Subcompartmentalized Polymer Hydrogel Capsules with Selectively Degradable Carriers and Subunits

Subcompartmentalized hydrogel capsules (SHCs) with selectively degradable carriers and subunits are designed for potential applications in drug delivery and microencapsulated biocatalysis. Thiolated poly(methacrylic acid) and poly(N‐vinyl pyrrolidone) are used to assemble 3‐µm‐diameter carrier capsules and 300‐nm‐diameter subunits, independently stabilized by a diverse range of covalent linkages. This paper presents examples of SHCs with tens of subcompartments and their successful drug loading, as well as selective degradation of the SHC carrier and/or subunits in response to multiple chemical stimuli.     

Poly(Methacrylic Acid) Polymer Hydrogel Capsules: Drug Carriers,Sub‐compartmentalized Microreactors,Artificial Organelles

Multilayered polymer capsules attract significant research attention and are proposed as candidate materials for diverse biomedical applications, from targeted drug delivery to microencapsulated catalysis and sensors. Despite tremendous efforts, the studies which extend beyond proof of concept and report on the use of polymer capsules in drug delivery are few, as are the developments in encapsulated catalysis with the use of these carriers. In this Concept article, the recent successes of poly(methacrylic acid) hydrogel capsules as carrier vessels for delivery of therapeutic cargo, creation of microreactors, and assembly of sub‐compartmentalized cell mimics are discussed. The developed technologies are outlined, successful applications of these capsules are highlighted, capsules properties which contribute to their performance in diverse applications are discussed, and further directions and plausible developments in the field are suggested.     

Triggered cargo release by encapsulated enzymatic catalysis in capsosomes

We report the coencapsulation of glutathione reductase and disulfide-linked polymer-oligopeptide conjugates into capsosomes, polymer carrier capsules containing liposomal subcompartments. The architecture of the capsosomes enables a temperature-triggered conversion of oxidized glutathione to its reduced sulfhydryl form by the encapsulated glutathione reductase. The reduced glutathione subsequently induces the release of the encapsulated oligopeptides from the capsosomes by reducing the disulfide linkages of the conjugates. This study highlights the potential of capsosomes to continuously generate a potent antioxidant while simultaneously releasing small molecule therapeutics.     

Stabilization of Polymer‐Hydrogel Capsules via Thiol–Disulfide Exchange

Polymer hydrogels are used in diverse biomedical applications including drug delivery and tissue engineering. Among different chemical linkages, the natural and reversible thiol–disulfide interconversion is extensively explored to stabilize hydrogels. The creation of macro‐, micro‐, and nanoscale disulfide‐stabilized hydrogels commonly relies on the use of oxidizing agents that may have a detrimental effect on encapsulated cargo. Herein an oxidization‐free approach to create disulfide‐stabilized polymer hydrogels via a thiol–disulfide exchange reaction is reported. In particular, thiolated poly(methacrylic acid) is used and the conditions of polymer crosslinking in solution and on colloidal porous and solid microparticles are established. In the latter case, removal of the core particles yields stable, hollow, disulfide‐crosslinked hydrogel capsules. Further, a procedure is developed to achieve efficient disulfide crosslinking of multilayered polymer films to obtain stable, liposome‐loaded polymer‐hydrogel capsules that contain functional enzymatic cargo within the liposomal subcompartments. This approach is envisaged to facilitate the development of biomedical applications of hydrogels, specifically those including fragile cargo.     

Polymersome-loaded capsules for controlled release of DNA

The formation of a novel drug-delivery carrier for the controlled release of plasmid DNA that comprises layer-by-layer polymer capsules subcompartmentalized with pH-sensitive nanometer-sized polymersomes is reported. The amphiphilic diblock copolymer poly(oligoethylene glycol methacrylate)-block-poly(2-(diisopropylamino)ethyl methacrylate) forms polymersomes at physiological pH, but transitions to unimeric polymer chains upon acidification to cellular endocytic pH. These polymersomes can thus release an encapsulated payload in response to a change in pH from physiological to endocytic conditions. Multicomponent layer-by-layer capsules are formed by exploiting the ability of tannic acid to act as an efficient hydrogen-bond donor for both the polymersomes and poly(N-vinyl pyrrolidone) at physiological pH. These capsules show release of a plasmid DNA payload encapsulated within the polymersome subcompartments in response to changes in pH between physiological and endocytic conditions.     

