Polylactide Core Research Articles

Manufacturing and Characterization of Highly Environmentally Friendly Sandwich Composites from Polylactide Cores and Flax-Polylactide Faces.

This work focuses on the manufacturing and characterization of highly environmentally friendly lightweight sandwich structures based on polylactide (PLA) honeycomb cores and PLA-flax fabric laminate skins or facings. PLA honeycombs were manufactured using PLA sheets with different thicknesses ranging from 50 to 500 μm. The PLA sheets were shaped into semi-hexagonal profiles by hot-compression molding. After this stage, the different semi-hexagonal sheets were bonded together to give hexagonal panels. The skins were manufactured by hot-compression molding by stacking two Biotex flax/PLA fabrics with 40 wt% PLA fibers. The combined use of temperature (200 °C), pressure, and time (2 min) allowed PLA fibers to melt, flow, and fully embed the flax fabrics, thus leading to thin composite laminates to be used as skins. Sandwich structures were finally obtained by bonding the PLA honeycomb core with the PLA-flax skins using an epoxy adhesive. A thin PLA nonwoven was previously attached to the external hexagonal PLA core, to promote mechanical interlock between the core and the skins. The influence of the honeycomb core thickness on the final flexural and compression properties was analyzed. The obtained results indicate that the core thickness has a great influence on the flexural properties, which increases with core thickness; nevertheless, as expected, the bonding between the PLA honeycomb core and the skins is critical. Excellent results have been obtained with 10 and 20 mm thickness honeycombs with a core shear of about 0.60 and facing bending stresses of 31–33 MPa, which can be considered as candidates for technical applications. The ultimate load to the sample weight ratio reached values of 141.5 N·g−1 for composites with 20 mm thick PLA honeycombs, which is comparable to other technical composite sandwich structures. The bonding between the core and the skins is critical as poor adhesion does not allow load transfer and, while the procedure showed in this research gives interesting results, new developments are necessary to obtain standard properties on sandwich structures.

Encapsulation of monomyristin into polymeric nanoparticles improved its in vitro antiproliferative activity against cervical cancer cells.

The cytotoxicity of monomyristin (MM), a monoacylglycerol, was investigated against cervical cancer cells (HeLa) and two normal cells (Vero and endometrial epithelial cells). MM exhibited cytotoxicity specifically to HeLa cells and not against normal cells except at the highest investigated doses (> 500 μg/mL). MM was showed to increase apoptotic dead cells by intrinsic mitochondrial pathway. To overcome the poor water solubility of MM and increase its efficacy against HeLa cells, MM was encapsulated into dextran-covered polylactide (PLA) nanoparticles (NPs). NPs comprised a PLA core which encapsulated MM and a superficial layer of dextran loops which was used for conjugating a protein, transferrin (Tf), known to be overexpressed on cancer cells' surface. Encapsulation of MM into NPs increased its cytotoxicity against HeLa cells at lower doses of MM than free MM. Additionally, the presence of conjugated Tf further increased the cytotoxicity of MM against HeLa cells as compared to non-conjugated NPs. Remarkably, both conjugated and non-conjugated MM loaded NPs were safe to normal cells (Vero and endometrial).

PLA-Based Triblock Copolymer Micelles Exhibiting Dual Acidic pH/Reduction Responses at Dual Core and Core/Corona Interface Locations.

