Moist heat as a promising method to decontaminate N95 masks: A large scale clinical study comparing four decontamination modalities-moist heat, steam, ultraviolet-C irradiation, and hydrogen peroxide plasma.

BACKGROUND: Early in the COVID-19 pandemic, there was a global shortage of masks. Although mask reprocessing was practiced, no clinical study has assessed systematically the impact of repeated cycles of wear and decontamination on the integrity of N95 filtering facepiece respirators (FFRs). METHODS: We evaluated mask fit assessed by qualitative respirator fit test (QRFT) after each cycle of wear and decontamination, as well as four measures of mask integrity-bacterial filtration efficacy, particle filtration efficacy, differential pressure, and splash resistance through five cycles of wear and decontamination using one of the four modalities (moist heat, steam, ultraviolet-C irradiation, and hydrogen peroxide plasma). RESULTS: A total of 60.6% (hydrogen peroxide plasma) to 77.5% (moist heat) of the FFRs passed five cycles of wear and decontamination, as assessed by the wearers passing QRFT all five times. Moist heat-decontaminated FFRs retained all technical measures of integrity through all five cycles. CONCLUSIONS: This is the first large-scale study to assess systematically the impact (clinically and quantitatively) on N95 FFR integrity of repeated cycles of wearing followed by decontamination. Our results suggest that moist heat is a promising method for decontaminating N95 FFRs. Performing QRFT after every cycle of wear and decontamination ensures wearer safety. Although there is currently no mask shortage, reprocessing may reduce medical waste and improve sustainability.

Erratum: A Transferrin-Conjugated Hollow Nanoplatform for Redox-Controlled and Targeted Chemotherapy of Tumor with Reduced Inflammatory Reactions: Erratum.

[This corrects the article DOI: 10.7150/thno.21194.].

Redox-Responsive Polymeric Nanocomplex for Delivery of Cytotoxic Protein and Chemotherapeutics.

Responsive delivery of anticancer proteins into cells is an emerging field in biological therapeutics. Currently, the delivery of proteins is highly compromised by multiple successive physiological barriers that reduce the therapeutic efficacy. Hence, there is a need to design a robust and sustainable nanocarrier to provide suitable protection of proteins and overcome the physiological barriers for better cellular accumulation. In this work, polyethylenimine (PEI) cross-linked by oxaliplatin(IV) prodrug (oxliPt(IV)) was used to fabricate a redox-responsive nanocomplex (PEI-oxliPt(IV)@RNBC/GOD) for the delivery of a reactive oxygen species-cleavable, reversibly caged RNase A protein (i.e., RNase A nitrophenylboronic conjugate, RNBC) and glucose oxidase (GOD) in order to realize efficient cancer treatment. The generation of hydrogen peroxide by GOD can uncage and restore the enzymatic activity of RNBC. On account of the responsiveness of the nanocomplex to highly reducing cellular environment, it would dissociate and release the protein and active oxaliplatin drug, causing cell death by both catalyzing RNA degradation and inhibiting DNA synthesis. As assessed by the RNA degradation assay, the activity of the encapsulated RNBC was recovered by the catalytic production of hydrogen peroxide from GOD and glucose substrate overexpressed in cancer cells. Monitoring of the changes in nanoparticle size confirmed that the nanocomplex could dissociate in the reducing environment, with the release of active oxaliplatin drug and protein. Confocal laser scanning microscopy (CLSM) and flow cytometry analysis revealed highly efficient accumulation of the nanocomplex as compared to free native proteins. In vitro cytotoxicity experiments using 4T1 cancer cells showed ∼80% cell killing efficacy, with highly efficient apoptosis induction. Assisted by the cationic polymeric carrier, it was evident from CLSM images that intracellular delivery of the therapeutic protein significantly depleted the RNA level. Thus, this work provides a promising platform for the delivery of therapeutic proteins and chemotherapeutic drugs for efficient cancer treatment.

A Mesoporous Nanoenzyme Derived from Metal-Organic Frameworks with Endogenous Oxygen Generation to Alleviate Tumor Hypoxia for Significantly Enhanced Photodynamic Therapy.

