Oridonin, a small molecule inhibitor of cancer stem cell with potent cytotoxicity and differentiation potential.

Cancer stem cells (CSCs) drive malignant tumor progression, recurrence, and metastasis with unique characteristics, including self-renewal and resistance to conventional treatments. Conventional differentiation inducers, although promising, have limited cytotoxicity and may inadvertently enhance CSC stemness. To address these challenges, ongoing efforts are dedicated to developing strategies that can effectively combine both cytotoxicity and differentiation-inducing effects. In this study, we introduce oridonin (Ori), a small molecule with dual differentiation-inducing and cytotoxicity properties capable of eliminating tumor CSCs. We isolated CSCs in B16F10 cells using the Hoechst side population method and assessed the differentiation effect of Ori. Ori's differentiation-inducing effect was further evaluated using human acute promyelocytic leukemia. The cytotoxic potential of Ori against MCF-7 and B16F10 cell lines was assessed through various methods. In vivo anti-tumor and anti-CSC efficacy of Ori was investigated using mouse melanoma and CSCs melanoma models. Safety evaluation included zebrafish embryotoxicity and mouse acute toxicity experiments. As a result, Ori effectively dismantles tumorspheres, inhibits proliferation, and reduces the expression of CSC-specific markers. It induces significant differentiation, especially in the case of NB4. Additionally, Ori upregulates TP53 expression, mitigates the hypoxic tumor microenvironment, suppresses stemness, and inhibits PD-L1 expression, prompting a robust anti-cancer immune response. Ori demonstrates pronounced cytotoxicity, inducing notable pro-apoptotic effects on B16F10 and MCF-7 cells, with specific triggering of mitochondrial apoptosis. Importantly, Ori maintains a commendable biosafety record. The dual-action prowess of Ori not only induces the differentiation of CSCs but also dispatches differentiated and residual tumor cells, effectively thwarting the relentless march of tumor progression.

A lava-inspired proteolytic enzyme therapy on cancer with a PEG-based hydrogel enhances tumor distribution and penetration of liposomes.

The enhanced permeability and retention (EPR) effect has become the guiding principle for nanomedicine against cancer for a long time. However, several biological barriers severely resist therapeutic agents' penetration and retention into the deep tumor tissues, resulting in poor EPR effect and high tumor mortality. Inspired by lava, we proposed a proteolytic enzyme therapy to improve the tumor distribution and penetration of nanomedicine. A trypsin-crosslinked hydrogel (Trypsin@PSA Gel) was developed to maintain trypsin's activity. The hydrogel postponed trypsin's self-degradation and sustained the release. Trypsin promoted the cellular uptake of nanoformulations in breast cancer cells, enhanced the penetration through endothelial cells, and degraded total and membrane proteins. Proteomic analysis reveals that trypsin affected ECM components and down-regulated multiple pathways associated with cancer progression. Intratumoral injection of Trypsin@PSA Gel significantly increased the distribution of liposomes in tumors and reduced tumor vasculature. Combination treatment with intravenous injection of gambogic acid-loaded liposomes and intratumoral injection of Trypsin@PSA Gel inhibited tumor growth. The current study provides one of the first investigations into the enhanced tumor distribution of liposomes induced by a novel proteolytic enzyme therapy.

Destruction of vascular endothelial glycocalyx during formation of pre-metastatic niches.

A special microenvironment called the "pre-metastatic niche" is thought to help primary tumor cells migrate to new tissues and invade them, in part because the normal barrier function of the vascular endothelium is compromised. While the primary tumor itself can promote the creation of such niches by secreting pro-metastatic factors, the underlying molecular mechanisms are still poorly understood. Here, we show that the injection of primary tumor-secreted pro-metastatic factors from B16F10 melanoma or 4T1 breast cancer cells into healthy mice can induce the destruction of the vascular endothelial glycocalyx, which is a polysaccharide coating on the vascular endothelial lumen that normally inhibits tumor cell passage into and out of the circulation. However, when human umbilical vein endothelial cultures were treated in vitro with these secreted pro-metastatic factors, no significant destruction of the glycocalyx was observed, implying that this destruction requires a complex in vivo microenvironment. The tissue section analysis revealed that secreted pro-metastatic factors could clearly upregulate macrophage-related molecules such as CD11b and tumor necrosis factor-α (TNF-α) in the heart, liver, spleen, lung, and kidney, which is associated with the upregulation and activation of heparanase. In addition, macrophage depletion significantly attenuated the degradation of the vascular endothelial glycocalyx induced by secreted pro-metastatic factors. This indicates that the secreted pro-metastatic factors that destroy the vascular endothelial glycocalyx rely primarily on macrophages. Our findings suggest that the formation of pre-metastatic niches involves degradation of the vascular endothelial glycocalyx, which may hence be a useful target for developing therapies to inhibit cancer metastasis.

