Synergistic Integration and Pharmacomechanical Function of Enzyme-Magnetite Nanoparticle Swarms for Low-Dose Fast Thrombolysis.

Magnetic micro-/nanoparticles are extensively explored over the past decade as active diagnostic/therapeutic agents for minimally invasive medicine. However, sufficient function integration on these miniaturized bodies toward practical applications remains challenging. This work proposes a synergistic strategy via integrating particle functionalization and bioinspired swarming, demonstrated by recombinant tissue plasminogen activator modified magnetite nanoparticles (rtPA-Fe3 O4 NPs) for fast thrombolysis in vivo with low drug dosage. The synthesized rtPA-Fe3 O4 NPs exhibit superior magnetic performance, high biocompatibility, and thrombolytic enzyme activity. Benefiting from a customized magnetic operation system designed for animal experiments and preclinical development, these agglomeration-free NPs can assemble into micro-/milli-scale swarms capable of robust maneuver and reconfigurable transformation for on-demand tasks in complex biofluids. Specifically, the spinning mode of the swarm exerts focused fluid shear stresses while rubbing on the thrombus surface, constituting a mechanical force for clot breakdown. The synergy of the NPs' inherent enzymatic effect and swarming-triggered fluid forces enables amplified efficacy of thrombolysis in an in vivo occlusion model of rabbit carotid artery, using lower drug concentration than clinical dosage. Furthermore, swarming-enhanced ultrasound signals aid in imaging-guided treatment. Therefore, the pharmacomechanical NP swarms herein represent an injectable thrombolytic tool joining advantages of intravenous drug therapy and robotic intervention.

A thermoplastic elastomer patch matrix for traditional Chinese medicine: design and evaluation.

OBJECTIVE: To design and evaluate a novel pressure sensitive adhesive (PSA) patch containing traditional Chinese medicine (TCM) using styrene-isoprene-styrene (SIS) copolymer. METHOD: A mixture D-optimal design with ternary response surface diagram was employed in the optimization process. The proportions of SIS copolymer, tackifying resin and plasticizer were selected as the independent variables while tack force, peel strength of the patch and skin penetrability of methyl salicylate were selected as the dependent variables. The optimized patch was then evaluated including in vivo absorption, pharmacological activities and skin irritation, by comparing with a commercial patch based on natural rubber. RESULTS: The optimized patch, which comprised 30.0% SIS copolymer, 26.6% tackifying resin and 43.4% plasticizer, was superior to commercial patch in skin permeation, pharmacological activities and skin biocompatibility. CONCLUSION: SIS copolymer was a suitable substitute to natural rubber in producing patches containing TCM formula.

Self-supplying Cu2+ and H2O2 synergistically enhancing disulfiram-mediated melanoma chemotherapy.

Disulfiram (DSF) can target and kill cancer cells by disrupting cellular degradation of extruded proteins and has therefore received particular attention for its tumor chemotherapeutic potential. However, the uncontrollable Cu2+/DSF ratio reduces the efficacy of DSF-mediated chemotherapy. Herein, self-supplying Cu2+ and oxidative stress synergistically enhanced DSF-mediated chemotherapy is proposed for melanoma-based on PVP-coated CuO2 nanodots (CPNDs). Once ingested, DSF is broken down to diethyldithiocarbamate (DTC), which is delivered into a tumor via the circulation. Under the acidic tumor microenvironment, CPNDs produce sufficient Cu2+ and H2O2. DTC readily chelates Cu2+ ions to generate CuET, which shows antitumor efficacy. CuET-mediated chemotherapy can be enhanced by H2O2. Sufficient Cu2+ generation can guarantee the maximum efficacy of DSF-mediated chemotherapy. Furthermore, released Cu2+ can be reduced to Cu+ by glutathione (GSH) and O2- in tumor cells, and Cu+ can react with H2O2 to generate toxic hydroxyl radicals (·OH) via a Fenton-like reaction, promoting the efficacy of CuET. Therefore, this study hypothesizes that employing CPNDs instead of Cu2+ ions could enhance DSF-mediated melanoma chemotherapy, providing a simple but efficient strategy for achieving chemotherapeutic efficacy.

A drug-in-adhesive matrix based on thermoplastic elastomer: evaluation of percutaneous absorption, adhesion, and skin irritation.