Tumor hypoxia compromises the therapeutic efficiency of photodynamic therapy (PDT) as the local oxygen concentration plays an important role in the generation of cytotoxic singlet oxygen (1 O2 ). Herein, a versatile mesoporous nanoenzyme (NE) derived from metal-organic frameworks (MOFs) is presented for in situ generation of endogenous O2 to enhance the PDT efficacy under bioimaging guidance. The mesoporous NE is constructed by first coating a manganese-based MOFs with mesoporous silica, followed by a facile annealing process under the ambient atmosphere. After removing the mesoporous silica shell and post-modifying with polydopamine and poly(ethylene glycol) for improving the biocompatibility, the obtained mesoporous NE is loaded with chlorin e6 (Ce6), a commonly used photosensitizer in PDT, with a high loading capacity. Upon the O2 generation through the catalytic reaction between the catalytic amount NE and the endogenous H2 O2 , the hypoxic tumor microenvironment is relieved. Thus, Ce6-loaded NE serves as a H2 O2 -activated oxygen supplier to increase the local O2 concentration for significantly enhanced antitumor PDT efficacy in vitro and in vivo. In addition, the NE also shows T2 -weighted magnetic resonance imaging ability for its in vivo tracking. This work presents an interesting biomedical use of MOF-derived mesoporous NE as a multifunctional theranostic agent in cancer therapy.

A Hypoxia-Responsive Albumin-Based Nanosystem for Deep Tumor Penetration and Excellent Therapeutic Efficacy.

Uncontrolled cancer cell proliferation, insufficient blood flow, and inadequate endogenous oxygen lead to hypoxia in tumor tissues. Herein, a unique type of hypoxia-responsive human serum albumin (HSA)-based nanosystem (HCHOA) is reported, prepared by cross-linking the hypoxia-sensitive azobenzene group between photosensitizer chlorin e6 (Ce6)-conjugated HSA (HC) and oxaliplatin prodrug-conjugated HSA (HO). The HCHOA nanosystem is stable under normal oxygen partial pressure with a size of 100-150 nm. When exposed to the hypoxic tumor microenvironment, the nanosystem can quickly dissociate into ultrasmall HC and HO therapeutic nanoparticles with a diameter smaller than 10 nm, significantly enabling their enhanced intratumoral penetration. After the dissociation, the quenched fluorescence of Ce6 in the produced HC nanoparticles can be recovered for bioimaging. At the same time, the production of singlet oxygen is increased because of the enhancement in the photoactivity of the photosensitizer. On account of these improvements, combined photodynamic therapy and chemotherapy is realized to display superior antitumor efficacy in vivo. Based on this simple strategy, it is possible to achieve the dissociation of hypoxic-responsive nanosystem to enhance the tumor penetration and therapeutic effect.

Catalase-Integrated Hyaluronic Acid as Nanocarriers for Enhanced Photodynamic Therapy in Solid Tumor.

Photodynamic therapy (PDT) as a treatment method has many advantages such as minimal invasiveness, repeatable dosage, and low systemic toxicity. Issues with conventional PDT agents include the limited availability of endogenous oxygen and difficulty in accumulation at the tumor site, which has hindered the successful treatment of tumors. Herein, we developed catalase-encapsulated hyaluronic-acid-based nanoparticles loaded with adamantane-modified photosensitizer for enhanced PDT of solid tumors. Chlorin e6 (Ce6) as the photosensitizer was modified with adamantane to yield adamantane-modified Ce6 (aCe6). The obtained nanosystem (HA-CAT@aCe6) could target overly expressed CD44 receptors on cancer cells, supplying oxygen by converting endogenous hydrogen peroxide (H2O2) to oxygen, and improving PDT efficacy upon light irradiation. HA-CAT@aCe6 nanoparticles showed high colloidal stability and monodispersity in aqueous solution. The uptake and targeting property of HA-CAT@aCe6 were demonstrated by confocal microscopy and flow cytometry in the MDA-MB-231 cell line possessing overly expressed CD44 receptors. The encapsulated catalase was able to decompose the endogenous H2O2 to generate O2 in situ for relieving hypoxia in cells incubated under hypoxic conditions. Cell viability assays indicated that HA-CAT@aCe6 possessed minimal cytotoxicity in the dark, while presenting high cellular toxicity under 660 nm light irradiation at normoxic conditions. As a result of the catalase capability in relieving hypoxia, HA-CAT@aCe6 also exhibited high cellular cytotoxicity under hypoxic condition. In vivo experiments revealed selective tumor accumulation of HA-CAT@aCe6 in MDA-MB-231 tumor bearing nude mice. Significant tumor regression was observed after intravenous injection of HA-CAT@aCe6 under light irradiation in comparison to the control system without loading catalase. Thus, HA-CAT@aCe6 demonstrated a great potential in overcoming hypoxia for targeted PDT.

Self-Assembled Oxaliplatin(IV) Prodrug-Porphyrin Conjugate for Combinational Photodynamic Therapy and Chemotherapy.