Polylactide (PLA)-based amphiphilic block copolymers and their nanoassemblies designed with stimuli-responsive degradation (SRD) hold great potential as promising candidates for tumor-targeting drug delivery. However, most of the smart PLA-based nanoassemblies are designed to respond to a single stimulus (typically reduction or acidic pH). Herein, a new strategy is reported to synthesize PLA-based block copolymer micelles exhibiting dual SRD at dual locations (DL-DSRD). The strategy utilizes a combination of ring opening polymerization, controlled radical polymerization, and facile coupling reactions to synthesize an ABA-type PLA-based triblock copolymer with a hydrophilic polymethacrylate (A) and PLA (B) blocks. Incorporation of an acidic pH-responsive ketal linkage in the center of PLA block and reduction-responsive disulfide linkages at PLA/hydrophilic polymethacrylate blocks ensure the formation of smart nanoassemblies featured with ketal linkages in the PLA cores and disulfide linkages at core/corona interfaces, thus attaining DL-DSRD. Such dual acidic pH/reduction-responses at dual locations lead to not only shedding of coronas at interfaces but also destabilization of cores, resulting in the synergistic and accelerated release of encapsulated model drugs, compared with the single stimulus systems. These results, along with lower cytotoxicity, suggest that DL-DSRD strategy can offer versatility in the development of tumor-targeting drug delivery nanocarriers.

Synthesis and Self-Assembly of Block Copolymers Containing Temperature Sensitive and Degradable Chain Segments.

In this work, polylactide-b-poly(N-isopropylacrylamide) were synthesized by the combination of controlled ring-opening polymerization and reversible addition fragmentation chain transfer polymerization. These block copolymers with molecular weight range from 7,900 to 12,000 g/mol and narrow polydispersity (≤1.19) can self-assemble into micelles (polylactide core, poly(N-isopropylacrylamide) shell) in water at certain temperature range, which have been evidenced by laser particle size analyzer proton nuclear magnetic resonance and transmission electron microscopy. Such micelles exhibit obvious thermo-responsive properties: (1) Poly(N-isopropylacrylamide) blocks collapse on the polylactide core as system temperature increase, leading to reduce of micelle size. (2) Micelles with short poly(N-isopropylacrylamide) blocks tend to aggregate together when temperature increased, which is resulted from the reduction of the system hydrophilicity and the decreased repulsive force between micelles.

Microporous organic nanotube networks from hyper cross-linking core-shell bottlebrush copolymers for selective adsorption study

We report a synthesis of microporous organic nanotube networks (MONNs) by a combination of hyper cross-linking and molecular templating of core-shell bottlebrush copolymers. The intrabrush and interbrush cross-linking of polystyrene (PS) shell layer in the core-shell bottlebrush copolymers led to the formation of micropores and large-sized nanopores (meso/macrospores) in MONNs, respectively, while selective removal of polylactide (PLA) core layer generated mesoporous tubular structure. The size of PLA-templated mesoporous cores and porous structure both at micro- and meso-scale could be controlled by simple tuning of the ratio of core/shell or the PLA core fraction in the bottlebrush precursors. Moreover, the resultant MONNs showed a highly selective adsorption capacity for the positively charged dyes on the basis of multi-porosity and carboxylate group-rich structure. In addition, MONNs also exhibited effective performance in size-selective adsorption of biomacromolecules. This work represents a new avenue for the preparation of MONNs and also provides a new application for molecular bottlebrushes in nanotechnology.

Amphiphilic dendritic nanomicelle-mediated co-delivery of 5-fluorouracil and doxorubicin for enhanced therapeutic efficacy

Combination cancer therapy has attracted considerable attention due to its enhanced antitumor efficacy and reduced toxicity granted by synergistic effects over monotherapy. The application of nanotechnology is expected to achieve coencapsulation of multiple anticancer agents with enhanced therapeutic efficacy. Herein, a unique nanomicelle based on amphiphilic dendrimer (AmD) consisting of a hydrophilic polyamidoamine dendritic shell and a hydrophobic polylactide core is developed for effectively loading and shuttling 5-fluorouracil (5-Fu) and doxorubicin (Dox). The yielded drug-encapsulated dendritic nanomicelle (5-Fu/Dox-DNM) has a modest average size of 68.6 ± 3.3 nm and shows pH-sensitive drug release manner. The parallel activity of 5-Fu and Dox show synergistic anticancer efficacy. The IC50 value of 5-Fu/Dox-DNM toward human breast cancer (MDA-MB-231) cells was 0.25 μg/mL, presenting an 11.2-fold and 6.1-fold increase in cytotoxicity compared to Dox-DNM and 5-Fu-DNM, respectively. Furthermore, 5-Fu/Dox-DNM significantly inhibits the progression of tumor growth in the MDA-MB-231 xenograft tumor mice model. In conclusion, we have demonstrated that our AmD-based combination therapeutic system has promising potential to open an avenue for coencapsulation of multiple chemotherapeutic agents to promote superior anticancer effect.

