Design, Synthesis, and Acid-Responsive Disassembly of Shell-Sheddable Block Copolymer Labeled with Benzaldehyde Acetal Junction.

Smart nanoassemblies degradable through the cleavage of acid-labile linkages have attracted significant attention because of their biological relevance found in tumor tissues. Despite their high potential to achieve controlled/enhanced drug release, a systematic understanding of structural factors that affect their pH sensitivity remains challenging, particulary in the consruction of effective acid-degradable shell-sheddable nanoassemblies. Herein, the authors report the synthesis and acid-responsive degradation through acid-catalyzed hydrolysis of three acetal and ketal diols and identify benzaldehyde acetal (BzAA) exhibiting optimal hydrolysis profiles in targeted pH ranges to be a suitable candidate for junction acid-labile linkage. The authors explore the synthesis and aqueous micellization of well-defined poly(ethylene glycol)-based block copolymer bearing BzAA linkage covalently attached to a polymethacrylate block for the formation of colloidally-stable nanoassemblies with BzAA groups at core/corona interfaces. Promisingly, the investigation on acid-catalyzed hydrolysis and disassembly shows that the formed nanoassemblies meet the criteria for acid-degradable shell-sheddable nanoassemblies: slow degradation at tumoral pH = 6.5 and rapid disassembly at endo/lysosomal pH = 5.0, while colloidal stability at physiological pH = 7.4. This work guides the design principle of acid-degradable shell-sheddable nanoassemblies bearing BzAA at interfaces, thus offering the promise to address the PEG dilemma and improve endocytosis in tumor-targeting drug delivery.

Dynamic Covalent Polyurethane Network Materials: Synthesis and Self-Healability.

Polyurethane (PU) has not only been widely used in the daily lives, but also extensively explored as an important class of the essential polymers for various applications. In recent years, significant efforts have been made on the development of self-healable PU materials that possess high performance, extended lifetime, great reliability, and recyclability. A promising approach is the incorporation of covalent dynamic bonds into the design of PU covalently crosslinked polymers and thermoplastic elastomers that can dissociate and reform indefinitely in response to external stimuli or autonomously. This review summarizes various strategies to synthesize self-healable, reprocessable, and recyclable PU materials integrated with dynamic (reversible) Diels-Alder cycloadduct, disulfide, diselenide, imine, boronic ester, and hindered urea bond. Furthermore, various approaches utilizing the combination of dynamic covalent chemistries with nanofiller surface chemistries are described for the fabrication of dynamic heterogeneous PU composites.

Imidazole-Mediated Dual Location Disassembly of Acid-Degradable Intracellular Drug Delivery Block Copolymer Nanoassemblies.

Acid-degradable (or acid-cleavable) polymeric nanoassemblies have witnessed significant progress in anti-cancer drug delivery. However, conventional nanoassemblies designed with acid-cleavable linkages at a single location have several challenges, such as, sluggish degradation, undesired aggregation of degraded products, and difficulty in controlled and on-demand drug release. Herein, a strategy that enables the synthesis of acid-cleavable nanoassemblies labeled with acetaldehyde acetal groups in both hydrophobic cores and at core/corona interfaces, exhibiting synergistic response to acidic pH at dual locations and thus inducing rapid drug release is reported. The systematic analyses suggest that the acid-catalyzed degradation and disassembly are further enhanced by decreasing copolymer concentration (i.e., increasing proton/acetal mole ratio). Moreover, incorporation of acid-ionizable imidazole pendants in the hydrophobic cores improve the encapsulation of doxorubicin, the anticancer drug, through π-π interactions and enhance the acid-catalyzed hydrolysis of acetal linkages situated in the dual locations. Furthermore, the presence of the imidazole pendants induce the occurrence of core-crosslinking that compensates the kinetics of acetal hydrolysis and drug release. These results, combined with in vitro cell toxicity and cellular uptake, suggest the versatility of the dual location acid-degradation strategy in the design and development of effective intracellular drug delivery nanocarriers.

Macromolecularly Engineered Thermoreversible Heterogeneous Self-Healable Networks Encapsulating Reactive Multidentate Block Copolymer-Stabilized Carbon Nanotubes.

