Camouflaging nanoreactor traverse the blood-brain barrier to catalyze redox cascade for synergistic therapy of glioblastoma.

The blood-brain barrier (BBB) is a complex and highly restrictive barrier that prevents most biomolecules and drugs from entering the brain. However, effective strategies for delivering drugs to the brain are urgently needed for the treatment of glioblastoma. Based on the efficient BBB penetration properties of exosomes derived from brain metastatic breast cancer cells (EB), this work prepared a nanoreactor (denoted as MAG@EB), which was constructed by self-assembly of Mn2+, arsenate and glucose oxidase (GOx) into nanoparticles wrapped with EB. MAG@EB can enhance the efficiency of traversing the BBB, target and accumulate at in situ glioblastoma sites. The GOx-driven glycolysis effectively cuts off the glucose supply while also providing an abundance of H2O2 and lowering pH. Meanwhile, the released Mn2+ mediated Fenton-like reaction converts elevated H2O2 into highly toxic ·OH. Besides, AsV was reduced to AsIII by glutathione, and the tumor suppressor gene P53 was activated by AsIII to kill glioblastoma cells. Glioblastoma succumbed to the redox cascade triggered by MAG@EB, as the results demonstrated in vivo and in vitro, yielding a remarkable therapeutic effect. This work provides a promising therapeutic option mediated by cascaded nanoreactors for the future treatment of glioblastoma.

Charged Gold Nanoparticles for Target Identification-Alignment and Automatic Segmentation of CT Image-Guided Adaptive Radiotherapy in Small Hepatocellular Carcinoma.

Because of the challenges posed by anatomical uncertainties and the low resolution of plain computed tomography (CT) scans, implementing adaptive radiotherapy (ART) for small hepatocellular carcinoma (sHCC) using artificial intelligence (AI) faces obstacles in tumor identification-alignment and automatic segmentation. The current study aims to improve sHCC imaging for ART using a gold nanoparticle (Au NP)-based CT contrast agent to enhance AI-driven automated image processing. The synthesized charged Au NPs demonstrated notable in vitro aggregation, low cytotoxicity, and minimal organ toxicity. Over time, an in situ sHCC mouse model was established for in vivo CT imaging at multiple time points. The enhanced CT images processed using 3D U-Net and 3D Trans U-Net AI models demonstrated high geometric and dosimetric accuracy. Therefore, charged Au NPs enable accurate and automatic sHCC segmentation in CT images using classical AI models, potentially addressing the technical challenges related to tumor identification, alignment, and automatic segmentation in CT-guided online ART.

Strategies to Regulate the Degradation and Clearance of Mesoporous Silica Nanoparticles: A Review.

Mesoporous silica nanoparticles (MSNs) have attracted extensive attention as drug delivery systems because of their unique meso-structural features (high specific surface area, large pore volume, and tunable pore structure), easily modified surface, high drug-loading capacity, and sustained-release profiles. However, the enduring and non-specific enrichment of MSNs in healthy tissues may lead to toxicity due to their slow degradability and hinder their clinical application. The emergence of degradable MSNs provided a solution to this problem. The understanding of strategies to regulate degradation and clearance of these MSNs for promoting clinical trials and expanding their biological applications is essential. Here, a diverse variety of degradable MSNs regarding considerations of physiochemical properties and doping strategies of degradation, the biodistribution of MSNs in vivo, internal clearance mechanism, and adjusting physical parameters of clearance are highlighted. Finally, an overview of these degradable and clearable MSNs strategies for biosafety is provided along with an outlook of the encountered challenges.

Integrated oral microgel system ameliorates renal fibrosis by hitchhiking co-delivery and targeted gut flora modulation.