COVID-19 cooling: Nanostrategies targeting cytokine storm for controlling severe and critical symptoms.

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to wreak havoc worldwide, the "Cytokine Storm" (CS, also known as the inflammatory storm) or Cytokine Release Syndrome has reemerged in the public consciousness. CS is a significant contributor to the deterioration of infected individuals. Therefore, CS control is of great significance for the treatment of critically ill patients and the reduction of mortality rates. With the occurrence of variants, concerns regarding the efficacy of vaccines and antiviral drugs with a broad spectrum have grown. We should make an effort to modernize treatment strategies to address the challenges posed by mutations. Thus, in addition to the requirement for additional clinical data to monitor the long-term effects of vaccines and broad-spectrum antiviral drugs, we can use CS as an entry point and therapeutic target to alleviate the severity of the disease in patients. To effectively combat the mutation, new technologies for neutralizing or controlling CS must be developed. In recent years, nanotechnology has been widely applied in the biomedical field, opening up a plethora of opportunities for CS. Here, we put forward the view of cytokine storm as a therapeutic target can be used to treat critically ill patients by expounding the relationship between coronavirus disease 2019 (COVID-19) and CS and the mechanisms associated with CS. We pay special attention to the representative strategies of nanomaterials in current neutral and CS research, as well as their potential chemical design and principles. We hope that the nanostrategies described in this review provide attractive treatment options for severe and critical COVID-19 caused by CS.

Interplay between G protein-coupled receptors and nanotechnology.

G protein-coupled receptors (GPCRs), as the largest family of membrane receptors, actively modulate plasma membrane and endosomal signalling. Importantly, GPCRs are naturally nanosized, and spontaneously formed nanoaggregates of GPCRs (natural nano-GPCRs) may enhance GPCR-related signalling and functions. Although GPCRs are the molecular targets of the majority of marketed drugs, the poor pharmacokinetics and physicochemical properties of GPCR ligands greatly limit their clinical applicability. Nanotechnology, as versatile techniques, can encapsulate GPCR ligands to assemble synthetic nano-GPCRs to overcome their obstacles, robustly elevating drug efficacy and safety. Moreover, endosomal delivery of GPCR ligands by nanoparticles can precisely initiate sustained endosomal signal transduction, while nanotechnology has been widely utilized for isolation, diagnosis, and detection of GPCRs. In turn, due to overexpression of GPCRs on the surface of various types of cells, GPCR ligands can endow nanoparticles with active targeting capacity for specific cells via ligand-receptor binding and mediate receptor-dependent endocytosis of nanoparticles. This significantly enhances the potency of nanoparticle delivery systems. Therefore, emerging evidence has revealed the interplay between GPCRs and nanoparticles, although investigations into their relationship have been inadequate. This review aims to summarize the interaction between GPCRs and nanotechnology for understanding their mutual influences and utilizing their interplay for biomedical applications. It will provide a fundamental platform for developing powerful and safe GPCR-targeted drugs and nanoparticle systems. STATEMENT OF SIGNIFICANCE: GPCRs as molecular targets for the majority of marketed drugs are naturally nanosized, and even spontaneously form nano aggregations (nano-GPCRs). Nanotechnology has also been applied to construct synthetic nano-GPCRs or detect GPCRs, while endosomal delivery of GPCR ligands by nanoparticles can magnify endosomal signalling. Meanwhile, molecular engineering of nanoparticles with GPCRs or their ligands can modulate membrane binding and endocytosis, powerfully improving the efficacy of nanoparticle system. However, there are rare summaries on the interaction between GPCRs and nanoparticles. This review will not only provide a versatile platform for utilizing nanoparticles to modulate or detect GPCRs, but also facilitate better understanding of the designated value of GPCRs for molecular engineering of biomaterials with GPCRs in therapeutical application.

