Novel Chlorhexidine-Loaded Polymeric Nanoparticles for Root Canal Treatment.

Persistence of microorganisms in dentinal tubules after root canal chemo-mechanical preparation has been well documented. The complex anatomy of the root canal and dentinal buffering ability make delivery of antimicrobial agents difficult. This work explores the use of a novel trilayered nanoparticle (TNP) drug delivery system that encapsulates chlorhexidine digluconate, which is aimed at improving the disinfection of the root canal system. Chlorhexidine digluconate was encapsulated inside polymeric self-assembled TNPs. These were self-assembled through water-in-oil emulsion from poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA), a di-block copolymer, with one hydrophilic segment and another hydrophobic. The resulting TNPs were physicochemically characterized and their antimicrobial effectiveness was evaluated against Enterococcus faecalis using a broth inhibition method. The hydrophilic interior of the TNPs successfully entrapped chlorhexidine digluconate. The resulting TNPs had particle size ranging from 140–295 nm, with adequate encapsulation efficiency, and maintained inhibition of bacteria over 21 days. The delivery of antibacterial irrigants throughout the dentinal matrix by employing the TNP system described in this work may be an effective alternative to improve root canal disinfection.

Histone Deacetylase Inhibitor (HDACi) Conjugated Polycaprolactone for Combination Cancer Therapy.

The short chain fatty acid, 4-phenylbutyric acid (PBA), is used for the treatment of urea cycle disorders and sickle cell disease as an endoplasmic reticulum stress inhibitor. PBA is also known as a histone deacetylase inhibitor (HDACi). We report here the effect of combination therapy on HeLa cancer cells using PBA as the HDACi together with the anticancer drug, doxorubicin (DOX). We synthesized γ-4-phenylbutyrate-ε-caprolactone monomer which was polymerized to form poly(γ-4-phenylbutyrate-ε-caprolactone) (PPBCL) homopolymer using NdCl3·3TEP/TIBA (TEP = triethyl phosphate, TIBA = triisobutylaluminum) catalytic system. DOX-loaded nanoparticles were prepared from the PPBCL homopolymer using poly(ethylene glycol) as a surfactant. An encapsulation efficiency as high as 88% was obtained for these nanoparticles. The DOX-loaded nanoparticles showed a cumulative release of >95% of DOX at pH 5 and 37 °C within 12 h, and PBA release was monitored by 1H NMR spectroscopy. The efficiency of the combination therapy can notably be seen in the cytotoxicity study carried out on HeLa cells, where only ∼20% of cell viability was observed after treatment with the DOX-loaded nanoparticles. This drastic cytotoxic effect on HeLa cells is the result of the dual action of DOX and PBA on the DNA strands and the HDAC enzymes, respectively. Overall, this study shows the potential of combination treatment with HDACi and DOX anticancer drug as compared to the treatment with an anticancer drug alone.

Combination Loading of Doxorubicin and Resveratrol in Polymeric Micelles for Increased Loading Efficiency and Efficacy.

Combined loading of doxorubicin (DOX) and resveratrol (RSV) in polymeric micelles enabled an increased loading of DOX into a micellar drug delivery system. Herein, we report the coloading of DOX and RSV in amphiphilic diblock copolymer micelles of poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) and poly(ethylene glycol)-b-poly(γ-benzyl-ε-caprolactone) (PEG-b-PBCL) for which an increase in the loading efficiency and increased in vitro cytotoxicity was observed. The increased loading was attributed to the favorable interactions of DOX and RSV as well as to the interaction with benzyl substituents of PEG-b-PBCL diblock copolymer micelles. Combination loaded micelles made of PEG-b-PBCL diblock copolymer showed a dramatic improvement in DOX loading in comparison to DOX-only loaded PEG-b-PBCL with an increase in encapsulation efficiency of DOX from 31.0 to 87.7%. Combination loaded micelles also showed increased cytotoxicity to HeLa cells as compared to that of DOX-only loaded micelles. Optimization of the combination loading, size and morphology, drug release, and cellular studies is also reported here. Combination loading was shown to improve the loading capacity and efficiency of both systems and shows promise to improve loading of DOX in polymer micelle systems regardless of the polymer used.

