Katherine E. Washington

Recent developments in micellar drug carriers featuring substituted poly(ε-caprolactone)s

In the field of drug delivery, synthetic polymers have been widely explored due to their range of properties and functions achievable by tuning their structures. Poly(e-caprolactone)s in particular have established themselves as excellent candidates for biomedical applications because of their biocompatibility, biodegradability, and synthetic versatility. In this review, applications of functional poly(e-caprolactone)s in drug delivery systems are highlighted. Recent studies regarding the encapsulation or direct conjugation of drugs, bioactive molecules and moieties for targeting are discussed. Also considered are advances in amphiphilic polymers with functional poly(e-caprolactone)s that exhibit stimuli-responsive behavior: pH-, thermo-, photo-, and reduction-sensitive. Ongoing research and development of functional poly(e-caprolactone)s continues to expand their potential for use in micellar drug delivery systems.

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.

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.

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.

Thermoresponsive star-like γ-substituted poly(caprolactone)s for micellar drug delivery

Temperature responsive drug carriers are attractive due to their ability to provide controlled release of the encapsulated cargo based on the use of external stimuli. In this work, 4- and 6-arm thermoresponsive star-like block copolymers were synthesized through the ring-opening polymerization of γ-substituted e-caprolactone monomers γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-e-caprolactone (MEEECL) and γ-ethoxy-e-caprolactone (ECL) using pentaerythritol and myo-inositol as multifunctional initiators. These amphiphilic block copolymers were shown to self-assemble into micelles and were characterized in terms of their feasibility as drug carriers. Both polymers were shown to be thermodynamically stable and demonstrated temperature responsivity in a desirable range for drug delivery, with lower critical solution temperatures of 39.4 °C and 39.8 °C for the 4- and 6-arm polymers, respectively. It was shown that the 6-arm star polymer had a higher drug loading capability and better stability in vitro, allowing it to function as a better vehicle for drug delivery in cytotoxicity experiments. These star polymers show promise as drug carriers due to their biocompatibility, biodegradability, and temperature controlled release of doxorubicin.

Benzo[1,2-b:4,5-b′]difuran and furan substituted diketopyrrolopyrrole alternating copolymer for organic photovoltaics with high fill factor

In comparison to the conjugated polymers synthesized from thiophene or thiophene derivatives, furan and its derivatives are promising alternative building units due to their desirable properties such as smaller heteroatom size, more electronegative heteroatom, and larger dipole moment. Considering the advantages of furan units, conjugated polymers synthesized from furan and its derivatives show a higher degree of conjugation with reduced twisting between adjacent units, smaller π-stacking distance, and improved solubility. To date, despite research on polymers constructed from furan derivatives gaining attention, conjugated polymers made up of only furan or its derivatives are still rare. Herein, we report a new conjugated polymer, poly(4,8-bis(5-(2-ethylhexyl)furan-2-yl)benzo[1,2-b:4,5-b′]difuran-alt-2,5-didodecyl-3,6-di(furan-2-yl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione), P(BDF-FDPP), for organic solar cells. The smaller oxygen atom in furan of P(BDF-FDPP) results in a planar conjugated backbone with negligible torsion (dihedral angle < 0.1°) determined by density functional theory. P(BDF-FDPP) exhibits broad absorption up to 940 nm with HOMO and LUMO located at −5.19 eV and −3.63 eV, respectively. Power conversion efficiency (PCE) of 5.55% with a high fill factor (FF) of 0.73 was obtained for the devices fabricated using DPE as an additive. The substantial changes in photovoltaic performance of the device fabricated with or without additives was further investigated with grazing incident wide-angle X-ray scattering, and transmission electron microscopy experiments. Preferential face-on orientation of P(BDF-FDPP) and sophisticated interpenetrated network for P(BDF-FDPP)/PC71BM blend films enabled relatively good PCEs and high FF in solar cell devices.

Influence of functionalized side chains of polythiophene diblock copolymers on the performance of CdSe quantum dot hybrid solar cells

The incorporation of functional groups into the side chains of polythiophenes can improve the phase separation of polymer : nanoparticle hybrid solar cells (HSCs). Our results showed that by introducing 17 mol% thiol functionality in the polymer, the Jsc and Voc can be increased by twofold in polymer : CdSe quantum dot (QD) HSCs.

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.

Stimuli-responsive poly (ε-caprolactone)s for drug delivery applications

Abstract Poly(caprolactone)s have found extensive use in drug delivery applications due to their attractive properties such as biocompatibility and biodegradability. Significant efforts have been made in recent years to develop stimuli-responsive systems using these polymers. Through the functionalization of e-caprolactone monomers, different stimuli-responsive properties can be instilled to the resulting polymers. Poly(caprolactone)s are usually formed through the ring-opening polymerization of e-caprolactone monomers, which can be accomplished through different mechanisms such as anionic, cationic, or coordination-insertion. The resulting poly(caprolactone)s can be used for various nanocarrier systems including micelles, nanoparticles, dendrimers, or polymersomes. Often, poly(caprolactone)s are used in combination with other polymers to form block copolymers that have hydrophobic and hydrophilic segments which can then form the nanocarriers through self-assembly. Stimuli-responsive nanocarriers created from poly(caprolactone)s can release the drug through either internal or external stimuli. Nanocarriers that are responsive to differences of the internal environment like reduction or pH have attracted a lot of interest in recent years. However, there has also been an interest in nanocarriers that are responsive where the application of an external stimulus, such as temperature or light, triggers the release of the drug. Recently, new effort has been focused to design nanocarriers that are sensitive to multiple stimuli. In this chapter, the extensive use of poly(caprolactone)s in stimuli-responsive nanocarriers will be discussed in detail.

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.