PLGA nanoparticles loaded with curcumin produced luminescence for cell bioimaging.

To revise the emission of curcumin (Cur) from "off" to "on", poly (D, L-lactide-co-glycolide) acid (PLGA) nanoparticles loaded with Cur were embedded in a polyvinyl alcohol (PVA) emulsifier (named Cur@PLGA-NPs). First, the emission intensities of different nanoformulations, including liposomes, bovine serum albumin (BSA) nanoparticles, and PLGA nanoparticles, were examined to discover the most effective carriers for Cur luminescence. As a result, Cur@PLGA-NPs exhibited the highest fluorescence intensity due to aggregation-induced emission (AIE), with quantum yields of 23.78% in aqueous solution and 21.52% in the solid state. According to X-ray diffraction (XRD) data, Cur@PLGA-NPs existed in the amorphous state, with a size of 217.2 ± 5.2 nm, an encapsulation efficiency (EE) of 69.98%, and a drug loading efficiency (LE) of 1.37%. The intramolecular interactions, which included hydrophobic interactions, electrostatic interactions, π-π interactions and solvatochromic effects, stabilized the chromophore cluster of Cur@PLGA-NPs in terms of nanoparticle formulation. Compared with free Cur, Cur@PLGA-NPs sensitized CT26 cells more efficiently with an IC50 value of 16.9 µmol/L and an apoptotic rate of 17.20% at 10 µmol/L Cur. Because of the robust fluorescence emission based on AIE, Cur@PLGA-NPs were utilized as a nano-AIE probe for cell bioimaging, and many red fluorescent signals were observed in CT26 cells after treatment. These results suggest that Cur@PLGA-NPs provide a novel amorphous AIE formulation with imaging and bioactive capabilities.

Postsurgical wound management and prevention of triple-negative breast cancer recurrence with a pryoptosis-inducing, photopolymerizable hydrogel.

Surgical removal remains the predominant treatment strategy for triple-negative breast cancer (TNBC). However, risks that include high locoregional recurrence and remote metastasis threaten patient survival and quality of life after surgery. In this study, a hydrogel based on poly (ethylene glycol) dimethacrylate and sericin methacryloyl was fabricated by photopolymerization to fill the resection cavity and prevent recurrence. The obtained hydrogel exhibited mechanical properties compatible with breast tissue and facilitated postsurgical wound management by promoting tissue regeneration. The DNA methylation inhibitor decitabine (DEC) and poly (lactic-co-glycolic acid)-encapsulated phytochemical gambogic acid (GA) were loaded into the hydrogel. The as-prepared hydrogel promoted fast release of DEC and sustained release of GA, leading to gasdermin E-mediated tumor cell pyroptosis and activating antitumor immune responses. Inducing postsurgical tumor cell pyroptosis inhibited local tumor recurrence and lung metastasis. While the dual-drug-loaded hydrogel system cured less than half of tumor-bearing mice, the cured mice survived for over half a year. These findings indicate that our hydrogel system is an excellent biocompatible platform for postsurgical TNBC therapy.

Nucleic acid nanoassembly-enhanced RNA therapeutics and diagnosis.

RNAs are involved in the crucial processes of disease progression and have emerged as powerful therapeutic targets and diagnostic biomarkers. However, efficient delivery of therapeutic RNA to the targeted location and precise detection of RNA markers remains challenging. Recently, more and more attention has been paid to applying nucleic acid nanoassemblies in diagnosing and treating. Due to the flexibility and deformability of nucleic acids, the nanoassemblies could be fabricated with different shapes and structures. With hybridization, nucleic acid nanoassemblies, including DNA and RNA nanostructures, can be applied to enhance RNA therapeutics and diagnosis. This review briefly introduces the construction and properties of different nucleic acid nanoassemblies and their applications for RNA therapy and diagnosis and makes further prospects for their development.