BACKGROUND: Renal fibrosis is a progressive process associated with chronic kidney disease (CKD), contributing to impaired kidney function. Active constituents in traditional Chinese herbs, such as emodin (EMO) and asiatic acid (AA), exhibit potent anti-fibrotic properties. However, the oral administration of EMO and AA results in low bioavailability and limited kidney accumulation. Additionally, while oral probiotics have been accepted for CKD treatment through gut microbiota modulation, a significant challenge lies in ensuring their viability upon administration. Therefore, our study aims to address both renal fibrosis and gut microbiota imbalance through innovative co-delivery strategies. RESULTS: In this study, we developed yeast cell wall particles (YCWPs) encapsulating EMO and AA self-assembled nanoparticles (NPYs) and embedded them, along with Lactobacillus casei Zhang, in chitosan/sodium alginate (CS/SA) microgels. The developed microgels showed significant controlled release properties for the loaded NPYs and prolonged the retention time of Lactobacillus casei Zhang (L. casei Zhang) in the intestine. Furthermore, in vivo biodistribution showed that the microgel-carried NPYs significantly accumulated in the obstructed kidneys of rats, thereby substantially increasing the accumulation of EMO and AA in the impaired kidneys. More importantly, through hitchhiking delivery based on yeast cell wall and positive modulation of gut microbiota, our microgels with this synergistic strategy of therapeutic and modulatory interactions could regulate the TGF-ß/Smad signaling pathway and thus effectively ameliorate renal fibrosis in unilateral ureteral obstruction (UUO) rats. CONCLUSION: In conclusion, our work provides a new strategy for the treatment of renal fibrosis based on hitchhiking co-delivery of nanodrugs and probiotics to achieve synergistic effects of disease treatment and targeted gut flora modulation.

A self-assembly active nanomodulator based on berberine for photothermal immunotherapy of breast cancer via dual regulation of immune suppression.

Breast cancer (BC) remains a significant global health concern, especially affecting women, necessitating the development of effective treatment strategies. Photothermal immunotherapy has holds promise for addressing BC by eradicating tumors, preventing metastasis, and reducing recurrence rates. However, the dynamic amplification of indoleamine 2,3-dioxygenase 1 (IDO-1) and programmed cell death-ligand 1 (PD-L1) triggered by photothermal therapy (PTT) poses presents a significant barrier to immune cell infiltration, thus promoting immune evasion. To enhance overall efficiency, a hyaluronic acid (HA)-coated berberine (BBR)-indocyanine green self-assembly active nano modulator (HBI NDs) was successfully developed. This nano modulator aims to reverse immune resistance and further contribute to the synergistic anti-tumor effects. The prepared HBI NDs demonstrated a uniform spherical morphology, high drug loading, and favorable optical properties. The results based on in vitro cell experiments and tumor animal models confirmed that HBI NDs selectively accumulated in tumor tissues, downregulated PD-L1 and IDO-1 protein expression, and induced elevated cell apoptosis. Consequently, these effects result in efficient immune infiltration and positive anti-tumor outcomes. In conclusion, the HBI NDs nanodrug exhibits considerable potential as a novel agent for enhancing anticancer efficacy and promoting immune infiltration.

Lyophilization enhances the stability of Panax notoginseng total saponins-loaded transfersomes without adverse effects on ex vivo/in vivo skin permeation.

