Engineering a hyaluronic acid-encapsulated tumor-targeted nanoplatform with sensitized chemotherapy and a photothermal effect for enhancing tumor therapy.

Chemotherapy remains one of the most widely used cancer treatment modalities in clinical practice. However, the characteristic microenvironment of solid tumors severely limits the anticancer efficacy of chemotherapy. In addition, a single treatment modality or one death pathway reduces the antitumor outcome. Herein, tumor-targeting O2 self-supplied nanomodules (CuS@DOX/CaO2-HA) are proposed that not only alleviate tumor microenvironmental hypoxia to promote the accumulation of chemotherapeutic drugs in tumors but also exert photothermal effects to boost drug release, penetration and combination therapy. CuS@DOX/CaO2-HA consists of copper sulfide (CuS)-loaded calcium peroxide (CaO2) and doxorubicin (DOX), and its surface is further modified with HA. CuS@DOX/CaO2-HA underwent photothermal treatment to release DOX and CaO2. Hyperthermia accelerates drug penetration to enhance chemotherapeutic efficacy. The exposed CaO2 reacts with water to produce Ca2+, H2O2 and O2, which sensitizes cells to chemotherapy through mitochondrial damage caused by calcium overload and a reduction in drug efflux via the alleviation of hypoxia. Moreover, under near infrared (NIR) irradiation, CuS@DOX/CaO2-HA initiates a pyroptosis-like cell death process in addition to apoptosis. In vivo, CuS@DOX/CaO2-HA demonstrated high-performance antitumor effects. This study provides a new strategy for synergistic enhancement of chemotherapy in hypoxic tumor therapy via combination therapy and multiple death pathways.

The construction of hierarchical assemblies with in situ generation of chemotherapy drugs to enhance the efficacy of chemodynamic therapy for multi-modal anti-tumor treatments.

The effectiveness of chemodynamic therapy (CDT) in cancer treatment is limited by insufficient endogenous H2O2 levels in tumor tissue and an increasing ratio of high valence metal ions. To overcome these challenges, a novel nanotherapeutic approach, named GOx-CuCaP-DSF, has been proposed. This approach involves the design of nanotherapeutics that aim to self-supply H2O2 within cancer cells and provide a supplement of low valence metal ions to enhance the performance of CDT. GOx-CuCaP-DSF nanotherapeutics are engineered by incorporating glucose oxidase (GOx) into Ca2+-doped calcium phosphate (CaP) nanoparticles and loading disulfiram (DSF) through surface adsorption. Under the tumor microenvironment, GOx catalyzes the conversion of tumor-overexpressed glucose (Glu) to liberate H2O2. The degradation of CaP further lowers the pH, facilitating the release of Cu2+ ions and DSF. The rapid reaction between Cu2+ and DSF leads to the generation of Cu+, increasing the Cu+/Cu2+ ratio and promoting the Cu+-based Fenton reaction, which enhances the efficiency of CDT. Simultaneously, DSF undergoes conversion to diethyldithiocarbamate acid (ET), forming a copper(II) complex (Cu(II)ET) by strong chelation with Cu ions. This Cu(II)ET complex, a potent chemotherapeutic drug, exhibits a synergistic therapeutic effect in combination with CDT. Moreover, the elevated Cu+ species resulting from DSF reaction promotes the aggregation of toxic mitochondrial proteins, leading to cell cuproptosis. Overall, the strategy of integrating the chemodynamic therapy efficiency of the Fenton reaction with the activation of efficacious cuproptosis using a chemotherapeutic drug presents a promising avenue for enhancing the effectiveness of multi-modal anti-tumor treatments.

Correlation between thyroid function indices and urine iodine levels in patients with nodular goiter.