HDAC Inhibitor Conjugated Polymeric Prodrug Micelles for Doxorubicin Delivery.

Amphiphilic diblock copolymers bearing histone deacetylase inhibitors (HDACi) (4-phenyl butyric acid and valproic acid) were synthesized by the ring-opening polymerization of γ-4-phenylbutyrate-ε-caprolactone (PBACL), γ-valproate-ε-caprolactone (VPACL), and ε-caprolactone (CL) from a poly(ethylene glycol) macroinitiator (PEG). These amphiphilic diblock copolymers self-assembled into stable pro-drug micelles and demonstrated excellent biocompatibility. High loading of doxorubicin (DOX) up to 5.1 wt% was achieved. Optimized micelles enabled sustained drug release in a concentration-dependent manner over time to expand the therapeutic window of cytotoxic small molecule drugs.

Bioerosion of Synthetic Sling Explants.

This study was performed to investigate the changes over time in polypropylene (PP) mesh explants from women with stress urinary incontinence originally treated with a midurethral PP sling. Following Institutional Review Board (IRB) approval, 10 PP explants removed for pain or obstructive symptoms between January and June 2016 were analyzed through various techniques to determine the degradation of the material in vivo. Exclusion criteria were exposed or infected mesh sling or sling in place for less than six months. One pristine control was studied for comparison. The explant samples were analyzed with scanning electron microscopy to visualize the surface defects as well as infrared spectroscopy and energy dispersive X-ray spectroscopy to determine if the degradation was oxidative in nature. The results show qualitative and quantitative bioerosion over the surface of the explant samples and an increase in the content of oxygen pointing toward oxidative degradation occurring in vivo.

Recent advances in aliphatic polyesters for drug delivery applications.

The use of aliphatic polyesters in drug delivery applications has been a field of significant interest spanning decades. Drug delivery strategies have made abundant use of polyesters in their structures owing to their biocompatibility and biodegradability. The properties afforded from these materials provide many avenues for the tunability of drug delivery systems to suit individual needs of diverse applications. Polyesters can be formed in several different ways, but the most prevalent is the ring-opening polymerization of cyclic esters. When used to form amphiphilic block copolymers, these materials can be utilized to form various drug carriers such as nanoparticles, micelles, and polymersomes. These drug delivery systems can be tailored through the addition of targeting moieties and the addition of stimuli-responsive groups into the polymer chains. There are also different types of polyesters that can be used to modify the degradation rates or mechanical properties. Here, we discuss the reasons that polyesters have become so popular, the current research focuses, and what the future holds for these materials in drug delivery applications. WIREs Nanomed Nanobiotechnol 2017, 9:e1446. doi: 10.1002/wnan.1446 For further resources related to this article, please visit the WIREs website.

Systematic Investigation of Benzodithiophene-Benzothiadiazole Isomers for Organic Photovoltaics.

Two new donor-acceptor small molecules based on benzo[1,2-b:4,5-b']dithiophene (BDT) and benzo[c][1,2,5]thiadiazole (BT) were designed and synthesized. Small molecules 4,4'-[(4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene-2,6-diyl)bis(2,2'-bithiophene)-5,5'-diyl]bis(benzo[c][1,2,5]thiadiazole) (BDT-TT-BT) and 4,4'-(4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene-2,6-diyl)bis[7-(2,2'-bithiophene-5-yl)benzo[c][1,2,5]thiadiazole] (BDT-BT-TT) are structural isomers with the 2,2-bithiophene unit placed either between the BDT and BT units or at the end of the BT units. This work is targeted toward finding the effect of structural variation on optoelectronic properties, morphology, and photovoltaic performance. On the basis of theoretical calculations, the molecular geometry and energy levels are different for these two molecules when the position of the 2,2-bithiophene unit is changed. Optical and electrochemical properties of these two small molecules were characterized using UV-vis and cyclic voltammetry. The results showed that BDT-BT-TT has broader absorption and an elevated HOMO energy level when compared with those of BDT-TT-BT. The performance of these two isomers in solar cell devices was tested by blending with [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM). Power conversion efficiencies as high as 3.22 and 3.71% were obtained in conventional solar cell structures for BDT-TT-BT and BDT-BT-TT, respectively. The morphology was studied using grazing incident wide-angle X-ray scattering and transmission electron microscopy, which revealed different phase separations of these two molecules when blended with PC71BM.

