Advances in nanotherapeutics for tumor treatment by targeting calcium overload.

Traditional antitumor strategies are facing challenges such as low therapeutic efficacy and high side effects, highlighting the significance of developing non-toxic or low-toxic alternative therapies. As a second messenger, calcium ion (Ca2+) plays an important role in cellular metabolism and communication. However, persistent Ca2+ overload leads to mitochondrial structural and functional dysfunction and ultimately induced apoptosis. Therefore, an antitumor strategy based on calcium overload is a promising alternative. Here, we first reviewed the classification of calcium-based nanoparticles (NPs) for exogenous Ca2+ overload, including calcium carbonate (CaCO3), calcium phosphate (CaP), calcium peroxide (CaO2), and hydroxyapatite (HA), calcium hydroxide, etc. Next, the current endogenous Ca2+ overload strategies were summarized, including regulation of Ca2+ channels, destruction of membrane integrity, induction of abnormal intracellular acidity and oxidative stress. Due to the specificity of the tumor microenvironment, it is difficult to completely suppress tumor development with monotherapy. Therefore, we reviewed the progress based on mitochondrial Ca2+ overload, which improved the treatment efficiency by combining photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), sonodynamic therapy (SDT), immunogenic cell death (ICD) and gas therapy. We further explored in detail the advantages and promising new targets of this combination antitumor strategies to better address future opportunities and challenges.

Reprogramming monocytes into M2 macrophages as living drug depots to enhance treatment of myocardial ischemia-reperfusion injury.

Delivering therapeutic agents efficiently to inflamed regions remains an intractable challenge following myocardial ischemia-reperfusion injury (MI/RI) due to the transient nature of the enhanced permeability and retention effect, which disappears after 24 h. Leveraging the inflammation-homing and plasticity properties of circulating monocytes (MN) as hitchhiking carriers and further inducing their polarization into anti-inflammatory phenotype macrophages upon reaching the inflamed sites is beneficial for MI/RI therapy. Herein, DSS/PB@BSP nanoparticles capable of clearing reactive oxygen species and inhibiting inflammation were developed by employing hollow Prussian blue nanoparticles (PB) as carriers to encapsulate betamethasone sodium phosphate (BSP) and further modified with dextran sulfate sodium (DSS), a targeting ligand for the scavenger receptor on MN. This formulation was internalized into MN as living cell drug depots, reprogramming them into anti-inflammation type macrophages to inhibit inflammation. In vitro assessments revealed the successful construction of the nanoparticle. In a murine MI/RI model, circulating MN laden with these nanoparticles significantly enhanced drug delivery and accumulation at the cardiac injury site, exhibiting favorable therapeutic ability and promoting M2-biased differentiation. Our study provides an effective approach with minimally invasion and biosecurity that makes this nanoplatform as a promising candidate for immunotherapy and clinical translation in the treatment of MI/RI.

Surface saturation of drug-loaded hollow manganese dioxide nanoparticles with human serum albumin for treating rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease accompanied by energy depletion and accumulation of reactive oxygen species (ROS). Inorganic nanoparticles (NPs) offer great promise for the treatment of RA because they mostly have functions beyond being drug carriers. However, conventional nanomaterials become coated with a protein corona (PC) or lose their cargo prematurely in vivo, reducing their therapeutic efficacy. To avoid these problems, we loaded methotrexate (MTX) into hollow structured manganese dioxide nanoparticles (H-MnO2 NPs), then coated them with a 'pseudo-corona' of human serum albumin (HSA) at physiological concentrations to obtain HSA-MnO2@MTX NPs. Efficacy of MTX, MnO2@MTX, and HSA-MnO2@MTX NPs was compared in vitro and in vivo. Compared to MnO2@MTX, HSA-coated NPs were taken up better by lipopolysaccharide-activated RAW264.7 and were more effective at lowering levels of pro-inflammatory cytokines and preventing ROS accumulation. HSA-MnO2@MTX NPs were also more efficient at blocking the proliferation and migration of fibroblast-like synoviocytes from rats with collagen-induced arthritis. In this rat model, HSA-MnO2@MTX NPs showed better biodistribution than other treatments, specifically targeting the ankle joint. Furthermore, HSA-MnO2@MTX NPs reduced swelling in the paw, regulated pro-inflammatory cytokine production, and limited cartilage degradation and signs of inflammation. These results establish the therapeutic potential of HSA-MnO2@MTX NPs against RA.

pH-responsive size-adjustable liposomes induce apoptosis of fibroblasts and macrophages for rheumatoid arthritis treatment.