Transfersomes (TFSs) have been extensively investigated to enhance transdermal drug delivery. As a colloidal dispersion system, TFSs are prone to problems such as particle aggregation and sedimentation, oxidation and decomposition of phospholipids. To enhance the stability of panax notoginseng saponins (PNS)-loaded transfersomes (PNS-TFSs) without adverse influences on their skin permeation, we prepared lyophilized PNS-loaded transfersomes (PNS-FD-TFSs), clarified their physicochemical characteristics and investigated their in vitro drug release, ex vivo skin permeation/deposition and in vivo pharmacokinetics. In this study, a simple, fast and controllable process was developed for preparing lyophilized PNS-TFSs. In the optimized PNS-FD-TFS formulation, sucrose and trehalose were added to the PNS-TFS dispersion with a mass ratio of trehalose, sucrose, and phospholipid of 3:2:1, and the mixture was frozen at -80 °C for 12 h followed by lyophilization at -45 °C and 5 Pa for 24 h. The optimized formulation of PNS-FD-TFSs was screened based on the appearance and reconstitution time of the lyophilized products, vesicle size, and PDI of the freshly reconstituted dispersions. It maintained stable physicochemical properties for at least 6 months at 4 °C. The vesicle size of PNS-FD-TFSs was below 100 nm and homogenous with a polydispersity index of 0.2 after reconstitution. The average encapsulation efficiencies of the five index saponins notoginsenoside R1 (NGR1), ginsenoside Rg1 (GRg1), ginsenoside Re (GRe), ginsenoside Rb1 (GRb1) and ginsenoside Rd (GRd) in PNS-FD-TFSs were 68.41 ± 5.77%, 68.95 ± 6.08%, 65.46 ± 10.95%, 91.50 ± 5.62% and 95.78 ± 1.70%, respectively. The reconstituted dispersions of PNS-FD-TFSs were similar to PNS-TFSs in in vitro release, ex vivo skin permeation, and deposition. The pharmacokinetic studies showed that, compared with the PNS liposomes (PNS-LPS), the PNS-FD-TFS-loaded drug could permeate through the skin and enter the blood rapidly. It can be concluded that the lyophilization process can effectively improve the stability of PNS-TFSs without compromising their transdermal absorption properties.

Programmed Co-delivery of tamoxifen and docetaxel using lipid-coated mesoporous silica nanoparticles for overcoming CYP3A4-mediated resistance in triple-negative breast cancer treatment.

PURPOSE: This study aims to revolutionize the treatment of aggressive triple-negative breast cancer (TNBC), notorious for its resistance to standard therapies. By ingeniously combining Tamoxifen (TMX) and Docetaxel (DTX) within a lipid-coated mesoporous silica nanoparticle (LP-MSN) delivery system, we intend to enhance therapeutic efficacy while circumventing DTX resistance mediated by CYP3A4 expression. METHODS: We rigorously tested TNBC cell lines to confirm the responsiveness to Docetaxel (DTX) and Tamoxifen (TMX). We adeptly engineered LP-MSN nanoparticles and conducted a thorough examination of the optimal drug release strategy, evaluating the LP-MSN system's ability to mitigate the impact of CYP3A4 on DTX. Additionally, we comprehensively analyzed its pharmacological performance. RESULTS: Our innovative approach utilizing TMX and DTX within LP-MSN showcased remarkable efficacy. Sequential drug release from the lipid layer and mesoporous core curbed CYP3A4-mediated metabolism, substantially enhancing cytotoxic effects on TNBC cells without harming normal cells. CONCLUSION: This pioneering research introduces a breakthrough strategy for tackling TNBC. By capitalizing on synergistic TMX and DTX effects via LP-MSN, we surmount drug resistance mediated by CYP3A4. This advancement holds immense potential for transforming TNBC treatment, warranting further clinical validation.

Recent Advances in Mesoporous Silica Nanoparticles Delivering siRNA for Cancer Treatment.

Silencing genes using small interfering (si) RNA is a promising strategy for treating cancer. However, the curative effect of siRNA is severely constrained by low serum stability and cell membrane permeability. Therefore, improving the delivery efficiency of siRNA for cancer treatment is a research hotspot. Recently, mesoporous silica nanoparticles (MSNs) have emerged as bright delivery vehicles for nucleic acid drugs. A comprehensive understanding of the design of MSN-based vectors is crucial for the application of siRNA in cancer therapy. We discuss several surface-functionalized MSNs' advancements as effective siRNA delivery vehicles in this paper. The advantages of using MSNs for siRNA loading regarding considerations of different shapes, various options for surface functionalization, and customizable pore sizes are highlighted. We discuss the recent investigations into strategies that efficiently improve cellular uptake, facilitate endosomal escape, and promote cargo dissociation from the MSNs for enhanced intracellular siRNA delivery. Also, particular attention was paid to the exciting progress made by combining RNAi with other therapies to improve cancer therapeutic outcomes.