Regulation of protein corona on liposomes using albumin-binding peptide for targeted tumor therapy.

Nanocarriers entering the body are usually coated by plasma protein, leading to a protein "corona" easily recognized by tissues and cells. Adjusting the composition of protein coronas may be an efficient way to change the properties and behavior of nanoparticles in vivo. In this study, we modified doxorubicin-loaded liposomes (Lip/DOX) with an albumin-binding domain (ABD) to prepare nanoparticles (ABD-Lip/DOX) that can specifically bind to albumin and form albumin-based protein coronas in vivo for targeted tumor therapy. The prepared liposomes were spherical with a particle size of about 100 nm. After incubating the liposomes with rat serum, the albumin content was eight times higher on ABD-Lip than on control liposomes. ABD-Lip significantly inhibited adsorption of IgG and complement activation in rat serum in vitro, while corona-coated ABD-Lip was internalized to a significantly greater extent than corona-coated control liposomes. In addition, ABD-Lip showed longer blood circulation time, higher tumor accumulation and greater antitumor efficacy than control liposomes in mice bearing 4 T1 tumors, while both liposome formulations showed similar biocompatibility. These results confirm that adjusting the component of protein coronas around nanoparticles can improve their therapeutic efficacy.

The hepatoprotective effects of plant-based foods based on the "gut-liver axis": a prospective review.

The importance of the "gut-liver axis" in the pathogenesis of liver diseases has been revealed recently; which promotes the process of developing preventive and therapeutic strategies. However, considering that there are still many challenges in the medical treatment of liver diseases, potential preventive dietary intervention may be a good alternative choice. Plant-based foods have received much attention due to their reported health-promoting effects in targeting multiple pathways involved in the pathogenesis of liver diseases as well as the relative safety for general use. Based on the PubMed and Web of Science databases, this review emphatically summarizes the plant-based foods and their chemical constituents with reported effects to impact the LPS/TLR4 signaling pathway of gut-liver axis of various liver diseases, reflecting their health benefits in preventing/alleviating liver diseases. Moreover, some plant-based foods with potential gut-liver effects are specifically analyzed from the reported studies and conclusions. This review intends to provide readers an overview of the current progress in the field of this research topic. We expect to see more hepatoprotective measures for alleviating the current prevalence of liver diseases.

SPK1/S1P axis confers gastrointestinal stromal tumors (GISTs) resistance of imatinib.

BACKGROUND: Imatinib mesylate (IM) is highly effective in the treatment of gastrointestinal stromal tumors (GISTs). However, the most of GISTs patients develop secondary drug resistance after 1-3 years of IM treatment. The aim of this study was to explore the IM-resistance mechanism via the multi-scope combined with plasma concentration of IM, genetic polymorphisms and plasma sensitive metabolites. METHODS: This study included a total of 40 GISTs patients who had been regularly treated and not treated with IM. The plasma samples were divided into three experiments, containing therapeutic drug monitoring (TDM), OCT1 genetic polymorphisms and non-targeted metabolomics. According to the data of above three experiments, the IM-resistant cell line, GIST-T1/IMR cells, was constructed for verification the IM-resistance mechanism. RESULTS: The results of non-targeted metabolomics analysis suggested that the sphingophospholipid metabolic pathway including the SPK1/S1P axis was inferred in IM-insensitive patients with GISTs. A GIST cell line (GIST-T1) was immediately induced as an IM resistance cell model (GIST-T1/IMR) and we found that blocking the signal pathway of SPK1/S1P in the GIST-T1/IMR could sensitize treatment of IM and reverse the IM-resistance. CONCLUSIONS: Our findings suggest that IM secondary resistance is associated with the elevation of S1P, and blockage the signaling pathway of SPK1/S1P warrants evaluation as a potential therapeutic strategy in IM-resistant GISTs. The design of this study from blood management, group information collection, IM plasma concentration with different elements, identification of sphingolipid metabolism and lastly verification the function of SPK1/S1P in the IM-resistance GISTs cells.

