The Induction of Combined Hyperthermal Ablation Effect of Irreversible Electroporation with Polydopamine Nanoparticle-Coated Electrodes.

Irreversible electroporation (IRE) is a prominent non-thermal ablation method widely employed in clinical settings for the focal ablation therapy of solid tumors. Utilizing high-voltage, short-duration electric pulses, IRE induces perforation defects in the cell membrane, leading to apoptotic cell death. Despite the promise of irreversible electroporation (IRE) in clinical applications, it faces challenges concerning the coverage of target tissues for ablation, particularly when compared to other thermal ablation therapies such as radiofrequency ablation, microwave ablation, and cryoablation. This study aims to investigate the induced hyperthermal effect of IRE by applying a polydopamine nanoparticle (Dopa NP) coating on the electrode. We hypothesize that the induced hyperthermal effect enhances the therapeutic efficacy of IRE for cancer ablation. First, we observed the hyperthermal effect of IRE using Dopa NP-coated electrodes in hydrogel phantom models and then moved to in vivo models. In particular, in in vivo animal studies, the IRE treatment of rabbit hepatic lobes with Dopa NP-coated electrodes exhibited a two-fold higher increase in temperature (ΔT) compared to non-coated electrodes. Through a comprehensive analysis, we found that IRE treatment with Dopa NP-coated electrodes displayed the typical histological signatures of hyperthermal ablation, including the disruption of the hepatic cord and lobular structure, as well as the infiltration of erythrocytes. These findings unequivocally highlight the combined efficacy of IRE with Dopa NPs for electroporation and the hyperthermal ablation of target cancer tissues.

Bisphosphonate-Conjugated Photo-Crosslinking Polyanionic Hyaluronic Acid Microbeads for Controlled BMP2 Delivery and Enhanced Bone Formation Efficacy.

In this study, we designed bisphosphonate-conjugated polyanionic hyaluronic acid (HA) microbeads (MBs) for the controlled delivery of bone morphogenetic protein 2 (BMP2). MBs were prepared via the photo-crosslinking of bisphosphonate (alendronate)-conjugated methacrylated HA (Alen-MHA). The polyanionic Alen-MHA MBs actively absorbed cationic BMP2 up to 91.0% of the loading efficacy and displayed a sustained release of BMP2 for 10 days. BMP2/Alen-MHA MBs induced osteogenic-related genes in cellular experiments and showed the highly increased bone formation efficacy in thigh muscle injection and rat spinal fusion animal models. Thus, BMP2/Alen-MHA MBs provide a promising opportunity to improve the delivery efficiency of BMP2.

Designing Smart Polymer Conjugates for Controlled Release of Payloads.

Incorporating labile bonds inside polymer backbone and side chains yields interesting polymer materials that are responsive to change of environmental stimuli. Drugs can be conjugated to various polymers through different conjugation linkages and spacers. One of the key factors influencing the release profile of conjugated drugs is the hydrolytic stability of the conjugated linkage. Generally, the hydrolysis of acid-labile linkages, including acetal, imine, hydrazone, and to some extent ß-thiopropionate, are relatively fast and the conjugated drug can be completely released in the range of several hours to a few days. The cleavage of ester linkages are usually slow, which is beneficial for continuous and prolonged release. Another key structural factor is the water solubility of polymer-drug conjugates. Generally, the release rate from highly water-soluble prodrugs is fast. In prodrugs with large hydrophobic segments, the hydrophobic drugs are usually located in the hydrophobic core of micelles and nanoparticles, which limits the access to the water, hence lowering significantly the hydrolysis rate. Finally, self-immolative polymers are also an intriguing new class of materials. New synthetic pathways are needed to overcome the fact that much of the small molecules produced upon degradation are not active molecules useful for biomedical applications.

Photocatalytic degradation of pesticides by nanofibrous membranes fabricated by colloid-electrospinning.

Photocatalytic degradation of organic pollutants is a promising way to clean wastewater. Herein, we develop and compare two processes for fabricating nanofibrous membranes with photocatalytic properties. Hybrid nanofibers are produced by colloid-electrospinning and composed of metal oxide nanoparticles on sintered SiO2 nanoparticles. The latter serves as support for the photocatalyst and preserves the structural integrity of nanofibers. Adsorption of metal salts on crosslinked polymer/SiO2 fibers followed by calcination allows for the obtention of fibers with large amounts of metal oxide. Nanofibrous membranes with supported ZnO, In2O3, or mixture of both, display photocatalytic activity upon UV irradiation. The membranes can degrade a dye and an organophosphate pesticide more effectively than membranes directly fabricated from the calcination of metal oxides.