Nanomedicine has emerged as a promising strategy for effective cancer treatment. A useful approach is to develop carrier-free nanodrugs via a facile supramolecular self-assembly process. To achieve high therapeutic effect, integrating photodynamic therapy with chemotherapy has been sought after. In this work, we designed a nanocarrier (PEG-Por-CD: oxliPt(IV)-ada) assembled with oxaliplatin prodrug (oxliPt(IV)-ada) and porphyrin photosensitizer (PEG-Por-CD) through host-guest interaction to achieve stimulus-responsive combination therapy. Contributed by excellent spatial control of the binding ratio between host and guest molecules, porphyrin and oxaliplatin were separately modified with ß-cyclodextrin and adamantane to prepare the amphiphilic host-guest complex for subsequent self-assembly into therapeutic nanoparticles. The obtained PEG-Por-CD: oxliPt(IV)-ada nanoparticles exhibited good colloidal stability with an average hydrodynamic size of 164 nm while undergoing the disassembly under reductive environment to release active therapeutic species. Confocal imaging demonstrated the ability of PEG-Por-CD: oxliPt(IV)-ada to effectively accumulate in the cells and produce reactive oxygen species in vitro upon 630 nm light irradiation. As compared with the monotherapy, the PEG-Por-CD: oxliPt(IV)-ada nanoparticles exhibited 3-fold enhanced cytotoxicity and 2-fold increase in the apoptosis. In vivo experiments using 4T1 tumor-bearing mice confirmed that the nanoparticles were efficient in suppressing the tumor growth without eliciting systemic toxicity. The present self-delivery nanosystem constructed from the self-assembly approach not only allows precise control over the drug and photosensitizer loading ratio but also eliminates systemic toxicity concern of the drug carriers, providing a solution for further development of combinational cancer treatment.

Liquid-Crystalline Hydroxyapatite/Polymer Nanorod Hybrids: Potential Bioplatform for Photodynamic Therapy and Cellular Scaffolds.

Recently, we found that self-organization of hydroxyapatite (HAp) with poly(acrylic acid) (PAA) leads to the formation of liquid-crystalline (LC) nanorod hybrids that form aligned films and show stimuli-responsive properties. Here, we demonstrate that these biocompatible HAp/PAA hybrid nanorods represent a platform technology as drug nanocarriers for photodynamic cancer therapy and as bioscaffolds for the control of cellular alignment and growth. To use hybrid nanorods as a drug nanocarrier, we introduced methylene blue (MB), a typical photosensitizer for photodynamic therapy, into the PAA nanolayer covering the surface of the HAp nanocrystals through electrostatic interactions. The stable MB-loaded HAp/PAA hybrid nanorods efficiently produced singlet oxygen from MB upon light irradiation and showed remarkable photodynamic therapeutic effects in cancer cells. Moreover, taking advantage of the mechanically responsive LC alignment properties of the HAp/PAA hybrid nanorods, macroscopically oriented bioscaffolds were prepared through a spin-coating process. The cells cultured on the oriented scaffolds showed cellular alignment and elongation along the oriented direction of the hybrid nanorods. The HAp/PAA hybrid nanorods demonstrate potential in drug delivery and tissue engineering. These unique LC HAp/PAA hybrid nanorods have significant potential as a platform for the development of various types of biomaterial.

Microneedle-Assisted Topical Delivery of Photodynamically Active Mesoporous Formulation for Combination Therapy of Deep-Seated Melanoma.

Topical treatment using photodynamic therapy (PDT) for many types of skin cancers has largely been limited by the inability of existing photosensitizers to penetrate into the deep skin tissue. To overcome these problems, we developed a mesoporous nanovehicle with dual loading of photosensitizers and clinically relevant drugs for combination therapy, while utilizing microneedle technology to facilitate their penetration into deep skin tissue. Sub-50 nm photodynamically active mesoporous organosilica nanoparticles were synthesized with photosensitizers covalently bonded to the silica matrix, which dramatically increased the quantum yield and photostability of these photosensitizers. The mesopores of the nanoparticles were further loaded with small-molecule inhibitors, i. e., dabrafenib and trametinib, that target the hyperactive mitogen-activated protein kinase (MAPK) pathway for melanoma treatment. As-prepared empty nanovehicle was cytocompatible with normal skin cells in the dark, while NIR-irradiated drug-loaded nanovehicle showed a synergistic killing effect on skin cancer cells mainly through reactive oxygen species and caspase-activated apoptosis. The nanovehicle could significantly inhibit the proliferation of tumor cells in a 3D spheroid model in vitro. Porcine skin fluorescence imaging demonstrated that microneedles could facilitate the penetration of nanovehicle across the epidermis layer of skin to reach deep-seated melanoma sites. Tumor regression studies in a xenografted melanoma mouse model confirmed superior therapeutic efficacy of the nanovehicle through combinational PDT and targeted therapy.

