1,6-heptadiynes based cyclopolymerization functionalized with mannose by post polymer modification for protein interaction.

Carbohydrate functionalized polymers or Glycopolymers have earned a great deal of interest in recent times for their potential biomedical applications. In the present study, a mannose containing glycopolymer was synthesized by cyclopolymerization of malonic acid derivative using second generation Hoveyda Grubbs' catalyst. Post-polymerization modification was done to install a propargyl moiety. Finally, functionalization of the propargylated polymer with 2-azidoethyl mannoside using azide-alkyne "click chemistry" furnished the target glycopolymer which was successfully characterized using NMR, FT-IR, mass spectroscopy and advanced polymer chromatography. The glycopolymer was found to self-assemble into capsule and spherical shape in water and DMSO respectively and these morphologies were observed through SEM and TEM. Upon interaction with Con A, the mannose containing glycopolymer showed an increment in aggregation induced fluorescence with increasing concentration of the lectin. In vitro cytotoxicity studies on MCF 7 cell line showed 90% cell viability up to glycopolymer concentration of 500 µg/mL.

Common arterial trunk with intact septum and hypoplastic right ventricle: An uncommon embryological entity.

Embryologically, the common arterial trunk (CAT) is due to the failure of septation by the major outflow cushions. This invariably leads to the presence of an associated large juxta-arterial ventricular septal defect. Overriding of the ventricular septum leads to its biventricular origin in more than 2/3rd of cases. Uncommonly, CAT may be associated with an intact ventricular septum (IVS) and univentricular origin. We describe an infant with CAT, intact IVS, hypoplastic right ventricle, and Ebstein's anomaly of the tricuspid valve who presented to us and palliated successfully. The embryological mechanisms are discussed in this report.

Iron(III) Coordinated Polymeric Nanomaterial: A Next-Generation Theranostic Agent for High-Resolution T1-Weighted Magnetic Resonance Imaging and Anticancer Drug Delivery.

Theranostic-based nanomedicine plays a crucial role in the field of cancer therapy. This is due to having the capability to combine both therapy and diagnosis together in a single system. Herein a new class of metal-ligand-based nanocarrier in a norbornene backbone has been designed as a theranostic system. Fe3+-terpyridine complex (Fe-Tpy) has been used here as T1 contrast agent for high-resolution MR imaging, and hydrazone-linked doxorubicin is used for effective pH-responsive delivery. Polyethylene glycol functionalized with a folic acid (peg folate) motif is used to make the entire polymeric system dispersible in water for longer retention and site-specific therapy. All these specialty functional groups are anchored in a single system by using the ring-opening metathesis polymerization (ROMP) technique under the norbornene backbone. Relaxivity study and 1D image experiments have shown the utility of Fe-Tpy complex as an effective T1 contrast agent. In vitro studies are performed to confirm the promising potentiality of the nanocarrier as the efficient nanotheranostic system in prostate cancer.

Selection of P-Glycoprotein Inhibitor and Formulation of Combinational Nanoformulation Containing Selected Agent Curcumin and DOX for Reversal of Resistance in K562 Cells.

PURPOSE: To select P-glycoprotein (P-gp) inhibitor from natural source for reversal of DOX resistance in K562 cells and to develop selected one in to nanoformulation in combination with DOX. METHODS: DOX resistant K562 (K562R) cells were developed and reversal of resistance by P-gp inhibitor was validated by co-treatment with verapamil. The p-gp inhibitors were evaluated for their potential to inhibit P-gp (calcein assay) and to reverse drug resistance (XTT cell viability assay). The selected agent, curcumin was formulated in to liposome along with DOX and characterized for size, zeta potential, encapsulation efficiency and release rate. Uptake, P-gp inhibition and reversal of acquired drug resistance in K562R cells were performed. RESULTS: P-gp inhibitors such as biochanin-A and curcumin were marked suitable for combination with DOX. However, only curcumin could increase the sensitivity of DOX at all dosing levels, therefore used for further studies. Liposomes loaded with curcumin were formulated and characterized where a prolonged release was observed. The uptake of liposomal curcumin was comparable to nanodispersed curcumin but had lower cytotoxicity. DOX and curcumin coloaded liposomes successfully reversed DOX resistance in K562 cells. CONCLUSION: The coloaded liposomes increased the safety of curcumin with improved efficacy thus can be employed for reversal of acquired DOX resistance.

Selection and optimization of nano-formulation of P-glycoprotein inhibitor for reversal of doxorubicin resistance in COLO205 cells.