Polymer capsules as micro-/nanoreactors for therapeutic applications: Current strategies to control membrane permeability

Polymer capsules, fabricated either with the aid of a sacrificial template or via the self-assembly of block copolymers into polymer vesicles (polymersomes), have attracted a great deal of attention for their potential use as micro-/nanoreactors and artificial organelles for therapeutic applications. Compared to other biomedical applications of polymer capsules, such as drug delivery vehicles, where the polymer shell undergoes irreversible disruption/rupture that allows the release of the payload, the polymer shell in polymer micro-/nanoreactors has to maintain mechanical integrity while allowing the selective diffusion of reagents/reaction products. In the present review, strategies that permit precise control of the permeability of the polymer shell while preserving its architecture are documented and critiqued. Together with these strategies, specific examples where these polymer capsules have been employed as micro-/nanoreactors as well as approaches to scale-up and optimize these systems along with future perspectives for therapeutic applications in several degenerative diseases are elucidated.     

Microcapsules for Enhanced Cargo Retention and Diversity

Prevention of undesired leakage of encapsulated materials prior to triggered release presents a technological challenge for the practical application of microcapsule technologies in agriculture, drug delivery, and cosmetics. A microfluidic approach is reported to fabricate perfluoropolyether (PFPE)‐based microcapsules with a high core‐shell ratio that show enhanced retention of encapsulated actives. For the PFPE capsules, less than 2% leakage of encapsulated model compounds, including Allura Red and CaCl₂, over a four week trial period is observed. In addition, PFPE capsules allow cargo diversity by the fabrication of capsules with either a water‐in‐oil emulsion or an organic solvent as core. Capsules with a toluene‐based core begin a sustained release of hydrophobic model encapsulants immediately upon immersion in an organic continuous phase. The major contribution on the release kinetics stems from the toluene in the core. Furthermore, degradable silica particles are incorporated to confer porosity and functionality to the otherwise chemically inert PFPE‐based polymer shell. These results demonstrate the capability of PFPE capsules with large core–shell ratios to retain diverse sets of cargo for extended periods and make them valuable for controlled release applications that require a low residual footprint of the shell material.     

New Ophthalmic Drug Delivery Systems

One of the ways to optimize ocular drug delivery is to prolonge precorneal drug residence time. This review focusses on recent findings on the formulation effects in ocular drug bioavailability, employing polymers for the preparation of hydrogels, bioadhesive dosage forms, in situ gelling systems and colloidal systems including liposomes and nanoparticles. The results observed suggested that mucoadhesion or bioadhesion played a role in the sustained action of drugs more significantly compared to non-mucoadhesive polymers. Encapsulation of drugs in liposomes and nanoparticles was correlated to an increase of the drug concentration in the ocular tissues. However, all the results described suggest that the physico-chemical properties of the encapsulated drug have a significant influence on the effect with the carrier. The results suggest also that the superficial charge, the binding type of the drug onto the nanoparticles and the nature of the polymer were the most important factors regarding the improvement of the therapeutic response of the drug.     

A W/O emulsion mediated film dispersion method for curcumin encapsulated pH-sensitive liposomes in the colon tumor treatment

The CaCO₃ encapsulated liposome with pH sensitivity is an efficient carrier for the delivery of chemotherapeutic drugs. Herein, we provided an innovative method that take advantage of a W/O emulsion to prepare CaCO₃ encapsulated liposomes for the delivery of curcumin. The liposomes with both CaCO₃ and curcumin encapsulated (LCC) showed high sensitivity to reduced pH (the environment of lysosomes). Due to the inherent pH sensitivity of CaCO₃, LCC swelled and released the encapsulated curcumin rapidly in acidic medium. The lysosome escape capability and promoted accumulation of curcumin in the cytosol from LCC was verified with respect to that of curcumin loaded liposomes (CLIPO). Despite the similar cytotoxicity within curcumin preparations in vitro at high concentration, LCC exhibited optimal antitumor effect in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal cancer model, which was attributed to the long circulation time and efficient intracellular delivery of curcumin from LCC. It is suggested that the solubility and cytosolic delivery of curcumin are greatly improved by LCC, which accounts for the increased pharmacodynamic effect of curcumin. Thus, the CaCO₃ encapsulated liposomes developed in this study is an ideal carrier for the hydrophobic drugs in potential clinical application.     

