Polycarbonate Block Copolymers Research Articles

Peptide-Decorated Degradable Polycarbonate Nanogels for Eliciting Antigen-Specific Immune Responses.

For successful therapeutic interventions in cancer immunotherapy, strong antigen-specific immune responses are required. To this end, immunostimulating cues must be combined with antigens to simultaneously arrive at antigen-presenting cells and initiate cellular immune responses. Recently, imidazoquinolines have shown their vast potential as small molecular Toll-like receptor 7/8 (TLR7/8) agonists for immunostimulation when delivered by nanocarriers. At the same time, peptide antigens are promising antigen candidates but require combination with immune-stimulating adjuvants to boost their immunogenicity and exploit their full potential. Consequently, we herein present biodegradable polycarbonate nanogels as versatile delivery system for adjuvants within the particles' core as well as for peptide antigens by surface decoration. For that purpose, orthogonally addressable multifunctional polycarbonate block copolymers were synthesized, enabling adjuvant conjugation through reactive ester chemistry and peptide decoration by strain-promoted alkyne-azide cycloaddition (SPAAC). In preparation for SPAAC, CD4+-specific peptide sequences of the model protein antigen ovalbumin were equipped with DBCO-moieties by site-selective modification at their N-terminal cysteine. With their azide groups exposed on their surface, the adjuvant-loaded nanogels were then efficiently decorated with DBCO-functional CD4+-peptides by SPAAC. In vitro evaluation of the adjuvant-loaded peptide-decorated gels then confirmed their strong immunostimulating properties as well as their high biocompatibility. Despite their covalent conjugation, the CD4+-peptide-decorated nanogels led to maturation of primary antigen-presenting cells and the downstream priming of CD4+-T cells. Subsequently, the peptide-decorated nanogels loaded with TLR7/8 agonist were successfully processed by antigen-presenting cells, enabling potent immune responses for future application in antigen-specific cancer immunotherapy.

Synthesis of sulfur-containing polycarbonate block copolymers via Salen-metal catalyzed copolymerization of CO2, propylene oxide, and phthalic thioanhydride

Sulfur-containing ABA-type polycarbonate triblock copolymers were synthesized via sequential copolymerization of propylene oxide (PO) and carbon dioxide (CO2), followed by propylene oxide (PO) and phthalic thioanhydride (PTA) in the presence of water and Salen-Metal catalysts. The reaction was catalyzed using Salen-Co(III)-Cl/[PPN]Cl and Salen-Cr(III)-Cl/[PPN]Cl catalyst systems. The content of thioester units in the copolymer chain could be adjusted by varying the feed ratios of PTA. These triblock polymers displayed a higher refractive index, reaching up to 1.561.

End Group Dye-Labeled Polycarbonate Block Copolymers for Micellar (Immuno-)Drug Delivery.

Defined conjugation of functional molecules to block copolymer end groups is a powerful strategy to enhance the scope of micellar carriers for drug delivery. In this study, an approach to access well-defined polycarbonate-based block copolymers by labeling their end groups with single fluorescent dye molecules is established. Following controlled polymerization conditions, the block copolymers' primary hydroxy end group can be converted into activated pentafluorophenyl ester carbonates and subsequently aminolyzed with fluorescent dyes that are equipped with primary amines. During a solvent-evaporation process, the resulting end group dye-labeled block copolymers self-assemble into narrowly dispersed ∼25nm-sized micelles and simultaneously encapsulate hydrophobic (immuno-)drugs. The covalently attached fluorescent tracer can be used to monitor both uptake into cells and stability under biologically relevant conditions, including incubation with blood plasma or during blood circulation in zebrafish embryos. By encapsulation of the toll-like receptor 7/8 (TLR7/8) agonist CL075, immune stimulatory polymeric micelles are generated that get internalized by various antigen-presenting dendritic cells and promote their maturation. Generally, such end group dye-labeled polycarbonate block copolymers display ideal features to permit targeted delivery of hydrophobic drugs to key immune cells for vaccination and cancer immunotherapy.

Orthogonally grown polycarbonate and polyvinyl block copolymers from mechanistically distinct (co)polymerizations

Mechanistically distinct polymerization systems can afford unique block copolymers that would not be accessible by mere sequential polymerization.

