissues in correlation with their normal architecture was observed microscopically and was manifold. The tissue-specific morphological alterations associated with somatic index (MAV- mean alteration value) were used as biomarker. The present study also highlighted the changes in the antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT). In order to estimate the sub-lethal toxic properties of GS, the genotoxicity and cytotoxicity of GS were evaluated using blood smear assay and HeLa cell line respectively. Results of the study exhibited potential biotoxicity where GS with the highest hydrophobicity showed upper most toxicity level under different exposure time, while GS with less hydrophobic features exhibited least stressful regimeto the tested animal. The prepared GS were also examined for their biodegradability following the die-away method. The theoretical approach estimates the structural information by computational simulation.

In-vitro evaluation of cytotoxic and antioxidant properties of drugs solubilized in EO-PO star block copolymer micelles.

Self-assembly of a biocompatible, nontoxic, commercially available star shaped polyethylene oxide-polypropylene oxide block copolymer, Tetronics®1107 (mol. wt. = 15000, % ethylene oxide = 70, and HLB 18-23) in aqueous solution was examined using surface tension, fluorescence, viscosity, cloud point and dynamic light scattering. The copolymer being very hydrophilic shows poor surface activity and forms thermo-, pH and salt responsive nanosize core-shell micelles above critical micellization temperatures. These micelles showed markedly enhanced solubilization of hydrophobic drugs curcumin and quercetin. In vitro antioxidant activities (by free radical scavenging, reducing capacity and superoxide anion radical scavenging methods) and cytotoxicity (against CHO-K1 cell line) showed desirable properties in micellar drugs as compared to free one and similar cytotoxic effects were observed for free as well as micellar drugs. This suggests T1107 as promising tool for drug delivery.

Pluronic®-bile salt mixed micelles.

The present study was aimed to examine the interaction of two bile salts viz. sodium cholate (NaC) and sodium deoxycholate (NaDC) with three ethylene polyoxide-polypropylene polyoxide (PEO-PPO-PEO) triblock copolymers with similar PPO but varying PEO micelles with a focus on the effect of pH on mixed micelles. Mixed micelles of moderately hydrophobic Pluronic® P123 were examined in the presence of two bile salts and compared with those from very hydrophobic L121 and very hydrophilic F127. Both the bile salts increase the cloud point (CP) of copolymer solution and decreased apparent micelle hydrodynamic diameter (Dh). SANS study revealed that P123 forms small spherical micelles showing a decrease in size on progressive addition of bile salts. The negatively charged mixed micelles contained fewer P123 molecules but progressively rich in bile salt. NaDC being more hydrophobic displays more pronounced effect than NaC. Interestingly, NaC shows micellar growth in acidic media which has been attributed to the formation of bile acids by protonation of carboxylate ion and subsequent solubilization. In contrast, NaDC showed phase separation at higher concentration. Nuclear Overhauser effect spectroscopy (NOESY) experiments provided information on interaction and location of bile salts in micelles. Results are discussed in terms of hydrophobicity of bile salts and Pluronics® and the site of bile salt in polymer micelles. Proposed molecular interactions are useful to understand more about bile salts which play important role in physiological processes.

A Comparative Study on Micellar and Solubilizing Behavior of Three EO-PO Based Star Block Copolymers Varying in Hydrophobicity and Their Application for the In Vitro Release of Anticancer Drugs.