An oxaliplatin(iv) prodrug-based supramolecular self-delivery nanocarrier for targeted colorectal cancer treatment.

A redox-responsive supramolecular nanocarrier was constructed from the self-assembly of spermine modified cyclodextrin and oxaliplatin prodrug. The nanocarrier could preferentially accumulate in polyamine transporter over-expressing HCT116 cells, releasing drugs under a reducing intracellular environment to maximize anticancer treatment.

Ultralong room temperature phosphorescence from amorphous organic materials toward confidential information encryption and decryption.

Ultralong room temperature phosphorescence (URTP) emitted from pure amorphous organic molecules is very rare. Although a few crystalline organic molecules could realize URTP with long lifetimes (>100 ms), practical applications of these crystalline organic phosphors are still challenging because the formation and maintenance of high-quality crystals are very difficult and complicated. Herein, we present a rational design for minimizing the vibrational dissipation of pure amorphous organic molecules to achieve URTP. By using this strategy, a series of URTP films with long lifetimes and high phosphorescent quantum yields (up to 0.75 s and 11.23%, respectively) were obtained from amorphous organic phosphors without visible fluorescence and phosphorescence under ambient conditions. On the basis of the unique features of URTP films, a new green screen printing technology without using any ink was developed toward confidential information encryption and decryption. This work presents a breakthrough strategy in applying amorphous organic materials for URTP.

Reduction-sensitive fluorescence enhanced polymeric prodrug nanoparticles for combinational photothermal-chemotherapy.

In this study, a reduction-sensitive supramolecular polymeric drug delivery system was developed for combinational photothermal-chemotherapy of cancer. The multifunctional system was self-assembled by specific host-guest interactions between hydrophilic ß-cyclodextrin functionalized hyaluronic acid and adamantane linked camptothecin/dye conjugate, where a near-infrared (NIR) absorbing dye IR825 was loaded. The hydrophilic hyaluronic acid shell endows the assembly with excellent colloidal stability and biocompatibility. The embedded disulfide bond in the camptothecin/dye conjugate was cleaved under reducing environment, leading to the release of the conjugated drug and the recovery of fluorescence emission. Meanwhile, the dye IR825 could efficiently transfer the absorbed light into local heat, making the nanoplatform an effective system for photothermal therapy. As evident by confocal microscopy images, the nanoplatform was quickly internalized by HeLa, MCF-7, and U14 cancer cells and released drug molecules inside the cells. In vitro cell viability assays confirmed that the cancer cells were efficiently killed by the treatment of the nanoplatform under NIR light irradiation. Significant tumor regression was also observed in the tumor-bearing mice upon the administration of the nanoplatform through combinational photothermal-chemotherapy therapy. Hence, this nanoplatform presented a great potential in site-specific combined photothermal-chemotherapy of tumor.

A Transferrin-Conjugated Hollow Nanoplatform for Redox-Controlled and Targeted Chemotherapy of Tumor with Reduced Inflammatory Reactions.

Purpose: In this study, we report the design, development and evaluation of a hollow drug delivery nanoplatform for cancer therapy in vitro and in vivo. This composite nanosystem was prepared by modifying hollow mesoporous silica nanoparticles (HMSNs) with transferrin (Tf) targeting moieties via redox-liable linkage, and was capable of delivering therapeutic cargos (doxorubicin) specifically to the tumor site and subsequently releasing them in an on-demand manner. Moreover, the Tf corona could simultaneously reduce the inflammatory response after intravenous administration in vivo. Methods: Nanostructural morphology of the drug delivery system was observed by scanning electron microscope and transmission electron microscope. The preparation process was monitored primarily using Fourier-transform infrared spectroscopy, dynamic light scattering, nitrogen adsorption/desorption isotherm, and thermogravimetric analysis. The release profile in solution was monitored by fluorescence spectroscopy. In vitro drug delivery efficacy was evaluated on MDA-MB-231 breast cancer cell line using confocal laser scanning microscopy, MTT assay and flow cytometry. In vitro inflammatory response was evaluated on RAW264.7 macrophage cells. In vivo therapeutic experiments were carried out using in situ mouse breast cancer models. Results: The experimental results evidently demonstrate that the developed nanocarrier could effectively deliver anticancer drugs to the tumor site in a targeted manner and release them in response to the elevated glutathione level inside tumor cells, resulting in improved anticancer efficacy both in vitro and in vivo. Moreover, the Tf conjugation significantly ameliorated the inflammatory reaction triggered by the administration of the nanocarrier. Conclusions: This manuscript demonstrated that the Tf-conjugated HMSNs could enhance the delivery efficiency of anticancer drugs, while simultaneously alleviating the adverse side effects. The current study presents a promising integrated delivery system toward effective and safe cancer treatment.