A novel drug-in-adhesive matrix was designed and prepared. A thermoplastic elastomer, styrene-isoprene-styrene (SIS) block copolymer, in combination with tackifying resin and plasticizer, was employed to compose the matrix. Capsaicin was selected as the model drug. The drug percutaneous absorption, adhesion properties, and skin irritation were investigated. The results suggested that the diffusion through SIS matrix was the rate-limiting step of capsaicin percutaneous absorption. [SI] content in SIS and SIS proportions put important effects on drug penetration and adhesion properties. The chemical enhancers had strong interactions with the matrix and gave small effect on enhancement of drug skin permeation. The in vivo absorption of samples showed low drug plasma peaks and a steady and constant plasma level for a long period. These results suggested that the possible side effects of drug were attenuated, and the pharmacological effects were enhanced with an extended therapeutic period after application of SIS matrix. The significant differences in pharmacokinetic parameters produced by different formulations demonstrated the influences of SIS copolymer on drug penetrability. Furthermore, the result of skin toxicity test showed that no skin irritation occurred in guinea pig skin after transdermal administration of formulations.

Evaluation of drug release profile from patches based on styrene-isoprene-styrene block copolymer: the effect of block structure and plasticizer.

We prepared pressure-sensitive adhesive (PSA) patches based on styrene-isoprene-styrene (SIS) thermoplastic elastomer using hot-melt coating method. The liquid paraffine is added in the PSA matrices as a plasticizer to moderate the PSA properties. Three drugs, methyl salicylate, capsaicin, and diphenhydramine hydrochloride are selected as model drugs. The Fourier transform infrared spectroscopy, differential scanning calorimetry test, and wide-angle X-ray diffraction test indicate a good compatibility between drugs and matrices. Peppas equation is used to describe drug release profile. Different drug-matrix absorption, as indicative of drug-matrix interaction, accounts for the variation in release profiles of different drugs. Furthermore, atomic force microscopy and rheological studies of the PSA samples are performed to investigate the effect of SIS structure and plasticizer of PSA on drug release behaviors. For methyl salicylate and capsaicin, drug diffusion in the PSA matrices is the main factor controlled by the release kinetic constant k. The high [SI] diblock content and high plasticizer amount in matrix provide the PSA with a homogeneous and soften microstructure, resulting in a high diffusion rate. But for water-soluble drugs such as diphenhydramine hydrochloride, the release rate is governed by water penetration with the competition from diffusion mechanisms.

Convenient, nondestructive monitoring and sustained-release of ethephon/chitosan film for on-demand of fruit ripening.

The microstructure changes (such as micro defects and free volume, etc.) is a deep factor that determines the sustained release behavior of polymer film. However, there are few reports exploring the micro defects of sustained-release materials. Herein, we develop a facile method to non-destructive monitoring and sustained-release ethylene within chitosan. The comprehensive means of positron annihilation lifetime spectroscopy, atomic force microscopy and Raman spectrums are performed together to study the microstructures change of ethylene sustained-release and its mechanism. When ethylene is in chitosan film, it shows good ripening performance and mechanical properties. The sustained-release ethylene improves its bioavailability and can control the fruit-ripening on-demand. More importantly, the microstructural changes of cavities have a significant impact on the sustained release of ethylene, due to the creation of cavities, the free volume of positrons undergoes a process of increasing from less to more and then gradually decreasing, reaching a maximum at 120 h. Furthermore, the ethephon/chitosan film could on-demand control the ripening time of mangoes and bananas. Therefore, this research presents a comprehensive means to study of microstructure change monitoring and controllable sustained release, and provides the possibility to solve the problem of on-demand ripening of fruit and reducing pesticide residue.

Importance of Robust and Reliable Nanochannel Sealing for Enhancing Drug Delivery Efficacy of Hollow Mesoporous Nanocontainer.