PH-Sensitive Nanodrug Carriers for Codelivery of ERK Inhibitor and Gemcitabine Enhance the Inhibition of Tumor Growth in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), a metabolic disorder, remains one of the leading cancer mortality sources worldwide. An initial response to treatments, such as gemcitabine (GEM), is often followed by emergent resistance reflecting an urgent need for alternate therapies. The PDAC resistance to GEM could be due to ERK1/2 activity. However, successful ERKi therapy is hindered due to low ligand efficiency, poor drug delivery, and toxicity. In this study, to overcome these limitations, we have designed pH-responsive nanoparticles (pHNPs) with a size range of 100-150 nm for the simultaneous delivery of ERKi (SCH 772984) and GEM with tolerable doses. These pHNPs are polyethylene glycol (PEG)-containing amphiphilic polycarbonate block copolymers with tertiary amine side chains. They are systemically stable and capable of improving in vitro and in vivo drug delivery at the cellular environment's acidic pH. The functional analysis indicates that the nanomolar doses of ERKi or GEM significantly decreased the 50% growth inhibition (IC50) of PDAC cells when encapsulated in pHNPs compared to free drugs. The combination of ERKi with GEM displayed a synergistic inhibitory effect. Unexpectedly, we uncover that the minimum effective dose of ERKi significantly promotes GEM activities on PDAC cells. Furthermore, we found that pHNP-encapsulated combination therapy of ERKi with GEM was superior to unencapsulated combination drug therapy. Our findings, thus, reveal a simple, yet efficient, drug delivery approach to overcome the limitations of ERKi for clinical applications and present a new model of sensitization of GEM by ERKi with no or minimal toxicity.

Biodegradable Cationic Polycarbonates as Vaccine Adjuvants.

In this study, biodegradable cationic polycarbonate and polylactide block copolymers were synthesized and successfully used as novel vaccine adjuvants to provide enhanced anticancer immunity. The polymers formed nanoparticles with the model vaccine, ovalbumin (OVA), and the immunostimulant toll-like receptor 3 agonist poly(I:C) (a synthetic analog of the double-stranded RNA). Higher uptake of poly(I:C) by the bone marrow-derived dendritic cells and macrophages and OVA by dendritic cells was observed when delivered using the polymer adjuvant. In vivo experiments showed that these nanoparticles remained longer in the subcutaneous injection site as compared to OVA alone and led to higher production of anti-OVA specific antibodies with prolonged immunostimulation. When OVA was combined with poly(I:C) that was either co-entrapped in the same particles or as separate particles, a comparable level of anti-OVA IgG1 antibodies and interleukin-6 (IL-6) was produced in mouse blood plasma, and a similar level of cytotoxic T lymphocyte (CTL) response in mice was stimulated as compared to OVA/Alum particles. Furthermore, tumor rejection in the mice that were vaccinated for 9 months with the formulations containing the polymer adjuvant was stronger than the other treatment groups without the polymer. Notably, the cationic polycarbonates were not associated with any adverse in vivo effects. Thus, these biodegradable polymers may be promising substitutes for aluminum-based adjuvants in vaccine formulations.

Carboxylic acid-functionalized polycarbonates as bone cement additives for enhanced and sustained release of antibiotics

Despite the good clinical outcomes of total joint replacements, prosthetic joint infections still remain a significant cause of implant failure. Primary prophylaxis is key to stemming this burgeoning problem and its associated complications. In this study, a series of bone cement formulations with enhanced antibacterial performance have been developed through the addition of carboxylic acid-functionalized polycarbonate block copolymers to commercially available bone cement. Block copolymer design features were specifically tailored to modulate the acidity for adsorption of antibiotic and phase separation of the copolymers within the polymerizing/hardening of the cement during application. The best performing polymers demonstrated sustained antimicrobial release for more than 259 days and 147 days against S. aureus and P. aeruginosa, respectively, compared to 70 days of activity seen with commercially available gentamicin-containing cement control; whilst in vitro gentamicin release was increased by 8-fold. Total porosity was also increased 3-fold from 4.3% to 12.5%, whilst maintaining the mechanical integrity, working characteristics and osteoblastic biocompatibility of bone cement. Taken together, carboxylic acid-functionalized polycarbonates represent a promising class of bone cement additives that can be used to enhance the antibacterial performance of the bone cement whilst maintaining mechanical strength and cellular biocompatibility.

Preparation of Degradable Polymeric Nanoparticles with Various Sizes and Surface Charges from Polycarbonate Block Copolymers

ABA-type polycarbonate block copolymers with pendant vinyl ether and benzyl functionalities were synthesized by sequential ring-opening polymerization of functional cyclic carbonate monomers using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as an organobase catalyst. The vinyl ether moieties on the resulting block copolymers were readily conjugated with 3-mercaptopropionic acid, cysteamine hydrochloride, and L-cysteine hydrochloride monohydrate through thiol-ene “click” reactions, yielding anionic, cationic, and zwitterionic self-assembled nanoparticles, respectively, in corresponding buffers. The effect of pH on the size and surface charge of nanoparticles were examined.