Voacamine is a novel inhibitor of EGFR exerting oncogenic activity against colorectal cancer through the mitochondrial pathway.

Colorectal cancer (CRC), among the most aggressive and prevailing neoplasms, is primarily treated with chemotherapy. Voacamine (VOA), a novel bisindole natural product, possesses a variety of conspicuous pharmacological activities. Within the current research, we evaluated in vitro and in vivo the anticancer efficacy of VOA against CRC and its potential mechanisms. Our results illustrated that VOA concentrationdependently suppressed the proliferation and migration of CT26 and HCT116 cells as correspondingly indicated by IC50 values of 1.38 ± 0.09 µM and 4.10 ± 0.14 µM. Furthermore, treatment of VOA also suppressed tumor cell colony formation, escalated the late-stage apoptosis rate of tumor cells, and evoked cell cycle of CT26 and HCT116 cells arrest inhibition in G2-M and G0-G1 phases, respectively. Meanwhile, VOA markedly disrupted the mitochondrial membrane potential eliciting mitochondrial dysfunction, decreased ATP production, and intermediated an enhanced accumulation of intracellular reactive oxygen species with a concentration-dependent pattern, accompanied by elevated expression levels of pro-apoptotic related protein Bax, Cyt-C, cleaved caspases 3/8/9 and by diminished Bcl-2, Bid, PRAP and caspases 3/8/9 expression. Further mechanistic studies revealed VOA treatment suppressed the EGFR/PI3K/Akt pathway with the evidence of the decreased phosphorylation proteins of EGFR, PI3K, Akt, and downstream proteins of p-mTOR, p-NF-kB, and p-P70S6. Additionally, molecular dynamics simulations further displayed VOA could enter the EGFR pocket followed by multiple mutual interaction effects. Interestingly, the EGFR activator (NSC228155) could slack the inhibitory capability of VOA on the EGFR/PI3K/Akt pathway as well as VOA-induced impairment of mitochondrial function. Finally, administration of VOA (15, 30 mg/kg every 2 days, i.p., for 16 days) in CT26 syngeneic mice dose-dependently suppressed the neoplastic development without appreciable organ toxicities. Taken together, our study demonstrated that VOA may be a prospective therapeutic agent for the treatment of CRC.

Injectable thermosensitive lipo-hydrogels loaded with ropivacaine for prolonging local anesthesia.

Reducing post-surgical pain can promote recovery of mobility, improve patient satisfaction, and reduce the risk of chronic pain syndrome. When managing post-surgical pain, single-injection local anesthesia is more convenient and involves lower risk to the patient than multi-injection regimes, but the effects are not long-lasting. Here we developed a system that can prolong local anesthesia after a single injection. In this system, ropivacaine (Ro) is encapsulated into liposomes, which are then loaded into Poloxamer 407-based thermosensitive hydrogels. The Ro-loaded liposome-in-gel system (Ro-Lip-Gel) is in a sol state before injection, and immediately after subcutaneous injection, it forms a gel in situ. We show through in vitro release and in vivo pharmacokinetics studies that this gel acts as a drug release depot. In rats, the initial burst release of Ro was smaller from Ro-Lip-Gel than from Ro solution or Ro-Gel, and Ro-Lip-Gel caused nerve blockade lasting four times longer than Ro solution. Ro-Lip-Gel degraded in vivo and showed good biocompatibility. Our results suggest that a liposome-in-gel system can show small initial burst release, long-term nerve blockade and good biocompatibility in vitro and in vivo. Therefore, such a system may be useful for sustained local anesthesia without systemic toxicity.

Ginsenosides emerging as both bifunctional drugs and nanocarriers for enhanced antitumor therapies.