The temperature and pH dependent self-assembly of three star shaped ethylene oxide-propylene oxide (EO-PO) block copolymers (Tetronics® 304, 904 and 908) with widely different hydrophobicity was examined in aqueous solutions. Physico-chemical methods viz. viscosity, cloud point, solubilization along with thermal, scattering and spectral techniques shows strongly temperature and salt dependent solution behavior. T304 possessing low molecular weight did not form micelles; moderately hydrophilic T904 remained as micelles at ambient temperature and showed micellar growth while very hydrophilic T908 formed micelles at elevated temperatures. The surface activity/micellization/solubilization power was favored in the presence of salt. The copolymers turn more hydrophilic in acidic pH due to protonation of central ethylene diamine moiety that hinders micelle formation. The solubilization of a model insoluble azo dye 1-(o-Tolylazo)-2-naphthol (Orange OT) and hydrophobic drugs (quercetin and curcumin) for copolymer solutions in aqueous and salt solutions are also reported. Among the three copolymers, T904 showed maximum solubility of dye and drugs, hence the in vitro release of drugs from T904 micelles was estimated and the effect on cytotoxicity of loading the drugs in T904 micelles was compared with the cytotoxicity of free drugs on the CHO-K1 cells. The results from the present work provide a better insight in selection of Tetronics® for their application in different therapeutic applications.

Glucose triggered enhanced solubilisation, release and cytotoxicity of poorly water soluble anti-cancer drugs fromT1307 micelles.

Tetronic® 1307 (here after written as T1307) is a hydrophilic ethylene oxide-propylene oxide (EO-PO) star block copolymer with long EO chains (Total MW- 18000 and 70% EO). Although biocompatible, its use as a nanocarrier is restricted owing to its high critical micelle concentration (CMC) and temperature (CMT). We examined if the addition of glucose, a common pharmaceutical ingredient promotes micellization. Scattering and thermal studies show formation of stable unimodal micelles and cloud point (CP) decreased linearly. The solubilization of anticancer drugs viz. curcumin (CN) and quercetin (QN) demonstrates improved controlled release kinetics and cytotoxicity. On the whole, modulation in micellar behaviour by glucose opens enchanting possibility of using T1307 micelles as nanoreservoirs.

NaCl-triggered self-assembly of hydrophilic poloxamine block copolymers.

Tetronic 1307 (T1307) is a hydrophilic poloxamine (HLB>24) with a high molecular mass owing to its long PEO and PPO blocks. In spite of good biocompatibility, its use as a component of drug delivery systems is limited by its high critical micelle concentration (CMC) and temperature (CMT). The aim of this work was to elucidate whether the addition of NaCl or the combination of salts and temperature may bring T1307 micellization and gelling features into more practically useful values. Increasing NaCl concentration in the 0.154 M (isotonic) to 2M (hypertonic) range made the copolymer more hydrophobic and more prone to self-assemble into unimodal micelles, as observed by means of π-A isotherms, (1)H NMR, dynamic light scattering (DLS), small-angle neutron scattering (SANS), and pyrene fluorescence. The decrease in CMC and CMT observed for T1307 in 0.5 M NaCl medium (tolerable hypertonic solution), compared to water, notably favored the solubility of hydrophobic drugs such as curcumin and quercetin. Moreover, phase diagram, intrinsic viscosity and sol-to-gel transition were markedly affected by NaCl concentration. Overall, the strong dependence of T1307 self-assembly features on NaCl opens interesting possibilities for tuning the performance of T1307 as a component of nanocarriers and in situ gelling systems.

Byssus thread: a novel support material for urease immobilization.

Byssus threads are tough biopolymer produced by mussels (Mytilus viridis) to attach themselves to rocks. These were collected from mussels in their natural habitat (N) and from animals maintained in laboratory condition (L) as a novel support. Byssus thread surfaces were characterized by SEM analysis, chemically modified and used for adsorption of urease. The efficiency of the immobilization was calculated by examining the relative enzyme activity of free and the immobilized urease. The pH stabilities of immobilized urease were higher (0.5 unit) than free enzyme. Immobilized enzymes on byssus (both N and L) when stored at 6 °C retained 50% of its activity after 30 days, but they were more stable in dry condition. The optimum temperature of immobilized enzymes was found to increase (25 °C). A Michaelis-Menten constant (K (m)) value for immobilized urease was also elevated (2.08 mol).

Interaction and solubilization of some phenolic antioxidants in Pluronic® micelles.