Lignin-assisted construction of sub-10 nm supramolecular self-assembly for photothermal immunotherapy and potentiating anti-PD-1 therapy against primary and distant breast tumors.

Photothermal therapy (PTT) has brought hope for cancer treatments, with hyperthermia-induced immunogenic cell death (ICD), which is a critical part of therapeutically induced antitumor immune responses. Limited immune stimulation response in PTT is the primary reason for incomplete tumor ablation, therefore demonstrating urgent requirements for ICD amplifier. Herein, a sub-10 nm supramolecular nanoassembly was formed by co-assembly of clinically approved aluminum adjuvant and commonly used indocyanine green (ICG) under the assistance of lignosulfonate (LS, a green and sustainable multifunctional lignin derivative) for localized photothermal-immunotherapy of breast cancer. The overall results revealed that LS-Al-ICG is capable of inducing amplified ICD, efficiently eliciting solid immune responses through dendritic cells (DCs) activation and cytotoxic T-cell responses initiation for tumor killing. Moreover, anti-PD-1 therapy blocked the PD-1 pathway and led to remarkable anti-tumor efficacy against laser-irradiated primary tumors and distant tumors by potentiating systemic tumor specific T cell immunity. The results of this study demonstrate a handy and extensible approach for engineering green natural lignin nanoparticles for cancer immunotherapy, which shows promise for delivering other therapeutics in biomedical applications.

Cooperative coordination-mediated multi-component self-assembly of "all-in-one" nanospike theranostic nano-platform for MRI-guided synergistic therapy against breast cancer.

Carrier-free multi-component self-assembled nano-systems have attracted widespread attention owing to their easy preparation, high drug-loading efficiency, and excellent therapeutic efficacy. Herein, MnAs-ICG nanospike was generated by self-assembly of indocyanine green (ICG), manganese ions (Mn2+), and arsenate (AsO4 3-) based on electrostatic and coordination interactions, effectively integrating the bimodal imaging ability of magnetic resonance imaging (MRI) and fluorescence (FL) imaging-guided synergistic therapy of photothermal/chemo/chemodynamic therapy within an "all-in-one" theranostic nano-platform. The as-prepared MnAs-ICG nanospike had a uniform size, well-defined nanospike morphology, and impressive loading capacities. The MnAs-ICG nanospike exhibited sensitive responsiveness to the acidic tumor microenvironment with morphological transformation and dimensional variability, enabling deep penetration into tumor tissue and on-demand release of functional therapeutic components. In vitro and in vivo results revealed that MnAs-ICG nanospike showed synergistic tumor-killing effect, prolonged blood circulation and increased tumor accumulation compared to their individual components, effectively resulting in synergistic therapy of photothermal/chemo/chemodynamic therapy with excellent anti-tumor effect. Taken together, this new strategy might hold great promise for rationally engineering multifunctional theranostic nano-platforms for breast cancer treatment.

Hydroxy-safflower yellow A composites: An effective strategy to enhance anti-myocardial ischemia by improving intestinal permeability.

Hydroxy-safflower yellow A (HSYA) is the chief component of safflower against myocardial ischemia (MI), and belongs to biopharmaceutics classification system (BCS) III drugs. Its structure contains multiple hydroxyl groups, contributing to its high polarity and poor oral bioavailability. The main objective of this study was to probe the potential of oral penetration enhancer n-[8-(2-hydroxybenzoyl) amino] sodium octanoate (SNAC) and cationic copolymer Eudragit®EPO (EPO) to promote absorption of HSYA. HSYA composites (SNAC-HSYA-EPO) were formed by hydrogen bonding and van der Waals force. SNAC-HSYA-EPO has biocompatibility, and can improve the membrane fluidity, uptake, transport, and penetration of Caco-2 cells. The mechanism of promoting of SNAC-HSYA-EPO may be related to energy and P-glycoprotein (P-gp) when compared with the inhibitor NaN3 and verapamil group. In the pharmacokinetic (PK) results, SNAC-HSYA-EPO significantly improved oral bioavailability. Pharmacodynamics (PD) results determined that SNAC-HSYA-EPO could improve the symptoms of MI. The mechanism of the SNAC-HSYA-EPO anti-MI is related to alleviating inflammation and anti-apoptosis to protect the heart. In summary, SNAC-HSYA-EPO prepared in this study possessed a complete appearance, high recombination rate and excellent oral permeability promoting ability. SNAC-HSYA-EPO has the potential to improve oral bioavailability and further enhance the anti-MI effect of HSYA.