Hollow mesoporous silica nanoparticles (HMSNPs) have been widely explored in the biomedical field as drug delivery nanocarriers by virtue of their large hollow cavity. However, the connectivity between the internal cavity and the outside environment by numerous nanochannels on the mesoporous shell allows for possible drug leakage, leading to nonsufficient drug loading due to unreliable capping of the nanopores. In addition, the issue of ensuring effective utilization of the hollow cavity for achieving high drug loading capacity of HMSNPs is seldom addressed. Thus, in this work, HMSNPs with the diameter of about 400 nm were prepared and completely encapsulated by growing an ultrathin nanolayer of aluminum oxide (Al2O3) of about 20 nm on the surface of the mesoporous shell with template-assisted sol-gel chemistry. The robust sealing layer of Al2O3 can ensure "zero release" of the delivery system under neutral conditions, which is crucial for achieving high drug loading capacity by physical encapsulation of cargo molecules within the hollow cavity. The Al2O3-coated HMSNP (denoted as HMSNP Al2O3 can improve the drug loading capacity up to about 35 wt %, realizing loading efficiency as high as ten times the maximum value without Al2O3 under the same conditions. Besides, the encapsulation nanolayer of Al2O3 would be degraded under the acidic condition to realize pH-responsive controlled release of the cargo molecules. We further carried out in vitro drug delivery experiments by using human epithelial cervix adenocarcinoma (HeLa) cells as the model and revealed much higher drug delivery efficacy within cancer cells compared to free doxorubicin (Dox) and Dox loaded HMSNP without sealing (HMSNP@Dox). The current work not only clarifies the importance of the surface encapsulation of the nanochannels when using HMSNPs as nanocarriers, but also provides a strategy to prepare fully encapsulated core-shell structures, which holds great potential for physically encapsulating various theranostic reagents in the biomedical field.

Facile Method To Prepare a Novel Biological HKUST-1@CMCS with Macroscopic Shape Control for the Long-Acting and Sustained Release.

We have developed a green and versatile method to prepare hierarchically porous Cu3(BTC)2@carboxymethyl chitosan (HKUST-1@CMCS) with a macroscopic shape control and designable performance via the cross-linking of Cu(II) ions with CMCS. Furthermore, atomic force microscopy, scanning electron microscopy, powder X-ray diffraction, Brunauer-Emmett-Teller, and X-ray photoelectron spectroscopy analyses showed that the morphology of HKUST-1 could be controlled and changed by tailoring the surface roughness ( Rq) of polymer matrix. For the ball-like, fiberlike, and membrane-like composites, the matrix Rq values were 887, 88.4, and 18.2 nm and the average sizes of HKUST-1 crystals were about 10.2, 5.9, and 1.7 µm, respectively. It was found that the larger the Rq of the polymer matrix, the higher the drug payload. The results of drug release showed that the release percentage of dimethyl fumarate from HKUST-1@CMCS was 66% in 326 h, whereas that of Cu@CMCS was only 12 h. Obviously, the HKUST-1@CMCS had a long-acting and sustained release property compared to that of Cu@CMCS due to its complementary advantages of metal-organic frameworks (MOFs) and polymers. Therefore, this study not only provided an interesting way to make up for the shortcomings of MOFs and natural polymer but also developed a long-acting delivery system for a huge potential application prospect.

Large-scale synthesis of monodisperse Prussian blue nanoparticles for cancer theranostics via an "in situ modification" strategy.

BACKGROUND: The intrinsic properties of Prussian blue (PB) nanoparticles make them an attractive tool in nanomedicine, including magnetic resonance imaging (MRI), photoacoustic imaging (PAI), and photothermal therapy (PTT) properties. However, there still remains the challenge of their poor dispersible stability in the physiological environment. In this study, we developed an efficient hydrothermal method to address the poor dispersible stability of PB nanoparticles in the physiological environment. MATERIALS AND METHODS: The concentration of H+, the mass of polyvinylpyrrolidone (PVP), and iron sources (K3[Fe(CN)6]) are very vital in the preparation of PB nanoparticles. Through exploring the preparation process, optimized PB nanoparticles (OPBs) with excellent physiological stability were prepared. Hydrodynamic diameter and UV-vis absorption properties were measured to verify the stability of the prepared OPBs. Properties of dual-mode imaging, including MRI/PAI, and PTT of OPBs were investigated both in vitro and in vivo. In addition, the in vivo biosafety of OPBs was systematically assessed. RESULTS: OPBs were stable in different environments including various media, pH, and temperatures for at least 90 days, indicating that they are suitable for biomedical application via intravenous administration and easily stored in a robust environment. Compared with other research into the synthesis of PB nanoparticles, the "in situ modification" synthesis of PB nanoparticles had advantages, including a simple process, low cost, and easy mass preparation. OPBs showed no significant signs of toxicity for 90 days. As a proof of concept, the OPBs served as dual-mode image contrast agents and photothermal conversion agents for cancer diagnosis and therapy both in vitro and in vivo. CONCLUSION: Our findings suggest a facile but efficient strategy with low cost to address the poor dispersible stability of PB nanoparticles in physiological environments. This will promote the development of further clinical transformations of PB nanoparticles, especially in cancer theranostics.