OBJECTIVE: The prime objective of current work was to develop a strategy for preparation of combinational nano-formulation for reversal of drug resistance. METHODS: As a model system, doxorubicin (DOX)-resistant COLO205 cells were developed and validated. From co-treatment studies with DOX, curcumin was selected as it reversed DOX-resistance at lowest concentration. In an attempt to increase its solubility, curcumin was encapsulated into hydroxypropyl-ß-cyclodextrin (HP-ß-CD). Here, we propose that presence of stabilizer overcomes its low encapsulation efficiency. Thus, we evaluated curcumin encapsulation in HP-ß-CD in presence of different stabilizers and organic solvents. Finally, the effect of nanocurcumin with liposomal DOX was studied for reversal of resistance in COLO205 cells. KEY FINDINGS: In the process encapsulation, selective optimization of organic solvent by freeze-drying was found to be appropriate among other methods. From optimization studies with different organic solvent (acetone and dichloromethane) and stabilizer [polyvinyl alcohol (PVA) and Pluronics], HP-ß-CD-encapsulated curcumin prepared using acetone in PVA-stabilized dispersion increased encapsulation (60%) with size of ~40 nm. Prepared nano-curcumin reversed the DOX resistance effectively in combination with liposomal DOX. CONCLUSIONS: Curcumin reversed DOX resistance in COLO205 cells at low concentration and enhanced curcumin encapsulation in HP-ß-CD was noted in presence of PVA. Further, it was observed that prepared HP-ß-CD-encapsulated curcumin is equi-efficacious to nano-dispersed curcumin.

Transcatheter pulmonary valve perforation using chronic total occlusion wire in pulmonary atresia with intact ventricular septum.

BACKGROUND: Perforation of pulmonary valve using radiofrequency ablation in pulmonary atresia with intact ventricular septum (PA IVS) is a treatment of choice. However, significant cost of the equipment limits its utility, especially in the developing economies. OBJECTIVE: To assess the feasibility, safety, and efficacy of perforation of pulmonary valve using chronic total occlusion (CTO) wires in patients with PA IVS as an alternative to radiofrequency ablation. METHODS: This is a single-center, nonrandomized, retrospective study conducted during June 2008 to September 2015. Twenty-four patients with PA IVS were selected for the procedure during the study period. The median age and weight of the study population were 8. days and 2.65 kg, respectively. Four patients were excluded after right ventricular angiogram as they showed right ventricular-dependent coronary circulation. The pulmonary valve perforation was attempted using various types of CTO wires based on the tip load with variable penetrating characteristics. RESULTS: The procedure was successful in 16 of twenty patients using CTO wires: Shinobi in nine, Miracle in four, CROSS-IT in two, and Conquest Pro in one. Two patients had perforation of right ventricular outflow tract (RVOT). Pericardiocentesis was required in one patient to relieve cardiac tamponade. Later, the same patient underwent successful hybrid pulmonary valvotomy. The other patient underwent ductus arteriosus (DA) stenting. Balloon atrial septostomy was needed in three cases with systemic venous congestion. Desaturation was persistent in five cases necessitating DA or RVOT stenting to augment pulmonary blood flow. There were two early and two late deaths. The mean follow-up was 22.66 ± 16 months. Three patients underwent one and half ventricle repair and one Blalock-Taussig shunt during follow-up. CONCLUSION: Perforation of the pulmonary valve can be done successfully using CTO wires in selected cases of pulmonary atresia with intact ventricular septum.

Formulation and Optimization of Doxorubicin and Biochanin A Combinational Liposomes for Reversal of Chemoresistance.

Circumvention of drug resistance still remains a challenge in the development of anticancer therapeutics. Combinational nano-formulations provide many avenues for effective cancer therapy and reversal of drug resistance. In the current study, combination of biochanin A (BioA) and doxorubicin (DOX) in liposomes were prepared and studied for its potential to reverse DOX resistance in COLO205 cells. After development and validation of DOX resistant cells of COLO205 (ColoR), dosing ratio of DOX and BioA for reversal of DOX resistance was determined by co-treatment in ColoR cells. As limited solubility and analytical data available for BioA, therefore solubility was studied for BioA and analytical method was developed for the combination. Combinational liposomes were prepared and optimized for both lipid content and surface charge by evaluating size, polydispersity index, zeta potential, and encapsulation efficiency. The optimized formulation had a size about 125 nm; zeta potential of -19.5 mV and 70% encapsulation efficiency (EE) for BioA. Thus, prepared combinational liposomes of DOX and BioA were evaluated for its cellular uptake and efficacy to reverse DOX resistance. From the study, increased DOX uptake and promising effect for reversal of DOX resistance was observed.