Multifunctional unimolecular micelles loaded with the anti-cancer drug aminoflavone for triple negative breast cancer therapy

Multifunctional unimolecular micelles loaded with the anti-cancer drug aminoflavone for triple negative breast cancer therapy

Reductively-sheddable cationic nanocarriers for dual chemotherapy and gene therapy with enhanced release

The development of a versatile strategy to synthesize cationic nanocarriers capable of co-delivery and enhanced release of drugs and oligonucleotides is promising for synergic dual chemotherapy and gene therapy. Herein, we report a novel cationic amphiphilic diblock copolymer having a single reduction-responsive disulfide linkage at a junction between a FDA-approved polylactide (PLA) block and a cationic methacrylate block (C-ssABP). The amphiphilic design of the C-ssABP enables the formation of cationic micellar aggregates possessing hydrophobic PLA cores, encapsulating anticancer drugs; cationic coronas, ensuring complementary complexation with negatively-charged oligonucleotides through electrostatic interactions; and disulfides at interfaces, leading to enhanced release of both encapsulated drugs and complexed oligonucleotides. The reduction-responsive intracellular trafficking results from flow cytometry, confocal laser scanning microscopy, and cell viability, as well as in vitro gene transfection assay suggest that C-ssABP offers versatility as an effective nanocarrier platform for dual chemotherapy and gene therapy.

New Route to Segmental Star-Shaped Copolymers of Lactic Acid

The star-like copolymers containing polylactide core and poly(propylene maleate) arms have been synthesized in two steps. The polylactide segments of Mn in the range 1000–8500 terminated either by OH or COOH functional groups were prepared by melt condensation of L-lactic acid in the presence of pentaerythritol, or 1,2,3,4-butanetetracarboxylic acid. Selected products were applied as coinitiators and chain transfer agents in the copolymerization of maleic anhydride with propylene oxide catalyzed by magnesium ethoxide or metal salen complexes. Four-arm stars of Mw in the range 11000–35000 have been prepared. Thermal analysis revealed a lower Tg for the copolymers compared to polylactide core.

Polyphosphoester-based nanoparticles with viscous flow core enhanced therapeutic efficacy by improved intracellular drug release.

The intracellular drug release rate from the hydrophobic core of self-assembled nanoparticles can significantly affect the therapeutic efficacy. Currently, the hydrophobic core of many polymeric nanoparticles which are usually composed of poly(ε-caprolactone) (PCL), polylactide (PLA), or poly(D, L-lactide-co-glycolide) (PLGA) may hinder the diffusion of drug from the core because of their glassy state at room temperature. To investigate the effect of the hydrophobic core state on therapeutic efficacy, we synthesized an amphiphilic diblock copolymers of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic polyphosphoester, which were in a viscous flow state at room temperature. The obtained copolymers self-assembled into core-shell nanoparticles, which efficiently encapsulate doxorubicin (DOX) in the hydrophobic polyphosphoester core (NP(PPE)/DOX). As speculated, compared with the nanoparticles bearing glassy core (hydrophobic PLA core, NP(PLA)/DOX), the encapsulated DOX was more rapidly released from NP(PPE)/DOX with viscous flow core, resulting in significantly increased cytotoxicity. Accordingly, the improved intracellular drug release from viscous flow core enhances the inhibition of tumor growth, suggesting the nanoparticles bearing viscous flow core show great potential in cancer therapy.