The development of heterogeneous covalent adaptable networks (CANs) embedded with carbon nanotubes (CNTs) that undergo reversible dissociation/recombination through thermoreversibility has been significantly explored. However, the carbon nanotube (CNT)-incorporation methods based on physical mixing and chemical modification could result in either phase separation due to structural incompatibility or degrading conjugation due to a disruption of π-network, thus lowering their intrinsic charge transport properties. To address this issue, the versatility of a macromolecular engineering approach through thermoreversibility by physical modification of CNT surfaces with reactive multidentate block copolymers (rMDBCs) is demonstrated. The formed CNTs stabilized with rMDBCs (termed rMDBC/CNT colloids) bearing reactive furfuryl groups is functioned as a multicrosslinker that reacts with a polymaleimide to fabricate robust heterogeneous polyurethane (PU) networks crosslinked through dynamic Diels-Alder (DA)/retro-DA chemistry. Promisingly, the fabricated PU network gels in which CNTs through rMDBC covalently embedded are flexible and robust to be bendable as well as exhibit self-healing elasticity and enhanced conductivity.

Dual-Location Dual-Acid/Glutathione-Degradable Cationic Micelleplexes through Hydrophobic Modification for Enhanced Gene Silencing.

Gene therapy holds great promise for the treatment of acquired genetic disorders such as cancer with reduced side effects compared to chemotherapy. For gene therapy to be successful, it is crucial to develop efficient and nontoxic gene carriers to overcome the poor in vivo stability and low cellular uptake of nucleic acid-based therapeutic agents. Here, we report a new and versatile approach exploring a combination of hydrophobic modifications and dual-stimuli-responsive degradation (SRD) for controlled gene delivery with amphiphilic block copolymer-based nanocarriers. The block copolymer, synthesized by atom transfer radical polymerization, is designed with an acid-labile acetal linkage at the block junction and a pendant disulfide group in the hydrophobic block. The incorporation of labile linkages enables both disulfide-core-cross-linking and dual-location dual-acid/reduction-responsive degradation (DL-DSRD). Furthermore, the disulfide linkages integrated as hydrophobic moieties facilitate the nucleic acids to condense into nanometer-sized micelleplexes through electrostatic interactions of pendant dimethylamino groups with the anionic phosphate groups of the nucleic acids. Our preliminary results demonstrate that the DL-DSRD approach through hydrophobic modification is a robust platform in the development of gene delivery systems with enhanced colloidal stability, reduced cytotoxicity, and improved gene transfection efficiency.

Direct Polymerization Approach to Synthesize Acid-Degradable Block Copolymers Bearing Imine Pendants for Tunable pH-Sensitivity and Enhanced Release.

The development of effective approaches to synthesize smart amphiphilic block copolymers (ABPs) exhibiting acid-responsive degradation through the cleavage of acid-labile imine bonds is extensively explored for controlled release of encapsulated biomolecules, particularly in drug delivery. Here, a new approach based on direct polymerization utilizing a controlled radical polymerization technique to synthesize acid-degradable ABPs bearing pendant imine linkages in hydrophobic block is reported. The approach centers on the synthesis of a novel methacrylate bearing benzoic imine group that can be polymerized to form the hydrophobic imine pendant block. The formed ABPs respond to mild acidic pHs equivalent to tumoral and endosomal/lysosomal acidic environments. This causes the dissociation of self-assembled nanoassemblies through change in their hydrophilic/hydrophobic balance upon the cleavage of pendant imine linkages to the corresponding aldehyde and primary amine, thus leading to the enhanced release of encapsulated drugs. The proof-of-concept results suggest that this robust approach is versatile to further design advanced nanoassemblies responding to dual/multiple stimuli, thus being more effective to intracellular drug delivery.

Microfluidic Assembly To Synthesize Dual Enzyme/Oxidation-Responsive Polyester-Based Nanoparticulates with Controlled Sizes for Drug Delivery.