Correlation between in vivo microdialysis pharmacokinetics and ex vivo permeation for sinomenine hydrochloride transfersomes with enhanced skin absorption.

Transdermal drug delivery systems have drawn increasing attention in recent decades. Estimation of the correlation between ex vivo permeation and in vivo absorption (EVIVC) is an indispensable issue in the research and development of transdermal pharmaceutical products. In this paper, sinomenine hydrochloride (SH) transfersomes (SHTs) were prepared with sodium deoxycholate as edge activator, while SH liposomes (SHLs) were prepared as a control preparation. The transdermal permeation characteristics differences between them were explored by an ex vivo skin permeation experiment with Franz diffusion cell and an in vivo skin/blood pharmacokinetic experiment facilitated by double-sited microdialysis sampling technique. The curves of percentage absorbed versus time (absorption curves) under the skin and in the blood were plotted according to the percentages calculated by the deconvolution approach with the application of Wagner-Nelson model, and were correlated with the ex vivo permeation curves to evaluate a level A correlation, while a level C correlation evaluation was conducted based on the in vivo steady-state blood concentration (Css) and the ex vivo steady-state transdermal permeation rate. The ex vivo permeation test indicated that the cumulative transdermal permeated amount of SH at 36 h in SHTs was about 1.7 times of that in SHLs. The skin pharmacokinetic data showed that the Css and AUC0-t of SHTs were about 8.8 and 8.0 times of those of SHLs, respectively, and the MRT0-t of SHTs was shorter. The blood pharmacokinetic data showed that the Css and AUC0-t of SHTs were about 3.7 and 2.9 times of those of SHLs, respectively. The in vivo absorption curves were correlated well with the ex vivo permeation curves. The squares of correlation coefficient (R2) for SHTs and SHLs were 0.9153 and 0.9355 respectively in the skin, were 0.8536 and 0.7747 respectively in the blood. As to level C EVIVC, there was no significant difference between the predicted Css from ex vivo and the measured Cssin vivo. The transfersomes can be employed as effective vehicles to promote the transdermal absorption of SH, and it is feasible to predict the in vivo skin/blood pharmacokinetic properties of SHLs and SHTs based on the ex vivo skin permeation characteristics.

Deoxycholic acid-chitosan coated liposomes combined with in situ colonic gel enhances renal fibrosis therapy of emodin.