OBJECTIVE: To retrospectively analyze the iodine nutritional status in patients with nodular goiter (NG) and investigate a possible association between urinary iodine levels and thyroid function indices. METHODS: A total of 173 patients diagnosed with nodular goiter in the Fourth Hospital of Hebei Medical University from January 2019 to May 2021 were selected as the NG group, and 172 healthy individuals without thyroid diseases were selected after a physical examination as a control group. The data of all the participants were retrospectively assessed to explore the association between urinary iodine levels and thyroid function indices. The content of urinary iodine in the two groups was compared, and the correlation of urinary iodine levels with thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) in the NG group was evaluated. RESULTS: The level of urinary iodine in the NG group was 163.97 ± 113.75 µg/L, which was higher than 121.47 ± 53.75 µg/L in the control group (P < 0.05). The iodine excess rate in females was higher than that in males (P < 0.05). The results of Pearson correlation analysis showed that the amount of urinary iodine in patients with hyperthyroidism with different urinary iodine statuses was negatively correlated with the level of TSH and positively correlated with levels of FT3 and FT4. CONCLUSION: There is a significant association between urinary iodine levels and thyroid hormone levels in NG patients. Therefore, regular monitoring of urinary iodine levels is essential for the appropriate use of iodine supplementation.

Multisubcellular organelle-targeting nanoparticle for synergistic chemotherapy and photodynamic/photothermal tumor therapy.

Background: The subcellular organelle-targeting strategy has attracted wide attention for a variety of reasons, including strong specificity, high accuracy, low dose administration and few side effects. It is an important and challenging task to explore the multisubcellular organelle-targeting strategy to achieve effective tumor treatment. Materials & methods: Using bovine serum albumin as a nanoreactor, BSA/Cu/NQ/IR780/DOX nanoparticles (NPs) were constructed via drug-induced protein self-assembly. Folic acid was then coupled to the surface of NPs to prepare folate receptor-targeted FA-BSA/Cu/NQ/IR780/DOX NPs. Results & conclusion: The FA-BSA/Cu/NQ/IR780/DOX NPs exhibit multifunctional properties, including multisubcellular organelle-targeting, induction of response release in the tumor microenvironment, fluorescence imaging capabilities and potential for synergistic chemotherapy and photodynamic/photothermal tumor therapy.

The subcellular organelle-targeting strategy has attracted wide attention for a variety of reasons, including strong specificity, high accuracy, low dose administration and few side effects. Previous research has been mostly restricted to one or two subcellular organelle therapies. Despite promising results, the impact of these studies is limited by the hostile conditions of lysosomes, drug efflux facilitated by P-glycoprotein (P-gp), and the expression of antiapoptotic factors, all of which undermine the effectiveness of the treatments. Therefore, it is an important and challenging task to explore the multisubcellular organelle-targeting strategy to achieve effective tumor treatment. Herein, a versatile nanoparticle was designed and constructed to target multiple subcellular organelles, respond to stimuli in the tumor microenvironment, enable fluorescence imaging and facilitate synergistic chemotherapy and photodynamic/photothermal tumor therapy.

Combined effect of heat shock protein inhibitor geldanamycin and free radicals on photodynamic therapy of prostate cancer.

Prostate cancer is the most common malignancy and the second leading cause of cancer-induced death among men. Recently, photodynamic therapy (PDT) has attracted great attention in prostate cancer treatment because of its high accuracy and no trauma. However, the hypoxic microenvironment of the tumor severely reduces the therapeutic efficacy of oxygen-dependent PDT in prostate cancer, which hampers the generation of reactive oxygen species (ROS). In addition, the PDT process induces the overexpression of pro-survival and anti-apoptotic proteins, thereby reducing the efficacy of PDT. This study proposed a novel multifunctional nanosystem for the targeted delivery of indocyanine green (ICG), 2,2'-azobis[2-(2-imidazolinI-2-yl) propane] dihydrochloride (AIBI), and heat shock protein 90 (Hsp90) inhibitor geldanamycin (17-AAG). Under near-infrared light irradiation, the photothermal effect of ICG induces AIBI decomposition and releases oxygen-independent free radicals, which rescues the hindered ICG-mediated ROS generation. Moreover, 17-AAG reduces heat resistance by inhibiting Hsp90, thereby achieving mild hyperthermia. Simultaneously, the inhibition of Hsp90 can inhibit the overexpression of its client proteins such as anti-apoptotic proteins (survivin) and androgen receptor (AR), thereby improving the efficacy of PDT and inducing prostate cancer cell apoptosis. Results show that the nanosystem enhances PDT by combining free radicals and 17-AAG, exhibiting a good anticancer effect on prostate cancer cells but less toxicity on normal cells.