Controlling the size and narrow size distribution of polymer-based nanocarriers for targeted drug delivery is an important parameter that significantly influences their colloidal stability, biodistribution, and targeting ability. Herein, we report a high-throughput microfluidic process to fabricate colloidally stable aqueous nanoparticulate colloids with tunable sizes at 50-150 nm and narrow size distribution. The nanoparticulates are designed with different molecular weight polyesters having both ester bonds (responsive to esterase) and sulfide linkages (to oxidative reaction) on the backbones, thus exhibiting dual esterase/oxidation responses, causing the destabilization of the nanoparticulates to lead to the controlled release of encapsulated therapeutics. The systematic investigation on both microfluidic and formulation parameters enables to control their properties as allowing for decreasing nanoparticulate sizes as well as improving colloidal stability and cytotoxicity. Further to such control over smaller size and narrow size distribution, dual stimuli-responsive degradation and excellent cellular uptake could suggest that the microfluidic nanoparticulates stabilized with polymeric stabilizers could offer the versatility toward dual smart drug delivery exhibiting enhanced release kinetics.

Thermally Labile Self-Healable Branched Gel Networks Fabricated by New Macromolecular Engineering Approach Utilizing Thermoreversibility.

A new approach based on macromolecular engineering through thermoreversibility is reported to fabricate the engineered gel networks of thermally labile branched polymers exhibiting robust self-healing. This approach centers on the synthesis of linear polymers having Diels-Alder cycloadducts in the backbones (DALPs) through A2 + B2 step-growth polymerization of a difunctional furan and a difunctional maleimide. Reactive mixtures of the resulting DALP with a polyfuran at elevated temperature allow for the formation of engineered gel networks through random dissociation of backbone DA linkages of the DALPs by retro-Diels-Alder reaction, followed by their reconstruction in the presence of polyfuran (with functionality > 2) by Diels-Alder reaction. Optimizing the ratio of furan to DA linkages in the reactive mixtures yields thermally labile networks exhibiting excellent thermoreversibility. Effective self-healing demonstrated with reconstruction from two separate pieces and complete void filling on surface cuts as well as recovery of healing viscoelasticity suggest that the new macromolecular engineering approach offers versatility toward the development of thermally mendable thermosets.

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.

Stimulus-Responsive Degradable Polylactide-Based Block Copolymer Nanoassemblies for Controlled/Enhanced Drug Delivery.

Polylactide (PLA) is biocompatible and FDA-approved for clinical use and thus has been a choice of the materials valuable for extensive applications in biomedical fields. However, conventionally designed PLA-based amphiphilic block copolymer (ABP) nanoassemblies exhibit slow and uncontrolled release of encapsulated drugs because of the slow biodegradation of hydrophobic PLA in physiological conditions. To improve potentials for clinical use and commercialization of conventional PLA-based nanoassemblies, stimulus-responsive degradation (SRD) platform has been introduced into the design of PLA-based nanoassemblies for enhanced/controlled release of encapsulated drugs. This review summarizes recent strategies that allow for the development of PLA-based ABPs and their self-assembled nanostructures exhibiting SRD-induced enhanced drug release. The review focuses on the design, synthesis, and evaluation of the nanoassemblies as intracellular drug delivery nanocarriers for cancer therapy. Further, the outlook is briefly discussed on the important aspects for the current and future development of more effective SRD PLA-based nanoassemblies toward tumor-targeting intracellular drug delivery.

Intracellular Delivery of Colloidally Stable Core-Cross-Linked Triblock Copolymer Micelles with Glutathione-Responsive Enhanced Drug Release for Cancer Therapy.

Design and development of amphiphilic block copolymer-based nanocarriers exhibiting enhanced colloidal stability upon dilution in the blood and cellular glutathione-responsive rapid drug release is highly desired for tumor-targeting chemotherapy. Herein, we report a novel ABA-type triblock copolymer consisting of a hydrophilic central poly(ethylene glycol) block and two terminal hydrophobic blocks of a polymethacrylate having pendant disulfides (PHMssEt), thus PHMssEt-b-PEG-b-PHMssEt (ssTP). Aqueous self-assembly and the following disulfide-exchange reaction of the resulting ssTP allow for formation of core-cross-linked micelles (CCMs) through the formation of new disulfide linkages, retaining enhanced colloidal stability in physiological conditions and in the presence of proteins. Further, they exhibit reduction-responsive enhanced release of encapsulated drugs in response to cellular concentrations of glutathione in cancer cells, confirmed by dynamic light scattering and spectroscopic analysis. Combined with these results, in vitro (cells) and in vivo (mouse model) biological results suggest that ssTP-based CCMs are effective candidates as intracellular nanocarriers targeting tumors for cancer therapy.