Delivery of molecules to cancer cells using liposomes from bacterial cultures

Liposomes have a variety of applications as model systems to study enclosed biological membranes, as delivery vehicles for a variety of drugs and as micro- and nano-reactors, amongst others. However, preparation of liposomes requires use of expensive raw material (synthetic lipids) from specialized commercial suppliers, and ability to make reproducible preparations remains a specialized art till date. In this work, we prepared liposomes using natural lipids extracted from the bacteria Escherichia coli (E. coli), which are extremely economical compared to the synthetic lipids. We demonstrate robust procedures for convenient and reproducible preparations of 200-300 nm diameter liposomes from bacterial cells. We also show a potential application of these bacterial liposomes in delivery of aqueous molecules to cancer cells. We show not only intracellular uptake, but also biodegradation of the liposomes inside cancer cells. Our economical liposomes promise to serve as excellent model systems for studies on encapsulation of molecules inside soft materials with desired efficiencies. Additionally, they certainly show a strong potential to be tools for research in diverse areas ranging from drug delivery applications to sub-micron reaction engineering for carrying out and understanding the mechanisms of chemical reactions in small enclosed volumes.     

25th Anniversary Article: Dynamic Interfaces for Responsive Encapsulation Systems

Encapsulation systems are urgently needed both as micrometer and sub‐micrometer capsules for active chemicals' delivery, to encapsulate biological objects and capsules immobilized on surfaces for a wide variety of advanced applications. Methods for encapsulation, prolonged storage and controllable release are discussed in this review. Formation of stimuli responsive systems via layer‐by‐layer (LbL) assembly, as well as via mobile chemical bonding (hydrogen bonds, chemisorptions) and formation of special dynamic stoppers are presented. The most essential advances of the systems presented are multifunctionality and responsiveness to a multitude of stimuli – the possibility of formation of multi‐modal systems. Specific examples of advanced applications – drug delivery, diagnostics, tissue engineering, lab‐on‐chip and organ‐on‐chip, bio‐sensors, membranes, templates for synthesis, optical systems, and antifouling, self‐healing materials and coatings – are provided. Finally, we try to outline emerging developments.     

Microfluidic Assembly of Monodisperse Multistage pH‐Responsive Polymer/Porous Silicon Composites for Precisely Controlled Multi‐Drug Delivery

We report an advanced drug delivery platform for combination chemotherapy by concurrently incorporating two different drugs into microcompoistes with ratiometric control over the loading degree. Atorvastatin and celecoxib were selected as model drugs due to their different physicochemical properties and synergetic effect on colorectal cancer prevention and inhibition. To be effective in colorectal cancer prevention and inhibition, the produced microcomposite contained hypromellose acetate succinate, which is insoluble in acidic conditions but highly dissolving at neutral or alkaline pH conditions. Taking advantage of the large pore volume of porous silicon (PSi), atorvastatin was firstly loaded into the PSi matrix, and then encapsulated into the pH‐responsive polymer microparticles containing celecoxib by microfluidics in order to obtain multi‐drug loaded polymer/PSi microcomposites. The prepared microcomposites showed monodisperse size distribution, multistage pH‐response, precise ratiometric controlled loading degree towards the simultaneously loaded drug molecules, and tailored release kinetics of the loaded cargos. This attractive microcomposite platform protects the payloads from being released at low pH‐values, and enhances their release at higher pH‐values, which can be further used for colon cancer prevention and treatment. Overall, the pH‐responsive polymer/PSi‐based microcomposite can be used as a universal platform for the delivery of different drug molecules for combination therapy.     

Simultaneous Quantification of Tumor Uptake for Targeted and Nontargeted Liposomes and Their Encapsulated Contents by ICPMS

Liposomes are intensively being developed for biomedical applications including drug and gene delivery. However, targeted liposomal delivery in cancer treatment is a very complicated multistep process. Unfavorable liposome biodistribution upon intravenous administration and membrane destabilization in blood circulation could result in only a very small fraction of cargo reaching the tumors. It would therefore be desirable to develop new quantitative strategies to track liposomal delivery systems to improve the therapeutic index and decrease systemic toxicity. Here, we developed a simple and nonradiative method to quantify the tumor uptake of targeted and nontargeted control liposomes as well as their encapsulated contents simultaneously. Specifically, four different chelated lanthanide metals were encapsulated or surface-conjugated onto tumor-targeted and nontargeted liposomes, respectively. The two liposome formulations were then injected into tumor-bearing mice simultaneously, and their tumor delivery was determined quantitatively via inductively coupled plasma mass spectroscopy (ICPMS), allowing for direct comparisons. Tumor uptake of the liposomes themselves and their encapsulated contents was consistent with targeted and nontargeted liposome formulations that were injected individually.     

