Artificial Assembled Macrophage Co-Deliver Black Phosphorus Quantum Dot and CDK4/6 Inhibitor for Colorectal Cancer Triple-Therapy.

In recent years, therapeutic strategies based on macrophages have been inspiringly developed, but due to the high intricacy and immunosuppression of the tumor microenvironment, the widespread use of these strategies still faces significant challenges. Herein, an artificial assembled macrophage concept (AB@LM) was presented to imitate the main antitumor abilities of macrophages of tumor targeting, promoting the antitumor immunity, and direct tumor-killing effects. The artificial assembled macrophage (AB@LM) was prepared through an extrusion method, which is to fuse the macrophage membrane with abemaciclib and black phosphorus quantum dot (BPQD)-loaded liposomes. AB@LM showed good stability and tumor targeting ability with the help of macrophage membrane. Furthermore, AB@LM reversed the immunosuppressive tumor microenvironment by inhibiting regulatory T cells (Tregs) and stimulating the maturation of antigen-presenting cells to activate the antitumor immune response through triggering an immunogenic cell death effect. More importantly, in the colorectal tumor model in vivo, a strong cooperative therapeutic effect of photo/chemo/immunotherapy was observed with high tumor inhibition rate (95.3 ± 2.05%). In conclusion, AB@LM exhibits excellent antitumor efficacy by intelligently mimicking the abilities of macrophages. A promising therapeutic strategy for tumor treatment based on imitating macrophages was provided in this study.

Self-assembly of paramagnetic amphiphilic copolymers for synergistic therapy.

Engineering nanoparticles (NPs) with multifunctionality has become a promising strategy for cancer theranostics. Herein, theranostic polymer NPs are fabricated via the assembly of amphiphilic paramagnetic block copolymers (PCL-b-PIEtMn), in which IR-780 and doxorubicin (DOX) were co-encapsulated, for magnetic resonance (MR) and near infrared fluorescence (NIRF) imaging as well as for photo thermal therapy (PTT)-enhanced chemotherapy. The synthesized amphiphilic paramagnetic block copolymers demonstrated high relaxivity (r1 = 7.05 mM-1 s-1). The encapsulated DOX could be released with the trigger of near infrared (NIR) light. In vivo imaging confirmed that the paramagnetic NPs could be accumulated effectively at the tumor sites. Upon the NIR laser irradiation, tumor growth was inhibited by PTT-enhanced chemotherapy. The advantages of the reported system lie in the one-step convergence of multiple functions (i.e., imaging and therapy agents) into a one delivery vehicle and the dual mode imaging-guided synergistic PTT and chemotherapy. This study represents a new drug delivery vehicle of paramagnetic NPs for visualized theranostics.

Promoting Early Diagnosis and Precise Therapy of Hepatocellular Carcinoma by Glypican-3-Targeted Synergistic Chemo-Photothermal Theranostics.

The specific-targeting approach could promote the specificity of diagnosis and the accuracy of cancer treatment. The choice of a specific-targeting receptor is the key step in this approach. Glypican-3 (GPC3) is an oncofetal proteoglycan anchored on the cell membrane. It is overexpressed even in the early stage of hepatocellular carcinoma (HCC), whereas it shows almost no expression in the healthy adult liver. Therefore, GPC3 may be applied as a specific-targeting receptor for HCC theranostics. In this study, a GPC3 specific-targeting theranostics nanodevice, GPC3 targeting peptide (named G12)-modified liposomes co-loaded with sorafenib (SF) and IR780 iodide (IR780), was developed (GSI-Lip), which aims to realize early diagnosis and precise chemo-photothermal therapy of HCC. SF was the first-line chemotherapy drug for the treatment of HCC. IR780 was used for photothermal therapy and near-infrared fluorescence imaging. The evaluation of early diagnosis verified that early-stage tumors (3.45 ± 0.98 mm3, 2 days after 5 × 105 H22 cells' inoculation in mice) could be clearly detected using GSI-Lip, which was significantly more sensitive than folic acid-modified liposomes ( p < 0.01, 32.90 ± 10.01 mm3, 4 days after 1 × 106 H22 cells' inoculation in mice). The study of the endocytic pathway indicated that specific G12/GPC3 recognition may induce caveolae-mediated endocytosis of GSI-Lip. Notably, the accumulation of GSI-Lip in tumors was significantly increased compared with that observed with folic acid-modified liposomes ( p < 0.01). Specific-targeting endowed the precise antitumor effect of GSI-Lip. GSI-Lip showed a higher antitumor efficacy in comparison with folic acid-modified liposomes (inhibition rate: 90.52% vs 84.22%, respectively; p < 0.01). During a period of 21 days, the synergistic chemo-photothermal therapy (GSI-Lip + laser) exhibited a better antitumor effect versus GSI-Lip without laser (inhibition rate: 94.93% vs 90.52%, respectively; p < 0.01). Overall, GPC3-targeted GSI-Lip promoted the sensitivity and specificity of HCC early diagnosis and achieved synergistic efficacy of chemo-photothermal theranostics, which has potential clinical applications. Furthermore, the present study revealed that a more specific-targeting ligand could further improve the efficacy of theranostics against HCC.

Preparation and evaluation of etoposide-loaded lipid-based nanosuspensions for high-dose treatment of lymphoma.