The solubilization of four phenolic antioxidants, namely p-hydroxybenzoic acid (PHBAA), syringic acid, sinapic acid, and quercetin in micelles of an ethylene oxide (EO)-propylene oxide (PO) triblock copolymer Pluronic® P104 (EO27-PO61-EO27, PPO mol wt=3540, % PEO=40) was examined at different temperatures, pHs, and in the presence of sodium chloride. The nano-size core-shell micelles of P104 characterized by dynamic light scattering had hydrodynamic diameter of about 18-20 nm with low polydispersity. Antioxidants induced micellization and micellar growth were observed. The critical micellar concentration (CMC), critical micellar temperature (CMT), cloud point (CP) of P104 decreased due to solubilization and interactions of antioxidants. The solubilization was favored at higher temperature, pH and in the presence of salt and follows the order PHBA>syringic acid>sinapic acid>quercetin which corresponds to the trend in their aqueous solubility. The location of antioxidant in micelles observed from NOESY spectra. Structure and hydrophobicity of antioxidants were found to be governing factors for their interaction and location in the micelles.

Micelles from PEO-PPO-PEO block copolymers as nanocontainers for solubilization of a poorly water soluble drug hydrochlorothiazide.

The effect of molecular characteristics of EO-PO triblock copolymers viz. Pluronic(®) P103 (EO(17)PO(60)PEO(17)), P123 (EO(19)PO(69)EO(19)), and F127 (EO(100)PO(65)EO(100)) on micellar behavior and solubilization of a diuretic drug, hydrochlorothiazide (HCT) was investigated. The critical micellization temperatures (CMTs) and size for empty as well as drug loaded micelles are reported. The CMTs and micelle size depended on the hydrophobicity and molecular weight of the copolymer; a decrease in CMT and increase in size was observed on solubilization. The solubilization of the drug hydrochlorothiazide (HCT) in the block copolymer nanoaggregates at different temperatures (28, 37, 45°C), pH (3.7, 5.0, 6.7) and in the presence of added salt (NaCl) was monitored by using UV-vis spectroscopy and solubility data were used to calculate the solubilization characteristics; micelle-water partition coefficient (P) and thermodynamic parameters of solubilization viz. Gibbs free energy (ΔG(s)°), enthalpy (ΔH(s)°) and entropy (ΔS(s)°). The solubility of the drug in copolymer increases with the trend: P103>P123>F127. The solubilized drug decreased the cloud point (CP) of copolymers. Results show that the drug solubility increases in the presence of salt but significantly enhances with the increase in the temperature and at a lower pH in which drug remains in the non-ionized form.

Solubilization of poorly water-soluble drug carbamezapine in pluronic micelles: effect of molecular characteristics, temperature and added salt on the solubilizing capacity.

The solubilization of a poorly water-soluble antiepileptic drug, carbamazepine (CBZ), in a series of micelle-forming PEO-PPO-PEO block copolymers with combinations of blocks having different molecular weight was studied. The drug solubility and micelle-water partition coefficient (P) were determined using UV-vis spectroscopy. Dynamic light scattering on copolymer solutions was used to measure size and polydispersity of nanoaggregates. Solubilization of carbamezapine increased with the rise in temperature and concentration of block copolymers, but no significant increase was observed with added salt (NaCl). The solubilization is also discussed from a thermodynamics viewpoint, by considering the standard free energy of solubilization (DeltaG degrees ).

Mixed micelles of cationic surfactants and sodium cholate in water.

Critical micelle concentrations (CMCs) of cationic surfactant (alkyltrimethylammonium bromides, CnTABr, where n = 10, 12, 14, 16 and 18), and a bile salt sodium cholate (NaC) were determined from surface tension, conductance and dye solubilization methods, while of their equimolar mixtures from surface tension and dye solubilization methods. The interaction parameter (beta) obtained from analysis of data, using Rubingh's theory showed strong interaction between NaC and cationic surfactant. Time-resolved fluorescence-quenching results revealed small-sized mixed spherical micelle with aggregation number much less than micelles of cationic surfactant.