Synthesis, Self-Assembly, and Drug-Release Properties of New Amphipathic Liquid Crystal Polycarbonates.

New amphiphilic liquid crystal (LC) polycarbonate block copolymers containing side-chain cholesteryl units were synthesized. Their structure, thermal stability, and LC phase behavior were characterized with Fourier transform infrared (FT-IR) spectrum, 1H NMR, gel permeation chromatographic (GPC), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), polarizing optical microscope (POM), and XRD methods. The results demonstrated that the LC copolymers showed a double molecular arrangement of a smectic A phase at room temperature. With the elevating of LC unit content in such LC copolymers, the corresponding properties including decomposition temperature (Td), glass temperature (Tg), and isotropic temperature (Ti) increased. The LC copolymers showed pH-responsive self-assembly behavior under the weakly acidic condition, and with more side-chain LC units, the self-assembly process was faster, and the formed particle size was smaller. It indicated that the self-assembly driving force was derived from the orientational ability of LC. The particle size and morphologies of self-assembled microspheres loaded with doxorubicin (DOX), together with drug release tracking, were evaluated by dynamic light scattering (DLS), SEM, and UV–vis spectroscopy. The results showed that DOX could be quickly released in a weakly acidic environment due to the pH response of the self-assembled microspheres. This would offer a new strategy for drug delivery in clinic applications.

Synthesis and properties of stereo mixtures of enantiomeric block copolymers of polylactide and aliphatic polycarbonate

AbstractABA triblock copolymers of polylactides (PLA: A) and aliphatic polycarbonates (APC: B) were prepared by ring‐opening polymerization of d‐ and l‐lactides with poly(hexamethylene carbonate) diol and poly(hexamethylene/pentamethylene carbonate) diol (PHPC) as macro‐initiators. The enantiomeric copolymers with similar block sequences (PLLA‐APC‐PLLA and PDLA‐APC‐PDLA) were mixed in a 1:1 weight ratio to form a stereocomplex of PLA blocks. The resultant stereo mixtures were found to be more thermally stable (up to 200 °C) than the single block copolymers. Polymer films of the stereo mixtures PLLA‐PHPC‐PLLA/PDLA‐PHPC‐PDLA exhibited higher elongation and lower modulus. It was therefore evident that the present enantiomeric block copolymer system can be applicable as a novel thermoplastic elastomer that is environmentally friendly in terms of its biobased nature and the use of carbon dioxide as feedstock. © 2014 Society of Chemical Industry

CO2‐Based Non‐ionic Surfactants: Solvent‐Free Synthesis of Poly(ethylene glycol)‐block‐Poly(propylene carbonate) Block Copolymers

Copolymerization of carbon dioxide (CO2) and propylene oxide (PO) is employed to generate amphiphilic polycarbonate block copolymers with a hydrophilic poly(ethylene glycol) (PEG) block and a nonpolar poly(propylene carbonate) (PPC) block. A series of poly(propylene carbonate) (PPC) di‐ and triblock copolymers, PPC‐b‐PEG and PPC‐b‐PEG‐b‐PPC, respectively, with narrow molecular weight distributions (PDIs in the range of 1.05–1.12) and tailored molecular weights (1500–4500 g mol−1) is synthesized via an alternating CO2/propylene oxide copolymerization, using PEG or mPEG as an initiator. Critical micelle concentrations (CMCs) are determined, ranging from 3 to 30 mg L−1. Non‐ionic poly(propylene carbonate)‐based surfactants represent an alternative to established surfactants based on polyether structures. image

Diels-alder click reaction for the preparation of polycarbonate block copolymers

The Diels-Alder reaction as a click reaction strategy is applied to the preparation of well-defined polycarbonate (PC)-block copolymers. A well-defined α-anthracene-terminated polycarbonate (PC-anthracene) is prepared using 9-anthracene methanol as an initiator in the ring opening polymerization of benzyl 5-methyl-2-oxo-1,3-dioxane-5-carboxylate in CH2Cl2 at room temperature for 5 h. Next, a well-defined α-furan protected maleimide-terminated-poly(ethylene glycol) (PEG11-MI or PEG37-MI), -poly(methyl methacrylate) (PMMA26-MI), and -poly(e-caprolactone) (PCL27-MI) were clicked with the PC-anthracene at reflux temperature of toluene to yield their corresponding PC-based block copolymers (PC-b-PEG, PC-b-PMMA, and PC-b-PCL). The homopolymer precursors and their block copolymers were characterized by using the GPC, NMR and UV analysis. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013