Synthesis and reduction-responsive disassembly of PLA-based mono-cleavable micelles

Stimuli-responsive block copolymers and their self-assembled nanostructures have been extensively studied as effective building blocks in construction of various nanomaterials in nanoscience and nanotechnology. A promising stimuli-responsive platform involves an incorportion of reduction-responsive disulfide linkages that can be cleaved to corresponding thiols when needed. Herein, we describe a novel approach utilizing a combination of ring-opening polymerization and a facile coupling reaction to synthesize a reduction-responsive triblock copolymer comprising biocompatible polylactide (PLA) and poly(ethylene glycol) (PEG) blocks, thus PEG-b(PLA-ss-PLA)-b-PEG (ssBCP). This copolymer self-assembles to form colloidally-stable mono-cleavable micelles having single disulfides in hydrophobic PLA cores surrounded with PEG coronas in aqueous solution. The reductive cleavage of the core disulfides results in changes in micelle morphologies to smaller nanostructures or larger aggregates, depending on the nature of reducing agents. In the presence of glutathione (a cellular reducing agent), the micelle size increases, which enhances the release of encapsulated anticancer drugs in vitro. For biological perspectives, the ssBCP micelles having hydrophilic PEG corona are non-cytotoxic and exhibit enhanced colloidal stability as well as non-specific interactions with proteins.

Glutathione-triggered disassembly of dual disulfide located degradable nanocarriers of polylactide-based block copolymers for rapid drug release.

Reduction-responsive degradation based on disulfide-thiol chemistry is highly desirable in the development of self-assembled block copolymer nanocarriers for multifunctional polymer-based drug delivery applications. Most conventional approaches involve the incorporation of disulfide linkages at a single location. Herein, we report a new dual disulfide located degradable polylactide (PLA)-based block copolymer (DL-ssABP) synthesized by a combination of ring opening polymerization, facile coupling reactions, and controlled radical polymerization. The amphiphilic design of the DL-ssABP enables the formation of self-assembled micelles having disulfides positioned both in the hydrophobic PLA core and at the core/corona interface. The reductive response to glutathione as a cellular trigger results in the cleavage of the disulfide linkage at the interface shedding hydrophilic coronas as well as the disulfides in the PLA core causing disintegration of PLA cores. Such dual disulfide degradation process leads to a synergistically enhanced release of encapsulated anticancer drugs in cellular environments. These results, combined with flow cytometry and confocal laser scanning microscopy (CLSM) as well as cell viability measurements, suggest that DL-ssABP offers versatility in tumor-targeting controlled/enhanced drug delivery applications.

Aqueous self-assembly of giant bottlebrush block copolymer surfactants as shape-tunable building blocks.

Programmed self-assembly of well-defined molecular building blocks enables the fabrication of precisely structured nanomaterials. In this work, we explore a new class of giant polymeric surfactants (Mn = (0.7-4.4) × 10(6) g/mol) with bottlebrush architecture and show that their persistent molecular shape leads to the formation of uniform aggregates in a predictable manner. Amphiphilic bottlebrush block copolymers containing polylactide (PLA) and poly(ethylene oxide) (PEO) side chains were synthesized by a grafting-from method, and their self-assembly in aqueous environment was studied by cryogenic transmission electron microscopy. The produced micelle structures with varying interfacial curvatures and core radii (19-55 nm) boasted rod-like hydrophilic PEO brushes protruding from the hydrophobic PLA cores normal to the interface. Highly uniform spherical micelles with low dispersities were obtained from bottlebrush amphiphiles with packing parameters of ∼0.3, estimated from the polymer structural data. Long cylindrical micelles and other nonspherical aggregates were observed for the first time for compositionally less asymmetric bottlebrush surfactants. Critical micelle concentration values of 1 nM, measured for PEO-rich bottlebrush amphiphiles, indicated an enhanced thermodynamic stability of the produced micelle aggregates. Shape-dependent assembly of bottlebrush surfactants allows for the rational fabrication of a range of micelle structures in narrow morphological windows.