Alkyl Passivation and Amphiphilic Polymer Coating of Silicon Nanocrystals for Diagnostic Imaging

A method to produce biocompatible polymer‐coated silicon nanocrystals for medical imaging is shown. Silica‐embedded Si nanocrystals are formed by HSQ thermolysis. The nanocrystals are then liberated from the oxide and terminated with Si–H bonds by HF etching, followed by alkyl monolayer passivation by thermal hydrosilylation. The Si nanocrystals have an average diameter of 2.1 nm ± 0.6 nm and photoluminesce with a peak emission wavelength of 650 nm, which lies within the transmission window of 650–900 nm that is useful for biological imaging. The hydrophobic Si nanocrystals are then coated with an amphiphilic polymer for dispersion in aqueous media with the pH ranging between 7 and 10 and an ionic strength between 30 mM and 2 M , while maintaining a bright and stable photoluminescence and a hydrodynamic radius of only 20 nm. Fluorescence imaging of polymer‐coated Si nanocrystals in biological tissue is demonstrated, showing the potential for in vivo imaging.     

Synthesis and Assembly of Click‐Nucleic‐Acid‐Containing PEG–PLGA Nanoparticles for DNA Delivery

Co‐delivery of both chemotherapy drugs and siRNA from a single delivery vehicle can have a significant impact on cancer therapy due to the potential for overcoming issues such as drug resistance. However, the inherent chemical differences between charged nucleic acids and hydrophobic drugs have hindered entrapment of both components within a single carrier. While poly(ethylene glycol)‐block‐poly(lactic‐co‐glycolic acid) (PEG–PLGA) copolymers have been used successfully for targeted delivery of chemotherapy drugs, loading of DNA or RNA has been poor. It is demonstrated that significant amounts of DNA can be encapsulated within PLGA‐containing nanoparticles through the use of a new synthetic DNA analog, click nucleic acids (CNAs). First, triblock copolymers of PEG‐CNA‐PLGA are synthesized and then formulated into polymer nanoparticles from oil‐in‐water emulsions. The CNA‐containing particles show high encapsulation of DNA complementary to the CNA sequence, whereas PEG‐PLGA alone shows minimal DNA loading, and non‐complementary DNA strands do not get encapsulated within the PEG‐CNA‐PLGA nanoparticles. Furthermore, the dye pyrene can be successfully co‐loaded with DNA and lastly, a complex, larger DNA sequence that contains an overhang complementary to the CNA can also be encapsulated, demonstrating the potential utility of the CNA‐containing particles as carriers for chemotherapy agents and gene silencers.     

Electrospun polymer nanofibers with internal periodic structure obtained by microphase separation of cylindrically confined block copolymers

Continuous fibers are described having concentric layer or aligned sphere microphase-separated, styrene-isoprene block copolymer morphologies. The fibers are obtained by a two-fluid coaxial electrospinning technique in which the desired block copolymer is encapsulated as the core component within a polymer shell having a high glass transition temperature (Tg). The fibers range in diameter from 300 to 800 nm, and the block copolymer core ranges from 50 to 500 nm. Subsequent annealing of the fibers above the upper Tg of the block copolymer but below the Tg of the shell polymer results in microphase separation of the block copolymer under cylindrical confinement. The resulting fibers exhibit improved long-range order. This two-step strategy creates the opportunity to fabricate continuous nanofibers with periodic internal structure.     

The Continuous Exudation of Micro‐Meniscus Capsules by Polymer Perspiration

Perspiration is a common phenomenon in many natural creatures in order to maintain their steady state. Here, through the facile use of a linear polymer of polymethylmethacrylate (PMMA) and an incompatible polymer of cross‐linked polydimethylsiloxane (PDMS) under an organic‐solvent atmosphere, the polymer system undergoes an analogous perspiration phenomenon as a result of the macroscopic phase separation between the two polymers. The resulting “sweat,” consisting of PMMA and solvent, are solidified into extraordinary micro‐meniscus capsules on the PDMS surface, which does not rely on the shape and topography of the PDMS substrates. Perspiration continues until the sweat of PMMA is exhausted, enabling the production of recoverable microstructures without complicated manufacturing processes. A thorough assessment of the influencing factors for the perspiration reveals that the formation of micro‐meniscus capsules follows a process of protrusion, ripening, and solidification. The micro‐meniscus capsules are primarily evaluated for applications in light scattering, in organic‐vapor sensing, and in bio‐macromolecular immobilization.     