BACKGROUND: Renal fibrosis is the final common pathological feature of various chronic kidney diseases (CKD). Despite recent advances, development of new treatments strategy is needed. Emodin (EMO), an important ingredient of Chinese medicine, rhubarb (Polygonaceae Rheum palmatum l.), has been reported to inhibit the development of renal fibrosis effectively. However, the poor oral bioavailability of EMO and the insufficient monotherapy therapy compromise its efficacy. PURPOSE: In order to enhance renal fibrosis therapy of emodin, an innovative combination therapy based on deoxycholic acid-chitosan coated liposomes (DCS-Lips) and in situ colonic gel (IGE) was developed. METHODS: For one, the DCS-Lips were prepared via electrostatic interaction by mixing anionic conventional Lips with cationic DCS, deoxycholic acid conjugated on the backbone of chitosan. The cellular uptake of FITC-labeled DCS-Lips in Caco-2 cell monolayer was evaluated by CLSM and flow cytometry, respectively. Permeability study was carried out using Caco-2 cell monolayer. For another, EMO-loaded in situ colonic gel (EMO-IGE) was prepared by mixing EMO nanosuspensions and plain in situ gel, which was obtained by the cold method. The EMO-IGE was assessed for morphology, gelation temperature, viscosity and in vitro drug release. Finally, the therapeutic efficacy of the combination strategy, oral DCS-Lips formulations and in situ colonic gel, was evaluated in unilateral ureteral obstruction (UUO) rat model. Additionally, 16S rDNA sequencing was performed on rats faces to investigate whether the combination strategy improves the microbial dysbiosis in UUO rats. RESULTS: The prepared DCS-Lips produced small, uniformly sized nanoparticles, and significantly enhanced the cellular uptake and in vitro permeability of EMO compared to non-coated liposomes. Moreover, the EMO-IGE was characterized by short gelation time, optimal gelling temperature, and excellent viscosity. In UUO model, the combination of DCS-Lips (gavage) and IGE (enema) attenuated renal fibrosis effectively. The results of 16S rDNA sequencing illustrated that IGE could restore the gut microbial dysbiosis of UUO rats. CONCLUSION: Overall, the combination of DCS-Lips and EMO-IGE alleviated renal fibrosis effectively, resulting from the improved oral bioavailability of EMO by DCS-Lips and the restoration of gut microbiota by EMO-IGE, thus, presenting an innovative and promising potential for renal fibrosis treatment.

Hierarchically structured microcapsules for oral delivery of emodin and tanshinone IIA to treat renal fibrosis.

Renal fibrosis is the expected outcome of many chronic kidney diseases, and effective treatments are needed. Emodin (EMO) and tanshinone IIA (Tan IIA) are active ingredients in traditional Chinese herbs and have been effective in treating renal fibrosis. However, their application is greatly limited by inferior oral absorption, unexpected drug-drug interactions, and their ability to influence their respective pharmacokinetic profiles when used in combination. To mitigate these limitations, a new co-delivery approach based on a nano-in-micro system was designed by embedding Tan IIA-loaded nanoparticles (Tan IIA-NPs) in EMO-containing microcapsules. Microcapsules were prepared using the sharp flow technique that resulted in uniform spherical morphology and high encapsulation efficiency and drug loading. Furthermore, the encapsulated Tan IIA-NPs within the microcapsules exhibited superior cellular internalization and transmembrane transport due to the modification with cell-penetrating peptides and polyethylene glycol that facilitated the oral absorption of Tan IIA. Additionally, this nano-in-micro system exhibited evident sequential drug release. The oral bioavailability of EMO and Tan IIA was significantly improved when they were loaded into the hierarchically structured microcapsules, ultimately contributing to superior therapeutic outcomes in rats with unilateral ureteral obstruction. Therefore, the nano-in-micro carrier designed in this study could provide an efficient strategy for the effective oral delivery of combined therapies to treat renal fibrosis.

pH-responsive hierarchical H2S-releasing nano-disinfectant with deep-penetrating and anti-inflammatory properties for synergistically enhanced eradication of bacterial biofilms and wound infection.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) biofilm-associated bacterial infection is the primary cause of nosocomial infection and has long been an ongoing threat to public health. MRSA biofilms are often resistant to multiple antimicrobial strategies, mainly due to the existence of a compact protective barrier; thus, protecting themselves from the innate immune system and antibiotic treatment via limited drug penetration. RESULTS: A hierarchically structured hydrogen sulfide (H2S)-releasing nano-disinfectant was presented, which was composed of a zinc sulfide (ZnS) core as a H2S generator and indocyanine green (ICG) as a photosensitizer. This nano-disinfectant (ICG-ZnS NPs) sensitively responded to the biofilm microenvironment and demonstrated efficient eradication of MRSA biofilms via a synergistic effect of Zn2+, gas molecule-mediated therapy, and hyperthermia. Physically boosted by released H2S and a near-infrared spectroscopy-induced hyperthermia effect, ICG-ZnS NPs destroyed the compactness of MRSA biofilms showing remarkable deep-penetration capability. Moreover, on-site generation of H2S gas adequately ameliorated excessive inflammation, suppressed secretion of inflammatory cytokines, and expedited angiogenesis, therefore markedly accelerating the in vivo healing process of cutaneous wounds infected with MRSA biofilms. CONCLUSION: ICG-ZnS NPs combined with NIR laser irradiation exhibited significant anti-biofilm activity in MRSA biofilms, can accelerate the healing process through deep-penetration and anti-inflammatory effectuation. The proposed strategy has great potential as an alternative to antibiotic treatment when combating multidrug-resistant bacterial biofilms.