The role of non-covalent interactions in anticancer drug loading and kinetic stability of polymeric micelles

A new series of acid- and urea-functionalized polycarbonate block copolymers were synthesized via organocatalytic living ring-opening polymerization using methoxy poly(ethylene glycol) (PEG) as a macroinitiator to form micelles as drug delivery carriers. The micelles were characterized for critical micelle concentration, particle size and size distribution, kinetic stability and loading capacity for a model anticancer drug, doxorubicin (DOX) having an amine group. The acid/urea groups were placed in block forms (i.e. acid as the middle block or the end block) or randomly distributed in the polycarbonate block to investigate molecular structure effect. The micelles formed from the polymers in both random and block forms provided high drug loading capacity due to strong ionic interaction between the acid in the polymer and the amine in DOX. However, the polymers with acid and urea groups placed in the block forms formed micelles with wider size distribution (two size populations), and their DOX-loaded micelles were less stable. The number of acid/urea groups in the random form was further varied from 5 to 8, 13 and 19 to study its effects on self-assembly behaviors and DOX loading. An increased number of acid/urea groups yielded DOX-loaded micelles with smaller size and enhanced kinetic stability because of improved inter-molecular polycarbonate–polycarbonate (urea–urea and urea–acid) hydrogen-bonding and polycarbonate–DOX (acid–amine) ionic interactions. However, when the number of acid/urea groups was 13 or higher, micelles aggregated in a serum-containing medium, and freeze-dried DOX-loaded micelles were unable to re-disperse in an aqueous solution. Among all the polymers synthesized in this study, 1b with 8 acid/urea groups in the random form had the optimum properties. In vitro release studies showed that DOX release from 1b micelles was sustained over 7 h without significant initial burst release. MTT assays demonstrated that the polymer was not toxic towards HepG2 and HEK293 cells. Importantly, DOX-loaded micelles were potent against HepG2 cells with IC50 of 0.26 mg/L, comparable to that of free DOX (IC50: 0.20 mg/L). In addition, DOX-loaded 1b micelles yielded lower DOX content in the heart tissue of the tested mice as compared to free DOX formulation after i.v. injection. These findings signify that 1b micelles may be a promising carrier for delivery of anticancer drugs that contain amine groups.

Thermoresponsive nanostructured polycarbonate block copolymers as biodegradable therapeutic delivery carriers

Water-soluble, thermoresponsive block copolymers based on a biodegradable platform were synthesized by the ring opening polymerization of cyclic carbonate monomers functionalized with hydrophilic and hydrophobic groups for application as nanocarriers in medicine. The approach based on cyclic carbonate monomers derived from 2,2-bis(methylol)propionic acid (bis-MPA) allowed a simple and versatile route to functional monomers capable of undergoing ring opening polymerization (ROP). The resulting polymers possessed the predicted molecular weights based on the molar ratio between monomers to initiators and the narrow molecular weight distributions. Transmittance measurement for aqueous polymer solutions provided an evidence for temperature-responsiveness with lower critical solution temperature (LCST) in the range of 36 °C–60 °C, depending on the molecular weight of hydrophilic poly(ethylene glycol) (PEG) chains, compositions of copolymers, molar ratios of hydrophilic to hydrophobic monomers in the corona, and the hydrophobic core. This study showed synthetic advancement toward the design and preparation of biodegradable thermoresponsive polymers with extremely low CMC values for injectable drug delivery systems. TRC350-10,30,60, which possessed an LCST of 36 °C in PBS, was identified as a useful model polymer. Paclitaxel, an anti-cancer drug, was loaded into the micelles efficiently, giving rise to nano-sized particles with a narrow size distribution. Paclitaxel release from the micelles was faster, and cellular uptake of the micelles was higher at the body temperature (i.e. 37 °C) as compared to a temperature below the LCST. While the polymer was not cytotoxic, paclitaxel-loaded micelles killed HepG2 human liver carcinoma cells more efficiently at the body temperature as compared to free paclitaxel and paclitaxel-loaded micelles at the temperature below the LCST. These micelles are ideally suited to deliver anti-cancer drugs to tumor tissues through local injection.