Multiblock Copolymer-Based Dual Dynamic Disulfide and Supramolecular Crosslinked Self-Healing Networks.

A new multiblock copolymer self-healing strategy is reported that centers on the synthesis of block copolymers designed with different self-healing motifs incorporated into individual blocks. As a proof of concept, a novel pentablock copolymer (ABCBA) consisting of a poly(ethylene glycol) middle block and self-healable symmetric blocks of a polymethacrylate with pendant disulfide linkages and carboxylic acids is synthesized by a combination of consecutive controlled radical polymerization with hydrolytic cleavage. Disulfide exchange reactions of pendant disulfide linkages and metal-ligand interactions of pendant carboxylic acids with ferric ions allow for the formation of dual crosslinked networks with dynamic disulfide and supramolecular crosslinkages. The resultant networks possessing self-healing viscoelasticity enable self-healing on macroscale damages through supramolecular metal-ligand interactions and disulfide exchange reactions at room or moderate temperatures. These preliminary results suggest that the strategy can offer the versatility in the development of multifunctional self-healable materials in dual or multiple self-healable mechanisms.

Enhancing targeted antibiotic therapy via pH responsive solid lipid nanoparticles from an acid cleavable lipid.

An acid cleavable lipid (SA-3M) was synthesized and used to develop pH-responsive solid lipid nanoparticles (SLNs) to deliver vancomycin base (VM-FB) to acidic infection sites. The size, polydispersity index and zeta potential of VM-FB_SA-3M_SLNs were 132.9±9.1nm, 0.159±0.01 and -26±4.4mV respectively, with 57.80±1.1% encapsulation efficiency. VM-FB release was significantly faster at pH6.5 than pH7.4. In vitro antibacterial activity against methicillin-susceptible and resistant Staphylococcus aureus (MSSA and MRSA) revealed that SLNs had enhanced activity at pH6.5 than pH7.4. In vivo study showed that the amount of MRSA remaining in the skin of VM-FB_SA-3M_SLNs treated mice was approximately 22-fold lower than VM-FB treated mice. Histological investigations revealed that signs of inflammation in the skin treated with VM-FB_SA-3M_SLNs were minimal. In conclusion, this study confirmed that SA-3M can form pH-responsive SLNs capable of releasing antibiotic specifically at acidic infection sites.

Reduction-Responsive Sheddable Carbon Nanotubes Dispersed in Aqueous Solution.

A new approach to stabilize carbon nanotubes (CNTs) in aqueous solution with a reduction-responsive water-soluble polymer is reported. The novel polymer synthesized by a controlled radical polymerization is functionalized with pendant pyrene groups capable of adhering to the surface of CNTs through π-π noncovalent interactions, and labeled with disulfide linkages to exhibit reduction-responsive cleavage. Upon the cleavage of junction disulfide linkages in a reducing environment, water-soluble polymers are shed, retaining clean CNT surfaces for electrochemical catalytic reactions.

Dual Location Dual Reduction/Photoresponsive Block Copolymer Micelles: Disassembly and Synergistic Release.

Self-assembled micellar systems designed with multiple stimuli-responsive degradation have been considered as effective candidates for polymer-based delivery systems exhibiting enhanced/controlled release. However, most conventional approaches involve the incorporation of single, dual, or multiple cleavable linkages positioned at single locations, as in hydrophobic cores or at core/corona interfaces. Herein, a novel dual location dual reduction and photoresponsive block copolymer containing a disulfide linkage at the block junction and pendant o-nitrobenzyl thioether (NBS) groups in the hydrophobic methacrylate block (PEG-ss-PhvM) are reported, which are synthesized by a combination of controlled radical polymerization and facile coupling reaction. The amphiphilic design of the PEG-ss-PhvM enables the formation of self-assembled micellar aggregates with disulfides at the core/corona interfaces and pendant photocleavable NBS groups in the hydrophobic cores. The dual cleavable linkages respond to each stimulus (GSH or light), exhibiting enhanced release; further to a combination of dual locational stimuli, promoting synergistic release at dual locations.

Dual Sulfide-Disulfide Crosslinked Networks with Rapid and Room Temperature Self-Healability.