Adsorption of Cu(ii), Zn(ii), and Pb(ii) from aqueous single and binary metal solutions by regenerated cellulose and sodium alginate chemically modified with polyethyleneimine.

In this paper, crosslinked cellulose/sodium alginate (SA) was modified with polyethyleneimine (PEI) as an adsorbent (PEI-RCSA) for comparative and competitive adsorption of Cu(ii), Zn(ii), and Pb(ii) in single and binary aqueous solutions. FTIR, SEM, TGA and specific surface area analysis were used to characterize the structural characteristics of PEI-RCSA. The effects of initial pH of solutions, contact time and initial concentration of heavy metal ions on the adsorption capacity of PEI-RCSA were investigated. The experimental results revealed that the removal of metal ions on the PEI-RCSA was a pH-dependent process with the maximum adsorption capacity at the initial solution pH of 5-6. The adsorption kinetics were followed by a pseudo-second-order kinetics model, and the diffusion properties played a significant role in the control of the adsorption kinetics. Meanwhile, adsorption isotherms were successfully described by the Langmuir model in a single aqueous solution system. The maximum adsorption capacities of PEI-RCSA for Cu(ii), Zn(ii), and Pb(ii) in a single system were 177.1, 110.2 and 234.2 mg g-1, respectively. The binary-component system was better described with the Langmuir competitive isotherm model. The removal efficiencies didn't change significantly when three adsorption-desorption experimental cycles were conducted. All the above results indicated that PEI-RCSA has promising applications in the treatment of toxic metal pollution.

Intermittent time-set technique controlling the temperature of magnetic-hyperthermia-ablation for tumor therapy.

Magnetic-hyperthermia-ablation is considered as an effective and minimally invasive technology for tumor therapy. However, inappropriate temperature control could induce an excessively high temperature which brings potential safety problems and limits clinical transformation of this technique. Herein, aiming to control the temperature during magnetic hyperthermia ablation, we develop an intermittent time-set technique for temperature control in magnetic hyperthermia ablation of tumors using a polylactic-co-glycolic acid (PLGA)-Fe3O4 implant. In vitro, the intermittent time is set as follows: tubes are continuously heated for 110 seconds. Then the heating process is paused for 20 seconds, and then the tubes are reheated for 10 seconds, followed by repeating the last two processes. The temperature elevation profile upon magnetic hyperthermia interestingly also demonstrates good controllability despite some differences in time-setting between in vitro and in vivo. The in vivo results show the temperature fluctuates within the range of 6.45 ± 1.34 °C after reaching the target temperature. Furthermore, we observe the deformation of an implant employing three-dimensional (3D) ultrasound to better understand the temperature change. The results show no significant deformation of the implant after being heated. The microscopic images prove that this simple technique can successfully cause tumor regression. This temperature control technique provides great benefits for hyperthermia ablation against tumors, advancing the magnetic hyperthermal ablation technology in clinical translation.

Injectable and thermally contractible hydroxypropyl methyl cellulose/Fe3O4 for magnetic hyperthermia ablation of tumors.

The development of efficient strategies for the magnetic hyperthermia ablation of tumors remains challenging. To overcome the significant safety limitations, we developed a thermally contractible, injectable and biodegradable material for the minimally invasive and highly efficient magnetic hyperthermia ablation of tumors. This material was composed of hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA) and Fe3O4. The thermal contractibility of HPMC/Fe3O4 was designed to avoid damaging the surrounding normal tissue upon heating, which was confirmed by visual inspection, ultrasound imaging and computed tomography (CT). The efficient injectability of HPMC/Fe3O4 was proven using a very small needle. The biosafety of HPMC/Fe3O4 was evaluated by MTT and biochemical assays as well as flow cytometry (FCM). All the aforementioned data demonstrated the safety of HPMC/Fe3O4. The results of in vitro and ex vivo experiments showed that the temperature and necrotic volume of excised bovine liver were positively correlated with the HPMC/Fe3O4 weight, iron content and heating duration. The in vivo experimental results showed that the tumors could be completely ablated using 0.06 ml of HPMC/60%Fe3O4 after 180 s of induction heating. We believe that this novel, safe and biodegradable material will promote the rapid bench-to-bed translation of magnetic hyperthermia technology, and it is also expected to bring a new concept for the biomaterial research field.