Regulating Payload Release from Hybrid Nanocapsules with Dual Silica/Polycaprolactone Shells.

We describe a facile strategy to synthesize hybrid nanocapsules with an oil core for hindering interactions between payloads and silica shell. Polycaprolactone/silica nanocapsules are synthesized by an interfacial sol-gel process occurring simultaneously with internal phase separation of the polymer produced by a miniemulsion-solvent evaporation technique. The localization of the polycaprolactone in the nanocapsules is depending on the ratio between polymer and silica. Formation of hybrid nanocapsules is found to significantly hinder interactions of drugs such as ibuprofen and carbamazepine with the silica surface.

Encapsulation and Release of Functional Nanodroplets Entrapped in Nanofibers.

A method is presented for preserving the structural integrity of nanodroplets produced by emulsification. Droplets of different hydrophobic liquids such as essential oils or monomers are produced by the miniemulsion process. The miniemulsions are then electrospun to yield dextran nanofibers entrapping the hydrophobic nanodroplets. The nanodroplets are then successfully redispersed by dissolving the nanofibers in water. Furthermore, it is shown that nanofibers can be used to store a monomer and a catalyst as healing agents for ring-opening metathesis polymerization. After dissolution, the healing agents are released and a self-healing reaction takes place. Embedding, storage, and release of emulsion nanodroplets is a promising method that avoids potential destabilization of droplets by coalescence or Ostwald ripening.

Encapsulation and Release of Essential Oils in Functional Silica Nanocontainers.

We describe the fabrication of mesoporous silica nanocontainers (SiO2NCs) that simultaneously encapsulate different antiseptic agents. Peppermint oil (PO), thyme oil (TO), cinnamon oil (CnO), and clove oil (CO), which are known to display antibacterial properties, are loaded in the core of the silica nanocontainers that are stabilized by antiseptic surfactants. The encapsulation efficiency, surface area, and pore size are controlled by the type of oil and surfactant. The release of essential oils is further controlled by grafting oxidized hyaluronic acid on silica nanocontainers functionalized with amino groups.

Calcium-Triggered Pulsatile Delivery of Parathyroid Hormone from Microbeads for Osteoporosis Treatment.

Recombinant human parathyroid hormone 1-34 (rhPTH 1-34) is the most potent anabolic drug recommended for patients with osteoporosis who do not respond to conventional treatment. However, subcutaneous intermittent injection is the only effective regimen due to its unusual action of mechanism. This regimen is inconvenient and is a big hurdle in clinical applications. In this study, we designed polyelectrolyte microbeads that can deliver rhPTH 1-34 in response to Ca2+ concentration, which indicates the osteoporotic status. Dextran photopolymer was synthesized, mixed with anionic monoacrylate, and photopolymerized by passing through capillary microfluidics to obtain the microbeads. The anionic property of microbeads was confirmed by toluidine blue staining. One microbead, loaded with a 1 day dose of rhPTH 1-34 (23.4 ± 0.9 µg), released rhPTH 1-34 in a triggered manner following the addition of Ca2+ ion. In vitro cell study demonstrated that rhPTH 1-34 released in a pulsatile manner from the microbeads induced osteogenic markers (ALP, RUNX2, and OPN) and precipitated mineral disposition more effectively.

Optimizing protein delivery rate from silk fibroin hydrogel using silk fibroin-mimetic peptides conjugation.