Ginsenosides, the main components isolated from Panax ginseng, can play a therapeutic role by inducing tumor cell apoptosis and reducing proliferation, invasion, metastasis; by enhancing immune regulation; and by reversing tumor cell multidrug resistance. However, clinical applications have been limited because of ginsenosides' physical and chemical properties such as low solubility and poor stability, as well as their short half-life, easy elimination, degradation, and other pharmacokinetic properties in vivo. In recent years, developing a ginsenoside delivery system for bifunctional drugs or carriers has attracted much attention from researchers. To create a precise treatment strategy for cancer, a variety of nano delivery systems and preparation technologies based on ginsenosides have been conducted (e.g., polymer nanoparticles [NPs], liposomes, micelles, microemulsions, protein NPs, metals and inorganic NPs, biomimetic NPs). It is desirable to design a targeted delivery system to achieve antitumor efficacy that can not only cross various barriers but also can enhance immune regulation, eventually converting to a clinical application. Therefore, this review focused on the latest research about delivery systems encapsulated or modified with ginsenosides, and unification of medicines and excipients based on ginsenosides for improving drug bioavailability and targeting ability. In addition, challenges and new treatment methods were discussed to support the development of these new tumor therapeutic agents for use in clinical treatment.

Factors Influencing the Steady-State Plasma Concentration of Imatinib Mesylate in Patients With Gastrointestinal Stromal Tumors and Chronic Myeloid Leukemia.

Imatinib mesylate (IM) is the standard treatment for advanced, metastatic gastrointestinal stromal tumors (GISTs) and chronic myeloid leukemia (CML) with a fixed daily standard dosage via the oral route. Interindividual and intraindividual variability in plasma concentrations have been closely linked to the efficacy of IM therapy. Therefore, this review identifies and describes the key factors influencing the plasma concentration of IM in patients with GISTs and CML. We used the following keywords to search the PubMed, EMBASE, Ovid, Wangfang, and CNKI databases to identify published reports: IM, plasma concentration, GISTs, CML, drug combination/interaction, pathology, and genotype/genetic polymorphism, either alone or in combination. This literature review revealed that only 10 countries have reported the mean concentrations of IM in GISTs or CML patients and the clinical outcomes in different ethnic groups and populations. There were totally 24 different gene polymorphisms, which were examined for any potential influence on the steady-state plasma concentration of IM. As a result, some genotype locus made discrepant conclusion. Herein, the more sample capacity, multicenter, long-term study was worthy to carry out. Eleven reports were enumerated on clinical drug interactions with IM, while there is not sufficient information on the pharmacokinetic parameters altered by drug combinations with IM that could help in investigating the actual drug interactions. The drug interaction with IM should be paid more attention in the future research.

Magnesium oxide-crosslinked low-swelling citrate-based mussel-inspired tissue adhesives.

Tissue adhesives are commonly used in surgeries and regenerative engineering for the repair and regeneration of topical and internal wounds on tissues and organs such as skin, heart, blood vessels, and bone. However, achieving rapid crosslinking, strong wet adhesion and cohesion strengths, and minimal cytotoxicity remains a critical roadblock for clinical translation. Herein, in contrast to harsh and cytotoxic oxidants, magnesium oxide (MgO) particles were found to facilitate rapid crosslinking for injectable citrate-based mussel-inspired tissue bioadhesives synthesized by reacting citric acid, PEG-PPG-PEG diol and dopamine (iC-EPE). Our results confirmed the role of MgO particles as both crosslinkers and composite fillers to concurrently enhance bioadhesive cohesion and adhesion. iC-EPE crosslinked by MgO with/without sodium periodate (PI) exhibit enhanced mechanical strengths (1.0 Mpa < tensile strength ≤ 4.5 MPa) compared to that of iC-EPE crosslinked only by PI (~0.75 MPa), high adhesion strength (up to 125 kPa, 8 fold that of fibrin glue (~15 kPa)), tunable degradability (full degradation from <1 week to > 1 month), excellent in vitro and in vivo biocompatibility, encouraging anti-bacterial performance, and favorable wound closure efficacy. Thus, MgO crosslinked bioadhesives possess great potential for a wide range of applications in surgery and regenerative engineering.

Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition.