Assembly of multifunction dyes and heat shock protein 90 inhibitor coupled to bovine serum albumin in nanoparticles for multimodal photodynamic/photothermal/chemo-therapy.

The proangiogenic protein, survivin, is a client protein for heat shock protein 90 (Hsp-90), whose overexpression is induced by photodynamic therapy (PDT), leading to the inhibition of capase-9 and the blockage of apoptosis. The overexpression of Hsp-90 in cancer cells can rapidly acquire thermoresistance during photothermal therapy (PTT), leading to insufficient apoptosis, increased cell viability, and tumor recurrence. A potential approach to block the PTT-induced overexpression of Hsp-90 and the overexpression of survivin is developed by using an Hsp-90 inhibitor and anticancer agent, namely, geldanamycin (GM). These inhibitors also develop a mild-temperature PTT strategy to reach synergistic PDT and PTT efficiency. Thus, Cy7-SQ is designed by a covalent disulfide linkage between a photothermal agent (i.e., canine dye 7 [Cy7]) and a photosensitizer (i.e., squaraine dye [SQ]) for the improved photostability and thermal stability of Cy7 and SQ. The cleavage of the Cy7-SQ linkage by glutathione in a tumor microenvironment increases the efficiency of synergistic PDT and PTT. In the current study, bovine serum albumin (BSA)/Cy7-SQ/GM nanoparticles are developed through the self-assembly of BSA, Cy7-SQ, and GM to accelerate the apoptosis of cancer cells via near-infrared (NIR) laser irradiation, thus realizing Hsp-90-regulated synergistic PDT/PTT combined with chemotherapy.

Width-Consistent Mesoporous Silica Nanorods with a Precisely Controlled Aspect Ratio for Lysosome Dysfunctional Synergistic Chemotherapy/Photothermal Therapy/Starvation Therapy/Oxidative Therapy.

Although differently shaped mesoporous silica is widely studied, the formation of width-consistent mesoporous silica nanorods (MSNRs) with a precisely controlled aspect ratio (AR: length/width) is challenging and has not been reported. Herein, width-consistent (100 nm) MSNRs with ARs of 2, 3, 4, 6, 8, and 10 were obtained by increasing the concentrations while maintaining the molar ratio of cetyltrimethylammonium bromide (CTAB) and tetraethyl orthosilicate (TEOS). The results demonstrated that the as-prepared MSNR with an AR of 6 (AR6) possesses high cellular-uptake efficiency and drug-loading capacity. Thus, AR6-based cancer-cell-targeting nanosystems were designed. These nanosystems encapsulated doxorubicin (DOX) into the porous channel of AR6, adsorbed glucose oxidase (GOx), and then formed a polydopamine (PDA) layer for Siramesine (Siram, a lysosome dysfunctional drug) adsorption and folic acid modification. In this design, the PDA shell could prevent the leakage of loading components and keep the activity of GOx during delivery while achieving an on-demand drug release in the targeted location and photothermal therapy under near-infrared irradiation. The increase in temperature was highly beneficial for elevating the catalytic efficiency of GOx, accelerating the consumption of intracellular glucose, and generating a relatively high level of cytotoxic H2O2, all of which enhanced starvation and oxidative therapies. Siram was employed to inhibit lysosomal metabolism and accompany GOx to reach a dual-enhanced starvation therapy effect. In addition, DOX entered the nucleus and altered DNA for chemotherapy. The results showed that the nanosystems have superior therapeutic efficacy against cancer cells and not much toxicity to normal cells. Therefore, this study provides a novel strategy for lysosome dysfunctional synergistic chemotherapy/photothermal therapy/starvation therapy/oxidative therapy based on MSNR.