Aim: High-dose administration of etoposide (VP16) was limited by its poor aqueous solubility and severe systemic toxicity on lymphoma therapy. Herein, a novel VP16-loaded lipid-based nanosuspensions (VP16-LNS) was developed for improving drug solubility, enhancing antitumor effect and reducing systemic toxicity. Materials & methods: VP16-LNS with soya lecithin and D-α-tocopheryl PEG 1000 succinate (TPGS) as stabilizers were prepared by nanoprecipitation method. Results: VP16-LNS exhibited uniform spherical morphology, small particle size and favorable colloidal stability. The concentration of VP16 in VP16-LNS was high enough (1017.67 µg/ml) for high-dose therapy on lymphoma. Moreover, VP16-LNS displayed long blood circulation time, selective intratumoral accumulation, remarkable antitumor effect and upregulated safety. Conclusion: VP16-LNS would be an efficient nanoformulation for clinical intravenous application against lymphoma.

Selenium Plays a Protective Role in Staphylococcus aureus-Induced Endometritis in the Uterine Tissue of Rats.

The essential trace element selenium (Se) modulates the functions of many regulatory proteins in signal transduction, conferring benefits in inflammatory diseases. Endometritis is a reproductive obstacle disease both in humans and animals. Staphylococcus aureus is the major pathogen that causes endometritis. The present study analyzes the protection and mechanism of Se-methylselenocysteine (MSC) and methylseleninic acid (MSA) on S. aureus-induced endometritis. An atomic fluorescence spectrophotometry study showed that the uterine Se content increased with the addition of MSC and MSA. Histopathology observation and TUNEL detection showed that Se supplementation displayed a greater defense against uterine inflammatory damage. The quantitative PCR (qPCR) and ELISA analyses showed that the expressions of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) increased with S. aureus infection and decreased with the addition of MSC and MSA. The Toll-like receptor 2 (TLR2) expression showed the same status as the inflammatory cytokines. The Western blot results showed that the increased phosphorylation of IκBα and NF-κB p65 was also reduced by the addition of MSC and MSA. The qPCR and Western blot results also showed that the transcription expressions and the protein dissociation of caspase-9, caspase-3, caspase-7, caspase-6, and poly(ADP-ribose) polymerase (PARP), which were increased by S. aureus infection, were inhibited by Se supplementation. All of the results displayed that the protection conferred by MSC was stronger than MSA. The present study indicated the Se supplementation might be a potential prevention and control measure for S. aureus-induced endometritis.

Selenium Induces an Anti-tumor Effect Via Inhibiting Intratumoral Angiogenesis in a Mouse Model of Transplanted Canine Mammary Tumor Cells.

Selenium (Se) has been widely reported to possess anti-tumor effects. Angiogenesis is the formation of new blood vessels and is required to supply oxygen, nutrients, and growth factors for tumor growth, progression, and metastasis. To explore whether the anti-tumor effect of Se was associated with angiogenesis in vivo, we studied the effects of sodium selenite (Sel) and methylseleninic acid (MSA) on tumors induced by canine mammary tumor cells (CMT1211) in mice; cyclophosphamide (CTX) served as a positive control. The results showed that the Se content was significantly increased in the Sel and MSA groups. Se significantly inhibited the tumor weights and volumes. Large necrotic areas and scattered and abnormal small necrotic areas were observed in the Se treatment group. Immunofluorescence double staining showed a reduction in the microvessel density (MVD) and increment in the vessel maturation index (VMI) compared with the untreated control group. As expected, the protein and mRNA levels of the angiogenesis factors angiopoietin-2 (Ang-2), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) were decreased in the Se-treated tumors by IHC, as shown by western blotting and RT-QPCR. We also found that organic Se MSA provided stronger inhibition of tumor growth compared with inorganic sodium selenite (Sel). Altogether, our results indicated that Se exerted anti-tumor effects in vivo at least partially by inhibiting angiogenic factors.

Knowledge and perceptions of sexual and reproductive health and HIV among perinatally HIV-infected adolescents in rural China.

Due to the success of highly active antiretroviral therapy, more children infected with HIV perinatally are living to adolescence. This brings new challenges on sexual and reproductive health (SRH) needs and psychosocial support specific to adolescents. To improve such efforts on long-term care of this vulnerable population, we assessed SRH and HIV knowledge and perceptions among perinatally HIV-infected adolescents (PHIVA). This descriptive cross-sectional study was conducted between July and September 2013 in a rural HIV clinic. A structured questionnaire focusing on SRH and HIV was administered to 124 PHIVA attending quarterly medical visit. Multivariable logistic regression was used to detect associated factors with knowledge acquisition. Among participants, 79% had never discussed puberty development or sexuality with parents. Over 50% had never heard of condoms and 20% reported not having any informational source of SRH and HIV knowledge. Only 5% correctly answered all questions regarding HIV knowledge and pregnancy, with 18% correctly answered questions regarding contraception. Adolescents older than age of 15 and who had been disclosed of HIV status were more likely to acquire correct knowledge of SRH and HIV. Most PHIVA did not report having access to comprehensive information on SRH and HIV, in part because of the early death of caretakers or unfavorable family status. Further integration of SRH services with HIV treatment programs is needed to provide comprehensive care for adolescents and prepare them for the transition to adult care.