Dual location disulfide degradable interlayer-crosslinked micelles with extended sheddable coronas exhibiting enhanced colloidal stability and rapid release

Amphiphilic block copolymer-based micellar nanocarriers hold great promise as a drug delivery platform; however, the colloidal stability of nanoassemblies upon intravenous injection remains a significant challenge. Further, enhanced/controlled release of encapsulated drugs by cleavage of dynamic covalent linkages in response to external stimuli is highly desired. Herein, we report new polylactide (PLA)-based triblock copolymers (PssDL) possessing thiol-responsive dynamic disulfide linkages at dual locations using a combination of ring opening polymerization and controlled radical polymerization techniques. These well-defined PssDL copolymers are designed to self-assemble to form aqueous micellar aggregates having multiple pendant disulfide linkages in a hydrophobic interlayer as well as single disulfides at interfaces of the interlayer and PLA core, surrounded by hydrophilic coronas. Through thiol-responsive cleavage of these dually located disulfide linkages, novel interlayer-crosslinked micelles (ICMs) with a crosslinkable and sheddable extended corona can be formed, thus combining the enhanced colloidal stability of crosslinked nanocarriers with rapid destabilization or disintegration of micelles typically found with sheddable systems. This dual location degradation process results in enhanced colloidal stability, along with controlled release of encapsulated anticancer drugs to promote the inhibition of cell proliferation after internalization into cancer cells.

New Design of Thiol‐Responsive Degradable Polylactide‐Based Block Copolymer Micelles

A new design to synthesize thiol-responsive degradable polylactide (PLA)-based micelles having a disulfide linkage in the middle of triblock copolymers is reported. They were synthesized by a new method that centers on the use of a disulfide-labeled diol as an initiator for ring-opening polymerization, followed by controlled radical polymerization. These well-controlled copolymers with monomodal and narrow molecular weight distribution (M(w) /M(n) < 1.15) self-assembled to form aqueous micellar aggregates with disulfide-containing PLA cores, which is not toxic to cells. Central disulfide linkages were cleaved in response to thiols; such thiol-triggered degradation enhanced the release of encapsulated anticancer drugs.

Single-Step Assembly of Cationic Lipid–Polymer Hybrid Nanoparticles for Systemic Delivery of siRNA

The clinical success of therapeutics of small interfering RNA (siRNA) is still hindered by its delivery systems. Cationic polymer or lipid-based vehicles as the major delivery systems of siRNA cannot sufficiently satisfy siRNA therapeutic applications. It is hypothesized that cationic lipid-polymer hybrid nanoparticles may take advantage of both polymeric and lipid-based nanoparticles for siRNA delivery, while diminishing the shortcomings of both. In this study, cationic lipid-polymer hybrid nanoparticles were prepared by a single-step nanoprecipitation of a cationic lipid (N,N-bis(2-hydroxyethyl)-N-methyl-N-(2-cholesteryloxycarbonyl aminoethyl) ammonium bromide, BHEM-Chol) and amphiphilic polymers for systemic delivery of siRNA. The formed hybrid nanoparticles comprised a hydrophobic polylactide core, a hydrophilic poly(ethylene glycol) shell, and a cationic lipid monolayer at the interface of the core and the shell. Such hybrid nanoparticles exhibited excellent stability in serum and showed significantly improved biocompatibility compared to that of pure BHEM-Chol particles. The hybrid nanoparticles were capable of delivering siRNA into BT474 cells and facilitated the escape of loaded siRNA from the endosome into the cytoplasm. The hybrid nanoparticles carrying polo-like kinase 1 (Plk1)-specific siRNA (siPlk1) remarkably and specifically downregulated expression of the oncogene Plk1 and induced cancer cell apoptosis both in vitro and in vivo and significantly suppressed tumor growth following systemic administration. We demonstrate that this system is stable, nontoxic, highly efficient, and easy to scale up, bringing the clinical application of siRNA therapy one important step closer to reality.