Controlled release of proteins, such as growth factors, from biocompatible silk fibroin (SF) hydrogel is valuable for its use in tissue engineering, drug delivery, and other biological systems. To achieve this, we introduced silk fibroin-mimetic peptides (SFMPs) with the repeating unit (GAGAGS)n. Using green fluorescent protein (GFP) as a model protein, our results showed that SFMPs did not affect the GFP function when conjugated to it. The SFMP-GFP conjugates incorporated into SF hydrogel did not change the gelation time and allowed for controlled release of the GFP. By varying the length of SFMPs, we were able to modulate the release rate, with longer SFMPs resulting in a slower release, both in water at room temperature and PBS at 37 °C. Furthermore, the SF hydrogel with the SFMPs showed greater strength and stiffness. The increased ß-sheet fraction of the SF hydrogel, as revealed by FTIR analysis, explained the gel properties and protein release behavior. Our results suggest that the SFMPs effectively control protein release from SF hydrogel, with the potential to enhance its mechanical stability. The ability to modulate release rates by varying the SFMP length will benefit personalized and controlled protein delivery in various systems.

Assessment of Hepatic Lesions After non-Thermal Tumor Ablation by Irreversible Electroporation in a Pig Model.

Irreversible electroporation (IRE) is a non-thermal and minimal invasive modality to ablate pathologic lesions such as hepatic tumors. Histological analysis of the initial lesions after IRE can help predict ablation efficacy. We aimed to investigate the histological characteristics of early hepatic lesions after IRE application using animal models. IRE (1500 V/cm, a pulse length of 100 µs, 60 or 90 pulses) was applied to the liver of miniature pigs. H&E and TUNEL staining were performed and analyzed. Ablated zones of pig liver were discolored and separated from the normal zone after IRE. Histologic characteristics of ablation zones included preserved hepatic lobular architecture with a unique hexagonal-like structure. Apoptotic cells were detected, and sinusoidal dilatation and blood congestion were observed, but hepatic arteries and bile ducts were intact around the ablation zones. The early lesions obtained by delivering monophasic square wave pulses through needle electrodes reflected typical histological changes induced by IRE. Therefore, it was found that the histological assessment of the early hepatic lesion after IRE can be utilized to predict the IRE ablation effect.

Enhanced Therapeutic Potential of Irreversible Electroporation under Combination with Gold-Doped Mesoporous Silica Nanoparticles against EMT-6 Breast Cancer Cells.

Irreversible electroporation (IRE) is a non-thermal tumor ablation technique that delivers short pulses of strong electric fields to cancer tissues and induces cell death through the destruction of cell membranes. Here, we synthesized gold-doped mesoporous silica nanoparticles (Au-MSNs) via incipient wetness impregnation and evaluated the therapeutic potentials of combination therapy with IRE. The fabricated Au-MSNs had around 80-100 nm of particle size and were successfully end-doped with Au nanoparticles. Combination treatment of IRE (800 V/cm) and Au-MSNs (100 µg/mL) increased cell membrane permeability by 25-fold compared with single IRE treatment. Cellular reactive oxygen species (ROS) and lipid peroxidation of EMT-6 cells were significantly increased by 14- and 265-fold, respectively, under combination treatment of IRE (800 V/cm) and Au-MSNs (100 µg/mL). Cytotoxic cell death increased by 28% under a combination treatment of IRE (800 V/cm) and Au-MSNs (100 ug/mL) over single IRE. Our studies suggest that the combination treatment of IRE with Au-MSNs can enhance the therapeutic efficacy of IRE for breast cancer.

Core-shell particles for drug-delivery, bioimaging, sensing, and tissue engineering.

Nanoparticles have been widely used for many applications such as catalysis, biomedicine, or self-healing. Core-shell nanoparticles are very promising for biomedical applications due to several features such as possibility of sequence-controlled release of drugs and protection of sensitive payloads from surrounding environment. Core-shell structures incorporating payloads such as drugs, peptides, or hormones have been investigated in pre-clinical studies. The present review describes state of the art techniques for designing core-shell particles for biomedical applications. We also present recent advances in the field of drug, protein/peptide, and gene delivery using different types of core-shell nanoparticles. The function of core-shell particles as contrast agents and labels for bioimaging in magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography imaging (CT), ultrasound, and optical imaging is highlighted as well as their applications as biosensors.

Emulsion Techniques for the Production of Pharmacological Nanoparticles.

Nanoparticles have the advantages over micron-sized particles to typically provide higher intracellular uptake and drug bioavailability. Emulsion techniques are commonly used methods for producing nanoparticles aiming at high encapsulation efficiency, high stability, and low toxicity. Here, the recent developments of nanoparticles prepared from emulsions, the synthesis of nanoparticles, their physicochemical properties, and their biomedical applications are discussed. Selection of techniques, such as emulsion polymerization, miniemulsion polymerization, microemulsion polymerization, and emulsion-solvent evaporation processes, strongly influences morphologies, size distributions, and particle properties. Details in the synthetic strategies governing the performance of nanoparticles in bioimaging, biosensing, and drug delivery are presented. Benefits and limitations of molecular imaging techniques are also discussed.