Physical aging of polycarbonate block copolymers: Ductility rejuvenation below the glass transition temperature

AbstractThermal aging of block copolymers of bisphenol A polycarbonate and polydimethylsiloxane (BPAPC and PDMS) have been studied. Changes in notched izod impact performance and yield stress are reported following aging at 120°C and 130°C for up to 20 days. Retention of impact at 120°C of the block copolymers was found to improve with increasing size of siloxane domains in the polycarbonate matrix. Quite contrary to our expectation, the retention of impact for a given sample at 130°C was found to be better than that of at120°C. These block copolymers showed (thermo) reversible ductility rejuvenation behavior at 130°C when the samples heat‐aged at 120°C were shifted from 120 to 130°C. Transmission electron microscopy, small‐angle X‐ray scattering, and dynamic mechanical analysis techniques were used to probe the observed phenomenon. POLYM. ENG. SCI., 2009. © 2009 Society of Plastics Engineers

A model of traps for yield in amorphous glassy polymers

Constitutive equations are derived for the viscoelastic and viscoplastic behavior of amorphous glassy polymers at isothermal loading with small strains. The model is based on the trapping concept: a disordered medium is treated as an ensemble of plastic flow units (with the characteristic size of micrometers), which, in turn, consist of a number of cooperative rearranging regions (with the characteristic length of nanometers). The viscoelastic response is described by rearrangement of relaxing regions, whereas the viscoplastic behavior is modeled as irreversible deformation of plastic units. Adjustable parameters are found by fitting observations for aromatic polyesters, nylon-66, polycarbonate block copolymers and an epoxy glass. Fair agreement is demonstrated between experimental data and results of numerical simulation.

Catalyst effect on the transesterification reactions between polycarbonate and polycaprolactone-B-polydimethylsiloxane triblock copolymers

Transesterification reactions between bisphenol-A polycarbonate and polydimethylsiloxane-polycaprolactone block copolymers were studied in melt at 270°C. Influence of the composition of reaction mixture and the catalyst type on the formation and properties of the products obtained were investigated by spectroscopic, chromatographic and thermal methods. Both of the catalysts used, zinc acetate and lanthanum acetylacetonate are very efficient transesterification catalysts for the system studied. GPC and DSC results clearly show the formation of novel polymers displaying combined properties of the polycarbonate and the silicone-ester copolymer.

Rheo-optical Fourier transform near-infrared spectroscopy of polydimethylsiloxane/polycarbonate block copolymers

A series of polydimethylsiloxane (PDMS)/polycarbonate (PC) block copolymers with varying compositions were investigated by simultaneous mechanical and Fourier transform near-infrared (FTNIR) spectroscopic (rheo-optical) measurements to study segmental orientation during elongation-to-break and cyclic elongation–recovery procedures. Depending on the composition and the block lengths of the copolymers, different orientational and recovery phenomena were observed for the hard (PC) and soft (PDMS) segments. © 1998 John Wiley & Sons, Inc. J. Appl. Polym. Sci. 70: 1349–1357, 1998

Rheo‐optical Fourier transform near‐infrared spectroscopy of polydimethylsiloxane/polycarbonate block copolymers

A series of polydimethylsiloxane (PDMS)/polycarbonate (PC) block copolymers with varying compositions were investigated by simultaneous mechanical and Fourier transform near-infrared (FTNIR) spectroscopic (rheo-optical) measurements to study segmental orientation during elongation-to-break and cyclic elongation–recovery procedures. Depending on the composition and the block lengths of the copolymers, different orientational and recovery phenomena were observed for the hard (PC) and soft (PDMS) segments. © 1998 John Wiley & Sons, Inc. J. Appl. Polym. Sci. 70: 1349–1357, 1998

Bisphenol-A polycarbonate/polydimethylsiloxane multiblock copolymers. I. Synthesis and characterization

Aminopropyl-terminated polydimethylsiloxane (PDMS)-bisphenol-A polycarbonate block copolymers were synthesized by interfacial phosgenation reaction of 2,2-bis(4-hydroxyphenyl) propane (BPA) and aminopropyl-terminated PDMS. A new synthetic procedure shows better conversion yield of PDMS oligomer. IR, 1H, 13C, and 29Si nuclear magnetic resonance spectra were used to identify the exact chemical structures of the PDMS-PC block copolymers. The conversions of PDMS of these copolymers were ∼ 90% and independent of the PDMS content. The intrinsic viscosities, IV, [γ] studied were in the range between 0.23 and 2.25 dL/g in dichloromethane at 25°C with different reaction conditions. The intrinsic viscosity and the glass transition temperature decreased with increasing PDMS content at the same reaction temperature, while the melting flow indices increase with increasing PDMS content. Transparent and colorless films, which showed good oxygen-to-nitrogen permselectivity, could be cast from dichloromethane. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 66: 57–66, 1997