Nanocarrier-based delivery of arsenic trioxide for hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) poses a severe threat to human health and economic development. Despite many attempts at HCC treatment, most are inevitably affected by the genetic instability and variability of tumor cells. Arsenic trioxide (ATO) has shown to be effective in HCC. However, time-consuming challenges, especially the optimal concentration in tumor tissue and bioavailability of ATO, remain to be overcome for its transition from the bench to the bedside. To bypass these issues, nanotechnology-based delivery systems have been developed for prevention, diagnosis, monitoring and treatment in recent years. This article is a systematic overview of the latest contributions and detailed insights into ATO-loaded nanocarriers, with particular attention paid to strategies for improving the efficacy of nanocarriers of ATO.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide; it is highly aggressive, has a poor prognosis and is often diagnosed late in the disease course. Arsenic trioxide (ATO), an established agent for the treatment of acute promyelocytic leukemia, has shown powerful therapeutic potential in the treatment of HCC. However, its narrow therapeutic window and severe toxicity, as well as resistance to ATO, limit its application for HCC treatment. Nanocarriers have been employed to deliver ATO to achieve effective therapeutic outcomes in HCC. This review describes the application of various nanocarrier-based delivery systems for ATO to enhance the effectiveness of tumor therapy and reduce its side effects, thus making it a promising therapeutic strategy for in HCC.

MMP2-responsive dual-targeting drug delivery system for valence-controlled arsenic trioxide prodrug delivery against hepatic carcinoma.

Arsenic trioxide (ATO) is the active ingredient in traditional Chinese medicine, i.e., Arsenic, which has shown excellent therapeutic effects on hepatocellular carcinoma. However, due to its poor tumor distribution and high toxicity, the mass adoption of ATO in clinical applications has been severely impeded. In this study, matrix metalloproteinase 2 (MMP2)-responsive cleaved cell-penetrating peptide (PF) and folate (FA) co-modified liposome coated calcium arsenate nanoparticles (FA/PF-LP-CaAs) were fabricated based on these two considerations: (1) The tumor microenvironment characterized by overexpressed MMP2 in extracellular matrix and folate receptor on the cell membrane can enhance drug accumulation and accelerate endocytosis; (2) leveraging different toxicity of arsenic in different valence states, i.e., AsV can be reduced to more toxic AsIII by glutathione in tumor cells. Furthermore, FA/PF-LP-CaAs could be responsively degraded by the mild acidic tumor environment, and the degraded product could escape from lysosomes after endocytosis. More importantly, in light of the in vivo biodistribution and pharmacodynamic studies, the vehicle was able to accumulate in the tumor efficiently. Also, it was able to exhibit excellent anti-tumor efficacy with minimized side effects when compared to single-modified counterparts. Thus, the novel strategy based on the tumor microenvironment proposed in this work can enhance the tumor-targeting efficiency and intratumor toxicity.

Baicalin Magnesium Salt Attenuates Lipopolysaccharide-Induced Acute Lung Injury via Inhibiting of TLR4/NF-κB Signaling Pathway.