In rheumatoid arthritis (RA), macrophages infiltrate joints, while fibroblast-like synovial cells proliferate abnormally, forming a barrier against drug delivery, which hinders effective drug delivery to joint focus. Here we firstly designed a pH-responsive size-adjustable nanoparticle, composed by methotrexate (MTX)-human serum albumin (HSA) complex coating with pH-responsive liposome (Lipo/MTX-HSA) for delivering drugs specifically to inflamed joints in acidic environments. We showed in vitro that the nanoparticles can induce mitochondrial dysfunction, promote apoptosis of fibroblast-like synoviocytes and macrophages, further reduce the secretion of inflammatory factors (TNF-α, IL-1ß, MMP-9), and regulate the inflammatory microenvironment. We also demonstrated similar effects in a rat model of arthritis, in which Lipo/MTX-HSA accumulated in arthritic joints, and at low pH, liposome phospholipid bilayer cleavage released small-sized MTX-HSA, which effectively reduced the number of fibroblast-synoviocytes and macrophages in joints, alleviated joint inflammation, and repaired bone erosion. These findings suggest that microenvironment-responsive size-adjustable nanoparticles show promise as a treatment against rheumatoid arthritis. STATEMENT OF SIGNIFICANCE: Abnormal proliferation of fibroblast synoviocytes poses a physical barrier to effective nanoparticle delivery. We designed size-adjustable nano-delivery systems by preparing liposomes with cholesterol hemisuccinate (CHEM), which were subsequently loaded with small-sized albumin nanoparticles encapsulating the cytotoxic drug MTX (MTX-HSA), termed Lipo/MTX-HSA. Upon tail vein injection, Lipo/MTX-HSA could be aggregated at the site of inflammation via the ELVIS effect in the inflamed joint microenvironment. Specifically, intracellular acidic pH-triggered dissociation of liposomes promoted the release of MTX-HSA, which was further targeted to fibroblasts or across fibroblasts to macrophages to exert anti-inflammatory effects. The results showed that liposomes with adjustable particle size achieved efficient drug delivery, penetration and retention in joint sites; the strategy exerted significant anti-inflammatory effects in the treatment of rheumatoid arthritis by inducing mitochondrial dysfunction to promote apoptosis in fibrosynoviocytes and macrophages.

Advances in Nanodelivery Systems Based on Metabolism Reprogramming Strategies for Enhanced Tumor Therapy.

Tumor development and metastasis are closely related to the complexity of the metabolism network. Recently, metabolism reprogramming strategies have attracted much attention in tumor metabolism therapy. Although there is preliminary success of metabolism therapy agents, their therapeutic effects have been restricted by the effective reaching of the tumor sites of drugs. Nanodelivery systems with unique physical properties and elaborate designs can specifically deliver to the tumors. In this review, we first summarize the research progress of nanodelivery systems based on tumor metabolism reprogramming strategies to enhance therapies by depleting glucose, inhibiting glycolysis, depleting lactic acid, inhibiting lipid metabolism, depleting glutamine and glutathione, and disrupting metal metabolisms combined with other therapies, including chemotherapy, radiotherapy, photodynamic therapy, etc. We further discuss in detail the advantages of nanodelivery systems based on tumor metabolism reprogramming strategies for tumor therapy. As well as the opportunities and challenges for integrating nanodelivery systems into tumor metabolism therapy, we analyze the outlook for these emerging areas. This review is expected to improve our understanding of modulating tumor metabolisms for enhanced therapy.

Multifunctional nanoparticles inhibit tumor and tumor-associated macrophages for triple-negative breast cancer therapy.

HYPOTHESIS: Tumor-associated macrophages (TAM) are the mainstay of immunosuppressive cells in the tumor microenvironment, and elimination of M2-type macrophages (M2-TAM) is considered as a potential immunotherapy. However, the interaction of breast cancer cells with macrophages hinders the effectiveness of immunotherapy. In order to improve the efficacy of triple-negative breast cancer (TNBC) therapy, strategies that simultaneously target the elimination of M2-TAM and breast cancer cells may be able to achieve a better therapy. EXPERIMENTS: LyP-SA/AgNP@Dox multifunctional nanoparticles were synthesized by electrostatic adsorption. They were characterized by particle size, potential and spectroscopy. And the efficacy of multifunctional nanoparticles was evaluated in 4 T1 cell lines and M2 macrophages, including their cell uptake intracellular reactive oxygen species (ROS) production and the therapeutic effect. Furthermore, based on the orthotopic xenotransplantation model of triple negative breast cancer, the biological distribution, fluorescence imaging, biosafety evaluation and combined efficacy evaluation of the nanoplatform were performed. FINDINGS: We have successfully prepared LyP-SA/AgNP@Dox and characterized. Administering the nanosystem to 4 T1 tumor cells or M2 macrophages in culture induced accumulation of reactive oxygen species, destruction of mitochondria and apoptosis, and inhibited replication and transcription. Animal experiments demonstrated the nanoparticle had favorable targeting and antitumor activity. Our nanosystem may be useful for simultaneously inhibiting tumor and tumor-associated macrophages in breast cancer and, potentially, other malignancies.

Nano-modulators with the function of disrupting mitochondrial Ca2+ homeostasis and photothermal conversion for synergistic breast cancer therapy.