An aza-BODIPY based near-infrared fluorescent probe for sensitive discrimination of cysteine/homocysteine and glutathione in living cells.

Discriminative detection of glutathione (GSH) from cysteine/homocysteine (Cys/Hcy) is achieved through two emission channel analysis using a stable, highly sensitive, and selective near-infrared fluorescent probe that bears 7-nitrobenzo-2-oxa-1,3-diazole and aza-BODIPY units. The probe was successfully applied for simultaneous determination of GSH and Cys/Hcy in living cells.

ZnO-DOX@ZIF-8 Core-Shell Nanoparticles for pH-Responsive Drug Delivery.

Developing multifunctional hybrid nanosystems for controlled drug delivery is a challenging task. In this work, we prepared hierarchical core-shell nanoparticles (ZnO-DOX@ZIF-8) composed of mesoporous ZnO core and microporous ZIF-8 shell, in which the core serves as the drug storage reservoir for the loading of anticancer drug doxorubicin (DOX) and the shell could be used to prevent premature release of loaded drug at physiological environment. The mesoporous ZnO nanoparticles were first prepared, followed by DOX drug loading. Such ZnO nanoparticles were then employed as the zinc source to react with 2-methylimidazole for the formation of ZnO-DOX@ZIF-8 core-shell nanoparticles. The core-shell nanoparticles exhibit good dispersibility and stability as well as pH-responsive drug release property. While only up to 20% of loaded DOX was released in the buffer of pH 7.4, over 80% of DOX was released in the buffer of pH 5.5 because of the decomposition of the ZIF-8 shell as well as the dissolution of the ZnO core under acidic conditions. The confocal microscopy studies show that the core-shell nanoparticles could be efficiently internalized by cancer cells, and the loaded DOX in the nanoparticles could be successfully released under acidic intracellular environment. The in vitro cytotoxicity measurements demonstrate that the core-shell nanoparticles free of drug exhibit a significant cytotoxicity when the concentration was above 25 µg/mL on account of the production of reactive oxygen species. The reactive oxygen species are only generated in acidic condition, which could combine with DOX for a synergistic cancer treatment with satisfactory therapeutic efficacy. On the other hand, the nanoparticles were stable and nontoxic in physiological environment. Thus, the ZnO-DOX@ZIF-8 core-shell nanoparticles are a promising pH-responsive drug delivery system for the cancer therapy.

Nanoscale covalent organic frameworks as smart carriers for drug delivery.

Two porous covalent organic frameworks (COFs) with good biocompatibility were employed as drug nanocarriers, where three different drugs were loaded for subsequent drug release in vitro. The present work demonstrates that COFs are applicable in drug delivery for therapeutic applications.

Recent advances in multifunctional silica-based hybrid nanocarriers for bioimaging and cancer therapy.

In recent years, there has been a considerable research focus on integrating cancer cell imaging and therapeutic functions into single nanoscale platforms for better treatment of cancer. This task could often be achieved by incorporating multiple components into a hybrid nanosystem. In this minireview, we highlight different types of silica-based hybrid nanosystems and their recent applications as integrated multifunctional platforms for cancer imaging and treatment. The discussions are divided into several sections focusing on various types of materials employed to integrate with silica, which include silica-metallic nanoparticle based hybrid nanocarriers, silica-gold nanoparticle based hybrid nanocarriers, silica-quantum dot based hybrid nanocarriers, silica-upconversion nanoparticle based hybrid nanocarriers, silica-carbon based hybrid nanocarriers, and organosilica nanocarriers. Therapeutic agents loaded in such hybrids include chemodrugs, proteins, DNA/RNA and photosensitizers. For targeted delivery into tumor sites, targeting ligands such as antibodies, peptides, aptamers, and other small molecules are grafted on the surface of the nanocarriers. At the end of the review, a brief summary and research outlook are presented. This minireview aims to provide a quick update of recent research achievements in the field.