Baicalin (BA) magnesium salt (BA-Mg) is a good water-soluble ingredient extracted from Scutellaria baicalensis Georgi, a commonly used traditional Chinese medicine. This study is aimed at investigating whether BA-Mg could exert a better protective effect on lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in mice and illuminate the underlying mechanisms in vivo and in vitro. Mice were intraperitoneally administrated with equimolar BA-Mg, BA, and MgSO4 before LPS inducing ALI. Lung tissues and bronchoalveolar lavage fluid were collected for lung wet/dry ratio, histological examinations, cell counts, and biochemical analyses at 48 h post-LPS exposure. Meanwhile, the protein expressions of TLR4/NF-κB signaling pathway and proinflammatory cytokines in lung tissues and lung bronchial epithelial cells (BEAS-2B) were detected. The results showed BA-Mg pronouncedly ameliorated LPS-induced inflammatory response and histopathological damages, elevated antioxidant enzyme activity (SOD), and downregulated myeloperoxidase (MPO) and malonaldehyde (MDA) levels through the inhibition of TLR4/NF-κB signaling pathway activation. Moreover, the effect of BA-Mg was significantly better than that of BA and MgSO4 in ameliorating symptoms. Overall, BA-Mg can effectively relieve inflammatory response and oxidative stress triggered by LPS, indicating it may be a potential therapeutic candidate for treating ALI.

Lipid/PAA-coated mesoporous silica nanoparticles for dual-pH-responsive codelivery of arsenic trioxide/paclitaxel against breast cancer cells.

Nanomedicine has attracted increasing attention and emerged as a safer and more effective modality in cancer treatment than conventional chemotherapy. In particular, the distinction of tumor microenvironment and normal tissues is often used in stimulus-responsive drug delivery systems for controlled release of therapeutic agents at target sites. In this study, we developed mesoporous silica nanoparticles (MSNs) coated with polyacrylic acid (PAA), and pH-sensitive lipid (PSL) for synergistic delivery and dual-pH-responsive sequential release of arsenic trioxide (ATO) and paclitaxel (PTX) (PL-PMSN-PTX/ATO). Tumor-targeting peptide F56 was used to modify MSNs, which conferred a target-specific delivery to cancer and endothelial cells under neoangiogenesis. PAA- and PSL-coated nanoparticles were characterized by TGA, TEM, FT-IR, and DLS. The drug-loaded nanoparticles displayed a dual-pH-responsive (pHe = 6.5, pHendo = 5.0) and sequential drug release profile. PTX within PSL was preferentially released at pH = 6.5, whereas ATO was mainly released at pH = 5.0. Drug-free carriers showed low cytotoxicity toward MCF-7 cells, but ATO and PTX co-delivered nanoparticles displayed a significant synergistic effect against MCF-7 cells, showing greater cell-cycle arrest in treated cells and more activation of apoptosis-related proteins than free drugs. Furthermore, the extracellular release of PTX caused an expansion of the interstitial space, allowing deeper penetration of the nanoparticles into the tumor mass through a tumor priming effect. As a result, FPL-PMSN-PTX/ATO exhibited improved in vivo circulation time, tumor-targeted delivery, and overall therapeutic efficacy.

Angiopep-2-modified calcium arsenite-loaded liposomes for targeted and pH-responsive delivery for anti-glioma therapy.

The blood-brain barrier (BBB) is the most critical obstacle in the treatment of central nervous system disorders, such as glioma, the most typical type of brain tumor. To overcome the BBB and enhance drug-penetration abilities, we used angiopep-2-modified liposomes to deliver arsenic trioxide (ATO) across the BBB, targeting the glioma. Angiopep-2-modified calcium arsenite-loaded liposomes (A2-PEG-LP@CaAs), with uniformly distributed hydrodynamic diameter (96.75 ± 0.57 nm), were prepared using the acetate gradient method with high drug-loading capacity (7.13 ± 0.72%) and entrapment efficiency (54.30 ± 9.81%). In the acid tumor microenvironment, arsenic was responsively released, thereby exerting an anti-glioma effect. The anti-glioma effect of A2-PEG-LP@CaAs was investigated both in vitro and in vivo. As a result, A2-PEG-LP@CaAs exhibited a potent, targeted anti-glioma effect mediated by the lipoprotein receptor-related (LRP) receptor, which is overexpressed in both the BBB and glioma. Therefore, A2-PEG-LP@CaAs could dramatically promote the anti-glioma effect of ATO, as a promising strategy for glioma therapy.