Increased Exciton Delocalization of Polymer upon Blending with Fullerene

Interfaces between donor and acceptor in a polymer solar cell play a crucial role in exciton dissociation and charge photogeneration. While the importance of charge transfer (CT) excitons for free carrier generation is intensively studied, the effect of blending on the nature of the polymer excitons in relation to the blend nanomorphology remains largely unexplored. In this work, electroabsorption (EA) spectroscopy is used to study the excited‐state polarizability of polymer excitons in several polymer:fullerene blend systems, and it is found that excited‐state polarizability of polymer excitons in the blends is a strong function of blend nanomorphology. The increase in excited‐state polarizability with decreased domain size indicates that intermixing of states at the interface between the donor polymers and fullerene increases the exciton delocalization, resulting in an increase in exciton dissociation efficiency. This conclusion is further supported by transient absorption spectroscopy and time‐resolved photoluminescence measurements, along with the results from time‐dependent density functional theory calculations. These findings indicate that polymer excited‐state polarizability is a key parameter for efficient free carrier generation and should be considered in the design and development of high‐performance polymer solar cells.     

Flexible Nanoparticles Reach Sterically Obscured Endothelial Targets Inaccessible to Rigid Nanoparticles

Molecular targeting of nanoparticle drug carriers promises maximized therapeutic impact to sites of disease or injury with minimized systemic effects. Precise targeting demands addressing to subcellular features. Caveolae, invaginations in cell membranes implicated in transcytosis and inflammatory signaling, are appealing subcellular targets. Caveolar geometry has been reported to impose a ≈50 nm size cutoff on nanocarrier access to plasmalemma vesicle associated protein (PLVAP), a marker found in caveolae in the lungs. The use of deformable nanocarriers to overcome that size cutoff is explored in this study. Lysozyme‐dextran nanogels (NGs) are synthesized with ≈150 or ≈300 nm mean diameter. Atomic force microscopy indicates the NGs deform on complementary surfaces. Quartz crystal microbalance data indicate that NGs form softer monolayers (≈60 kPa) than polystyrene particles (≈8 MPa). NGs deform during flow through microfluidic channels, and modeling of NG extrusion through porous filters yields sieving diameters less than 25 nm for NGs with 150 and 300 nm hydrodynamic diameters. NGs of 150 and 300 nm diameter target PLVAP in mouse lungs while counterpart rigid polystyrene particles do not. The data in this study indicate a role for mechanical deformability in targeting large high‐payload drug‐delivery vehicles to sterically obscured targets like PLVAP.     

Low‐Density Lipoprotein‐Mimicking Nanoparticles for Tumor‐Targeted Theranostic Applications

This study introduces multifunctional lipid nanoparticles (LNPs), mimicking the structure and compositions of low‐density lipoproteins, for the tumor‐targeted co‐delivery of anti‐cancer drugs and superparamagnetic nanocrystals. Paclitaxel (4.7 wt%) and iron oxide nanocrystals (6.8 wt%, 11 nm in diameter) are co‐encapsulated within folate‐functionalized LNPs, which contain a cluster of nanocrystals with an overall diameter of about 170 nm and a zeta potential of about ‐40 mV. The folate‐functionalized LNPs enable the targeted detection of MCF‐7, human breast adenocarcinoma expressing folate receptors, in T₂‐weighted magnetic resonance images as well as the efficient intracellular delivery of paclitaxel. Paclitaxel‐free LNPs show no significant cytotoxicity up to 0.2 mg mL^?1, indicating the excellent biocompatibility of the LNPs for intracellular drug delivery applications. The targeted anti‐tumor activities of the LNPs in a mouse tumor model suggest that the low‐density lipoprotein‐mimetic LNPs can be an effective theranostic platform with excellent biocompatibility for the tumor‐targeted co‐delivery of various anti‐cancer agents.