Polymer-based crosslinked networks with intrinsic self-repairing ability have emerged due to their built-in ability to repair physical damages. Here, novel dual sulfide-disulfide crosslinked networks (s-ssPxNs) are reported exhibiting rapid and room temperature self-healability within seconds to minutes, with no extra healing agents and no change under any environmental conditions. The method to synthesize these self-healable networks utilizes a combination of well-known crosslinking chemistry: photoinduced thiol-ene click-type radical addition, generating lightly sulfide-crosslinked polysulfide-based networks with excess thiols, and their oxidation, creating dynamic disulfide crosslinkages to yield the dual s-ssPxNs. The resulting s-ssPxN networks show rapid self-healing within 30 s to 30 min at room temperature, as well as self-healing elasticity with reversible viscoelastic properties. These results, combined with tunable self-healing kinetics, demonstrate the versatility of the method as a new means to synthesize smart multifunctional polymeric materials.

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.

Multidentate block-copolymer-stabilized ultrasmall superparamagnetic iron oxide nanoparticles with enhanced colloidal stability for magnetic resonance imaging.

Ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) with diameters <5 nm hold great promise as T1-positive contrast agents for in vivo magnetic resonance imaging. However, control of the surface chemistry of USPIOs to ensure individual colloidal USPIOs with a ligand monolayer and to impart biocompatibility and enhanced colloidal stability is essential for successful clinical applications. Herein, an effective and versatile strategy enabling the development of aqueous colloidal USPIOs stabilized with well-defined multidentate block copolymers (MDBCs) is reported. The multifunctional MDBCs are designed to consist of an anchoring block possessing pendant carboxylates as multidentate anchoring groups strongly bound to USPIO surfaces and a hydrophilic block having pendant hydrophilic oligo(ethylene oxide) chains to confer water dispersibility and biocompatibility. The surface of USPIOs is saturated with multiple anchoring groups of MDBCs, thus exhibiting excellent long-term colloidal stability as well as enhanced colloidal stability at biologically relevant electrolyte, pH, and temperature conditions. Furthermore, relaxometric properties as well as in vitro and in vivo MR imaging results demonstrate that the MDBC-stabilized USPIO colloids hold great potential as an effective T1 contrast agent.

Recent strategies to develop polysaccharide-based nanomaterials for biomedical applications.

Polysaccharides are abundant in nature, renewable, nontoxic, and intrinsically biodegradable. They possess a high level of functional groups including hydroxyl, amino, and carboxylic acid groups. These functional groups can be utilized for further modification of polysaccharides with small molecules, polymers, and crosslinkers; the modified polysaccharides have been used as effective building blocks in fabricating novel biomaterials for various biomedical applications such as drug delivery carriers, cell-encapsulating biomaterials, and tissue engineering scaffolds. This review describes recent strategies to modify polysaccharides for the development of polysaccharide-based biomaterials; typically self-assembled micelles, crosslinked microgels/nanogels, three-dimensional hydrogels, and fibrous meshes. In addition, the outlook is briefly discussed on the important aspects for the current and future development of polysaccharide-based biomaterials, particularly tumor-targeting intracellular drug delivery nanocarriers.

Air-spun PLA nanofibers modified with reductively sheddable hydrophilic surfaces for vascular tissue engineering: synthesis and surface modification.

Polylactide (PLA) is a class of promising biomaterials that hold great promise for various biological and biomedical applications, particularly in the field of vascular tissue engineering where it can be used as a fibrous mesh to coat the inside of vascular prostheses. However, its hydrophobic surface providing nonspecific interactions and its limited ability to further modifications are challenges that need to be overcome. Here, the development of new air-spun PLA nanofibers modified with hydrophilic surfaces exhibiting reduction response is reported. Surface-initiated atom transfer radical polymerization allows for grafting pendant oligo(ethylene oxide)-containing polymethacrylate (POEOMA) from PLA air-spun fibers labeled with disulfide linkages. The resulting PLA-ss-POEOMA fibers exhibit enhanced thermal stability and improved surface properties, as well as thiol-responsive shedding of hydrophilic POEOMA by the cleavage of its disulfide linkages in response to reductive reactions, thus tuning the surface properties.