Loss of function in tumor suppressor genes is commonly associated with the onset/progression of cancer and treatment resistance. The p53 tumor suppressor gene, a master regulator of diverse cellular pathways, is frequently altered in various cancers, for example, in ~36% of hepatocellular carcinomas (HCCs) and ~68% of non-small cell lung cancers (NSCLCs). Current methods for restoration of p53 expression, including small molecules and DNA therapies, have yielded progressive success, but each has formidable drawbacks. Here, a redox-responsive nanoparticle (NP) platform is engineered for effective delivery of p53-encoding synthetic messenger RNA (mRNA). We demonstrate that the synthetic p53-mRNA NPs markedly delay the growth of p53-null HCC and NSCLC cells by inducing cell cycle arrest and apoptosis. We also reveal that p53 restoration markedly improves the sensitivity of these tumor cells to everolimus, a mammalian target of rapamycin (mTOR) inhibitor that failed to show clinical benefits in advanced HCC and NSCLC. Moreover, cotargeting of tumor-suppressing p53 and tumorigenic mTOR signaling pathways results in marked antitumor effects in vitro and in multiple animal models of HCC and NSCLC. Our findings indicate that restoration of tumor suppressors by the synthetic mRNA NP delivery strategy could be combined together with other therapies for potent combinatorial cancer treatment.

Dual-responsive, Methotrexate-loaded, Ascorbic acid-derived Micelles Exert Anti-tumor and Anti-metastatic Effects by Inhibiting NF-κB Signaling in an Orthotopic Mouse Model of Human Choriocarcinoma.

Gestational trophoblastic neoplasia (GTN), the most aggressive form of which is choriocarcinoma, can result from over-proliferation of trophoblasts. Treating choriocarcinoma requires high doses of systemic chemotherapeutic agents, which result in nonspecific drug distribution and severe toxicity. To overcome these disadvantages and enhance chemotherapeutic efficacy, we synthesized redox- and pH-sensitive, self-assembling, ascorbic acid-derived (PEG-ss-aAPP) micelles to deliver the drug methotrexate (MTX). Methods: We developed and tested self-assembling PEG-ss-aAPP micelles, which release their drug cargo in response to an intracellular reducing environment and the acidity of the early lysosome or tumoral microenvironment. Uptake into JEG3 choriocarcinoma cancer cells was examined using confocal microscopy and transmission electron microscopy. We examined the ability of MTX-loaded PEG-ss-aAPP micelles to inhibit metastasis in an orthotopic mouse model of human choriocarcinoma. Results: Drug-loaded micelles had encapsulation efficiency above 95%. Particles were spherical based on transmission electron microscopy, with diameters of approximately 229.0 nm based on dynamic light scattering. The drug carrier responded sensitively to redox and pH changes, releasing its cargo in specific environments. PEG-ss-aAPP/MTX micelles efficiently escaped from lysosome/endosomes, and they were effective at producing reactive oxygen species, strongly inducing apoptosis and inhibiting invasion and migration. These effects correlated with the ability of PEG-ss-aAPP/MTX micelles to protect IκBα from degradation, which in turn inhibited translocation of NF-κB p65 to the nucleus. In an orthotopic mouse model of human choriocarcinoma, PEG-ss-aAPP/MTX micelles strongly inhibited primary tumor growth and significantly suppressed metastasis without obvious side effects. Conclusions: Our results highlight the potential of PEG-ss-aAPP micelles for targeted delivery of chemotherapeutic agents against choriocarcinoma.

Drug Delivery Strategies for the Treatment of Metabolic Diseases.

Metabolic diseases occur when normal metabolic processes are disrupted in the human body, which can be congenital or acquired. The incidence of metabolic diseases worldwide has reached epidemic proportions. So far, various methods including systemic drug therapy and surgery are exploited to prevent and treat metabolic diseases. However, current pharmacotherapeutic options for treatment of these metabolic disorders remain limited and ineffective, especially reducing patient compliance to treatment. Therefore, it is desirable to exploit effective drug delivery approaches to effectively treat metabolic diseases and reduce side effects. This brief review summarizes novel delivery strategies including local, targeted, and oral drug delivery strategies, as well as intelligent stimulus-responsive drug delivery strategy, for the treatment of metabolic disorders including diabetes, obesity, and atherosclerosis.