Programming pH-responsive release of two payloads from dextran-based nanocapsules.

Controlled release of payloads such as drugs or corrosion inhibitors from nanocapsules is a prerequisite for their utilization. Indeed, premature leaching and contamination of the environment can be avoided. Herein, we investigate the pH-dependence of release kinetics of corrosion inhibitors from nanocapsules. Nanocapsules are formed by interfacial crosslinking of dextran derivatives in inverse miniemulsion and subsequently re-dispersed in aqueous solutions. Release kinetics are highly dependent on pH value and can be explained by a complex interplay involving swelling of nanocapsules shell, solubility of corrosion inhibitors, and electrostatic interactions between payloads and the shell.

NIR-responsive ROS generating core and ROS-triggered 5'-Deoxy-5-fluorocytidine releasing shell structured water-swelling microgel for locoregional combination cancer therapy.

Combination chemotherapy now becomes the most standard cancer treatment protocol. Here, we present a core-shell type polymeric microgel (CSPM) which combines photodynamic and chemo therapeutic modalities in one-pot system. CSPM localizes in the malignant lesion after intratumoral injection, releases reactive oxygen species (ROS) and anticancer drug (5'-deoxy-5-fluorocytidine; DFCR) under the near-infrared (NIR) laser treatment. Pheophorbide A (PheoA)-linked poly(hydroxyethyl methacrylate) (poly-HEMA) was designated to a ROS-generating core, and chemically covered with a chitosan shell. In addition, phenylboronic acid was employed in chitosan shells and linked to DFCR to form an ROS cleavable boronic ester. The core-shell structure of CSPM was determined by transmission electron microscopy. NIR-responsive photodynamic ROS generation was confirmed by the oxidative reduction of 9,10-dimethylanthracene (a fluorescent dye), and the cascadic release of DFCR by ROS was confirmed by a release study and a live and dead cell imaging study. Typically, poly-HEMA cored microgel increased its volume by 48.9-fold after absorption of body fluid. This swelling property ensured CSPM was retained in tumor tissues after subtumoral injection and the suitability of CSPM for locoregional phototherapy. The therapeutic effect of CSPM was attributed to the combined, cascadic deliveries of cytotoxic ROS and DFCR and confirmed by growth inhibition studies in in vitro pancreatic cancer cells and in vivo colon cancer mouse model.

Recent advances in polymerizations in dispersed media.

Advances in chemistry heterophase polymerizations reflect new developments in polymer chemistry. Although some few polymerization reactions cannot be performed in dispersed media, new polymerization reactions can still benefit from advantages of heterophase reactions, which are fast kinetics due to high local concentration of reagents and advantageous heat exchange. We describe here advances in heterophase polymerizations, with a focus on miniemulsion polymerization, which are mainly driven by academic interest for biomedicine and energy science. Click-reactions in dispersion are particularly interesting because they are bioorthogonals. Synthesis of highly crosslinked polymer colloids, especially with conjugated polymers, has found applications in gas storage, catalysis, and production of energy. Finally, we show how spatial segregation in heterophase polymerization can help to obtain polymer materials with unique structures.

Saccharides, oligosaccharides, and polysaccharides nanoparticles for biomedical applications.

Modern requirements for designing efficient nanocarriers against diseases such as cancer are very complex. A suitable nanocarrier should indeed remain colloidally stable in the body, be biodegradable, target specific tumor cells, and release efficiently drugs. These challenging tasks can be overcome by using the chemistry of saccharides and polysaccharides. We discuss here recent applications of carbohydrates-based materials for providing biodegradability, enhancing contrast in bioimaging, a stealth effect for controlling the composition of protein corona, and targeting ability.

MT1-MMP Responsive Doxorubicin Conjugated Poly(lactic-co-glycolic Acid)/Poly(styrene-alt-maleic Anhydride) Core/Shell Microparticles for Intrahepatic Arterial Chemotherapy of Hepatic Cancer.