PEG based anti-cancer drug conjugated prodrug micelles for the delivery of anti-cancer agents.

Due to the high cost and uncertain success of new drug development, tremendous effort is devoted to increasing the efficacy of established anti-cancer drugs. Development of polymer prodrug conjugates has evolved recently in the nano-medicine field for cancer diagnosis and treatment. The major advantage of using polymer drug conjugates is that the chemical and physical properties of polymers can be tuned to increase the efficacy and to reduce the toxicity of the drug. The stimuli responsiveness provides the release of the prodrug in a controlled manner which avoids undesired side effects, organ damage, and toxicity caused by the fluctuations associated with periodic administration. A large number of anti-cancer drug polymer conjugates have been studied for cancer therapy due to their promising clinical applications in chemotherapy. In this paper, poly(ethylene glycol) (PEG) based anti-cancer drug conjugates will be discussed followed by a review of different types of PEG-b-poly(ε-caprolactone) (PEG-b-PCL) copolymer drug conjugates and histone deacetylase inhibitor polymer conjugates as novel therapeutics. The pH sensitive release of prodrugs will be discussed for polymer prodrug conjugates that are currently under investigation.

Fine-tuning thermoresponsive functional poly(ε-caprolactone)s to enhance micelle stability and drug loading.

Block copolymers synthesized by the ring-opening polymerization of γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-ε-caprolactone (ME3CL), γ-2-methoxyethoxy-ε-caprolactone (ME1CL), and ε-caprolactone (CL) are reported. Previously, diblock copolymers of PME3CL-b-PME1CL displayed excellent thermoresponsive tunability (31-43 °C) and self-assembled into micelles with moderate thermodynamic stability. In this report, two strategies are employed to enhance thermodynamic stability of PME3CL/PME1CL-type block copolymer micelles while maintaining their attractive thermoresponsive qualities: modification of the end group position and alteration of hydrophobic block composition by using both ME1CL and CL. These new thermoresponsive amphiphilic block copolymers showed lower critical micelle concentration (CMC) values by one order of magnitude and formed thermodynamically stable micelles. Furthermore they demonstrated good biocompatibility and up to 4.97 wt% doxorubicin loading, more than double the amount loaded into the PME3CL-type polymeric micelles previously reported.

Towards smart polymeric drug carriers: self-assembling γ-substituted polycaprolactones with highly tunable thermoresponsive behavior.

Synthesis and ring opening polymerization of a new γ-substituted ε-caprolactone monomer, γ-(2-methoxyethoxy)-ε-caprolactone is reported. Amphiphilic diblock copolymers comprised of poly[γ-(2-methoxyethoxy)-ε-caprolactone] and thermosensitive poly{γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-ε-caprolactone} as the hydrophobic and hydrophilic blocks, respectively, were prepared. The copolymers exhibited fully biodegradable backbones and highly tunable thermoresponsive behavior in the range of 31-43 °C. Additionally, the copolymers were shown to self-assemble in aqueous media above their respective critical micelle concentrations, on the order of 10-2 g L-1. Due to their thermosensitive, self-assembling, and biodegradable properties, these copolymers demonstrate potential for the use in polymeric micellar drug delivery systems.