Breast cancer treatment has been a global puzzle, and apoptosis strategies based on mitochondrial Ca2+ overload have attracted extensive attention. However, various limitations of current Ca2+ nanogenerators make it difficult to maintain effective Ca2+ overload concentrations. Here, we constructed a multimodal Ca2+ nano-modulator that, for the first time, combined photothermal therapy (PTT) and mitochondrial Ca2+ overload strategies to inhibit tumor development. By crosslinking sodium alginate (SA) on the surface of calcium carbonate (CaCO3) nanoparticles encapsulating with Cur and ICG, we prepared a synergistic Ca2+ nano-regulator SA/Cur@CaCO3-ICG (SCCI). In vitro studies have shown that SCCI further enhanced photostability while preserving the optical properties of ICG. After uptake by tumor cells, SCCI can reduce mitochondrial membrane potential and down-regulate ATP production by producing large amounts of Ca2+ at low pH. Near-infrared light radiation (NIR) laser irradiation made the tumor cells heat up sharply, which not only accelerated the decomposition of CaCO3, but also produced large amounts of reactive oxygen species (ROS) followed by cell apoptosis. In vivo studies have revealed that the Ca2+ nano-regulators had excellent targeting, biocompatibility, and anti-tumor effects, which can significantly inhibit the proliferation of tumor cells and play a direct killing effect. These findings indicated that therapeutic strategies based on ionic interference and PTT had great therapeutic potential, providing new insights into antitumor therapy.

Oral hydrogel nanoemulsion co-delivery system treats inflammatory bowel disease via anti-inflammatory and promoting intestinal mucosa repair.

BACKGROUND: Due to oral nano-delivery systems for the treatment of inflammatory bowel disease (IBD) are often failed to accumulated to the colonic site and could not achieve controlled drug release, it's urgent to develop a microenvironment responsive drug delivery to improve therapy efficacy. Inflammation at the IBD site is mainly mediated by macrophages, which are the key effector cells. Excessive inflammation leads to oxidative stress and intestinal mucosal damage. The use of curcumin (CUR) and emodin (EMO) together for the treatment of IBD is promising due to their respective anti-inflammatory and intestinal mucosal repair effects. In view of the pH gradient environment of gastrointestinal tract, here we prepared pH-responsive sodium alginate (SA) hydrogel-coated nanoemulsions to co-deliver CUR and EMO (CUR/EMO NE@SA) to achieve controlled drug release and specifically target macrophages of the colon. RESULTS: In this study, a pH-responsive CUR/EMO NE@SA was successfully developed, in which the CUR/EMO NE was loaded by chitosan and further crosslinked with sodium alginate. CUR/EMO NE@SA had a pH-responsive property and could achieve controlled drug release in the colon. The preparation could significantly alleviate and improve the colon inflammatory microenvironment by decreasing TNF-α and IL-6 expression, increasing IL-10 expression, scavenging reactive oxygen species in macrophages, and by ameliorating the restoration of intestinal mucosal tight junction protein expression. Furthermore, we revealed the molecular mechanism of the preparation for IBD treatment, which might due to the CUR and EMO synergic inhibition of NF-κB to improve the pro-inflammatory microenvironment. Our study provides a new IBD therapy strategy via synergically inhibiting inflammatory, repairing mucosal and clearing ROS by pH-sensitive hydrogel-encapsulated nanoemulsion drug delivery system, which might be developed for other chronic inflammatory disease treatment. CONCLUSIONS: It's suggested that pH-sensitive hydrogel-coated nanoemulsion-based codelivery systems are a promising combinatorial platform in IBD.

Nonintrusive measurement of the liquid refractive index by using properties of the cuvette wall.

We present a method of nonintrusive measurement of the refractive index of a liquid in a glass cuvette, which uses some optical properties of the cuvette wall and the principle of total internal reflection. By coating a transmission-scattering paint layer on the outer surface of the cuvette, we transform an incident laser beam into a transmitted scattered light. When the transmitted scattered light reaches the interface between the container wall and the liquid inside, the light beams satisfying the condition of total internal reflection are reflected to the coating layer, automatically forming a circular dark pattern that is related to the refractive index of the liquid. Based on an analytic relation between the diameter of the circular dark pattern and the refractive index of the liquid, we devised a method of in situ nonintrusive refractive index measurement. We tested the effect of several parameters on the measuring accuracy and found that the optimal thickness of the transmission-scattering layer is in the range of 50-70 µm, and the aperture of the diaphragm should be in the range of 0.7-1.0 mm. We measured the refractive indices of ethanol, Coca Cola, and red wine, and achieved an accuracy of ±3×10-4 RIU (refractive index unit).

[Science of Meridians, Collaterals and Acupoints--Exploration on teaching method of meridian syndromes].

Meridian syndromes are the required basic knowledge for mastering Science of Meridians, Collaterals and Acupoints but have not brought the adequate attention on the teaching program. The writers discovered' that the content of this section occupied a decisive role for developing the students' clinical thinking ability and, stimulating their interests to learn classical TCM theories. It's necessary to enhance the importance on meridian syndromes during teaching program. The teaching program was discussed in three aspects, named workshop pattern, competitive pattern and multimedia pattern. This teaching method may improve students' interests in the study on classical TCM theories, deepen the understanding on knowledge and motivate students' learning autonomy so that the teaching quality can be improved.