Comparative Study of Different Nano-Formulations of Curcumin for Reversal of Doxorubicin Resistance in K562R Cells.

PURPOSE: Curcumin is very well established as a chemo-therapeutic, chemo-preventive and chemo-sensitizing agent in diverse disease conditions. As the isolated pure form has poor solubility and pharmacokinetic problems, therefore it is encapsulated in to several nano-formulations to improve its bioavailability. Here in the current study, we aim to compare different nano-formulations of curcumin for their chemo-sensitizing activity in doxorubicin (DOX) resistant K562 cells. METHODS: Four different curcumin formulations were prepared namely DMSO assisted curcumin nano-dispersion (CurD, 260 nm), liposomal curcumin (CurL, 165 nm), MPEG-PCL micellar curcumin (CurM, 18 nm) and cyclodextrin encapsulated curcumin (CurN, 37 nm). The formulations were subjected to particle characterizations (size, zeta potential, release studies), followed by biological assays such as cellular uptake, P-gp inhibitory activity and reversal of DOX resistance by co-treatment with DOX. RESULTS: Curcumin uptake in K562N and K562R cells was mildly reduced when treated with CurL and CurM, while for CurD and CurN the uptake remained equivalent. However, CurL retained P-gp inhibitory activity of curcumin and with a considerable chemo-sensitizing effect but CurM showed no P-gp inhibitory activity. CurN retained above biological activities, but requires a secondary carrier under in vivo conditions. CONCLUSIONS: From the results, CurM was found to be most suitable for solubilization of curcumin where as CurL can be considered as most suitable nano-formulation for reversal of DOX resistance.

Nanoformulations for delivery of biomolecules: focus on liposomal variants for siRNA delivery.

The potency of biomolecules assures therapy for as well as prevention of many disorders. However, their stability and delivery to the site of action remain a major challenge for successful therapeutic application. With advantages of nanoformulations, such as systemic environmental protection, controlled and site specific release, many of these bio-molecules have found their place in preventive, curative, or immunization-based therapies. Nanoformulations have indeed become a boon for the delivery of biomolecules with such challenges. Among biomolecules, small interfering RNA (siRNA)-based therapeutics has broad range of applications for disorders that may be pathological, metabolic, or physiological. However, certain challenges with respect to biological and delivery constraints need a priori consideration. From this perspective, liposomal delivery has made substantial progress to meet most of the delivery-related (pharmacokinetic) problems associated with siRNA. Furthermore, need-based development has led to the evolution of variants of liposomes. In this review we focus on the scope of siRNA and the trend of rationalized development of liposomal variants to explore its potential therapeutic implication.

Polymeric modification and its implication in drug delivery: poly-ε-caprolactone (PCL) as a model polymer.

Biodegradable polymers provided the opportunity to explore beyond conventional drug delivery and turned out to be the focus of current drug delivery. In spite of availability of diverse class of polymers, several of these polymers lack important physicochemical and biological properties, limiting their widespread application in pharmaceutical drug delivery. However, most polymers in the form of blends, copolymers and functionally modified polymers have exhibited their applicability to overcome specific limitations and to produce novel and/or functionalized formulations for drug delivery as well as tissue engineering. This review aims to provide the need of polymeric modification, approaches adopted to modify and their scope. Special emphasis has been given to synthetic polyester PCL, as it is widely demonstrated in its modified form to overcome its problem of hydrophobicity and much slower degradation over the past decade. Past studies show a significantly higher utility of modified form of PCL in comparison to its native form. From the statistical analysis of these modifications and the formulations prepared, we present a basic understanding of the impact of selective modifications on the formulation design. In conclusion, we remark that a thorough understanding of the polymer and its modification has a huge potential to be the future trend for drug delivery and tissue engineering applications.

Poly-є-caprolactone based formulations for drug delivery and tissue engineering: A review.

Biodegradable polymer based novel drug delivery systems have provided many avenues to improve therapeutic efficacy and pharmacokinetic parameters of medicinal entities. Among synthetic biodegradable polymer, poly-є-caprolactone (PCL) is a polymer with very low glass transition temperature and melting point. Owing to its amicable nature and tailorable properties it has been trialed in almost all novel drug delivery systems and tissue engineering application in use/investigated so far. This review aims to provide an up to date of drugs incorporated in different PCL based formulations, their purpose and brief outcomes. Demonstrated PCL formulations with or without drugs, intended for drug delivery and/or tissue engineering application such as microsphere, nanoparticles, scaffolds, films, fibers, micelles etc. are categorized based on method of preparation.