Biodegradable Block Copolymer Micelles with Thiol-Responsive Sheddable Coronas

Novel sheddable micelles having hydrophilic coronas capable of being shed from biodegradable polylactide (PLA) cores by the cleavage of disulfide linkages in response to thiols were prepared by aqueous micellization of PLA-based amphiphilic block copolymers functionalized with disulfides at block junctions. These well-defined copolymers were synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization in the presence of a new disulfide-functionalized double-head initiator having both terminal OH and Br groups. (1)H NMR and GPC results indicate that both polymerizations were well-controlled with molecular weight distribution as low as M(w)/M(n) < 1.2. Aqueous micellization to form core/shell micelles with disulfides at the interface of PLA cores and hydrophilic coronas and their thiol-responsive degradation were investigated. In the presence of water-soluble thiols, disulfide linkages in the micelles were cleaved and hydrophilic coronas were lost, causing PLA cores to precipitate due to the loss of colloidal stability. In a biomedical perspective, the new sheddable micelles were not cytotoxic and hence biocompatible.

Synthesis of Segmented Polylactide Molecular Brushes and Their Transformation to Open-End Nanotubes

Segmented polylactide (PLA) core−shell molecular brushes, where the shell layer was located only in the middle part of the bottlebrush, were synthesized and converted to organic nanotubes with controlled dimensions and open ends. Segmented bottlebrush copolymer precursors were prepared from a triblock copolymer backbone with orthogonally protected hydroxyl groups and consisted of a poly(solketal methacrylate) middle block and poly(2-(p-methoxybenzyloxy)ethyl methacrylate) end blocks. The use of two selective protecting groups allowed for the sequential grafting of the middle and end PLA brushes with different end-groups. The shell layer of poly(4-(3-butenyl)styrene) was added by RAFT polymerization from the middle PLA brushes. Nanotubes were obtained by cross-linking of the shell layer under dilute conditions and subsequent removal of the PLA core. Transmission electron microscopy characterization revealed the formation of nanotubes with uniform size and open pore structure. The cylindrical shape of the b...

Copolymer-Derived Nanotubes

The synthesis of organic nanotube structures with well-defined dimensions is described. Multicomponent bottlebrush copolymers 5 are synthesized, which adopt a cylindrical shape. The alkene side chains are cross-linked via cross-metathesis, and the internal polylactide core is degraded to generate hollow nanotubes. Water-soluble nanotubes can also be generated by varying the nature of the polymeric precursors.

Synthesis of magnetite core–shell nanoparticles by surface-initiated ring-opening polymerization of l-lactide

Fe 3O 4–polylactide (PLA) core–shell nanoparticles were perpared by surface functionalization of Fe 3O 4 nanoparticles and subsequent surface-initiated ring-opening polymerization of l-lactide. PLA was directly connected onto the magnetic nanoparticles surface through a chemical linkage. Fourier transform infrared (FT-IR) spectra directly provided evidence of the PLA on the surface of the magnetic nanoparticles. Transmission electron microscopy images (TEM) showed that the magnetic nanoparticles were coated by PLA with a 3-nm-thick shell. The amount of grafted polymer determined by thermal gravimetric analysis was ∼13.3% by weight. X-ray diffraction (XRD) patterns of as-prepared core–shell nanoparticles showed the same structure (spinel cubic lattice type) to that of the bare core materials with similar intensity of the corresponding peaks, and that the polymer coating was amorphous. The particles could be stably dispersed in chloroform for several weeks. The prepared Fe 3O 4–PLA core–shell nanoparticles were superparamagnetic behavior with a saturation magnetization value nearly identical to that of the bare magnetic nanoparticles, rendering the Fe 3O 4–PLA nanoparticles for potential applications in both the material technology and biomedical fields.