In this study, we demonstrated that the MT1-MMP-responsive peptide (sequence: GPLPLRSWGLK) and doxorubicin-conjugated poly(lactic-co-glycolic acid/poly(styrene-alt-maleic anhydride) core/shell microparticles (PLGA/pSMA MPs) can be applied for intrahepatic arterial injection for hepatocellular carcinoma (HCC). PLGA/pSMA MPs were prepared with a capillary-focused microfluidic device. The particle size, observed by scanning electron microscopy (SEM), was around 22 ± 3 µm. MT1-MMP-responsive peptide and doxorubicin (DOX) were chemically conjugated with pSMA segments on the shell of MPs to form a PLGA/pSMA-peptide-DOX complex, resulting in high encapsulation efficiency (91.1%) and loading content (2.9%). DOX was released from PLGA/pSMA-peptide-DOX MPs in a pH-dependent manner (∼25% at pH 5.4 and ∼8% at pH 7.4) and accumulated significantly in an MT1-MMP-overexpressing Hep3B cell line. An in vivo intrahepatic injection study showed localization of MPs on the hepatic vessels and hepatic lobes up to 24 h after the injection without any shunting to the lung. Moreover, MPs efficiently inhibited tumor growth of Hep3B hepatic tumor xenografted mouse models. We expect that PLGA/pSMA-peptide-DOX MPs can be utilized as an effective intrahepatic drug delivery system for the treatment of HCC.

Capillary microfluidics-derived doxorubicin-containing human serum albumin microbeads for transarterial chemoembolization of hepatic cancer.

In this study, we prepared doxorubicin (DOXO)-loaded albumin microbeads (DOXO-MBs) using a capillary microfluidic device for transarterial chemoembolization of hepatic cancer. Albumin droplets were fabricated using the capillary microfluidic device and solidified by addition of glutaraldehyde. The acquired DOXO-MBs were homogeneous and the size was adjustable from 183.2 ± 12.2 µm to 351.5 ± 7.9 µm by changing the flow rate of fluidic solutions. The loading amount of DOXO was 9.7 ± 1.5 mg/g, and over 15.7% of DOXO was released over one month in pH7.2 buffer. Intra-portal injection of DOXO-MBs on normal liver of rats proved microbeads efficiently embolized hepatic vessels. Hepatic lobes, recovered 24 days after intra-portal injection, showed that the DOXO-MBs remained in hepatic vessels and released DOXO to surrounding hepatic tissues. In the hepatic tumor xenograft mouse model, DOXO-MBs inhibited tumor growth more efficiently than intravenous (I.V.) injection of free DOXO (p<0.01).

Enhanced conjugation stability and blood circulation time of macromolecular gadolinium-DTPA contrast agent.

In this study, we prepared macromolecular MR T1 contrast agent: pullulan-conjugated Gd diethylene triamine pentaacetate (Gd-DTPA-Pullulan) and estimated residual free Gd(3+), chelation stability in competition with metal ions, plasma and tissue pharmacokinetics, and abdominal MR contrast on rats. Residual free Gd(3+) in Gd-DTPA-Pullulan was measured using colorimetric spectroscopy. The transmetalation of Gd(3+) incubated with Ca(2+) was performed by using a dialysis membrane (MWCO 100-500 Da) and investigated by ICP-OES. The plasma concentration profiles of Gd-DTPA-Pullulan were estimated after intravenous injection at a dose 0.1 mmol/kg of Gd. The coronal-plane abdominal images of normal rats were observed by MR imaging. The content of free Gd(3+), the toxic residual form, was less than 0.01%. Chelation stability of Gd-DTPA-Pullulan was estimated, and only 0.2% and 0.00045% of Gd(3+) were released from Gd-DTPA-Pullulan after 2h incubation with Ca(2+) and Fe(2+), respectively. Gd-DTPA-Pullulan displayed the extended plasma half-life (t1/2,α=0.43 h, t1/2,ß=2.32 h), much longer than 0.11h and 0.79 h of Gd-EOB-DTPA. Abdominal MR imaging showed Gd-DTPA-Pullulan maintained initial MR contrast for 30 min. The extended plasma half-life of Gd-DTPA-Pullulan probably allows the prolonged MR acquisition time in clinic with enhanced MR contrast.