Nanodiamond-based multifunctional platform for oral chemo-photothermal combinational therapy of orthotopic colon cancer.

Combination therapy system has become a promising strategy for achieving favorable antitumor efficacy. Herein, a novel oral drug delivery system with colon localization and tumor targeting functions was designed for orthotopic colon cancer chemotherapy and photothermal combinational therapy. The polydopamine coated nanodiamond (PND) was used as the photothermal carrier, through the coupling of sulfhydryl-polyethylene glycol-folate (SH-PEG-FA) on the surface of PND to achieve systematic colon tumor targeting, curcumin (CUR) was loaded as the model drug, and then coated with chitosan (CS) to achieve the long gastrointestinal tract retention and colon localization functions to obtain PND-PEG-FA/CUR@CS nanoparticles. It has high photothermal conversion efficiency and good photothermal stability and exhibited near-infrared (NIR) laser-responsive drug release behavior. Folate (FA) modification effectively promotes the intracellular uptake of nanoparticles by CT26 cells, and the combination of chemotherapy and photothermal therapy (CT/PTT) can enhance cytotoxicity. Compared with free CUR group, nanoparticles prolonged the gastrointestinal tract retention time, accumulated more in colon tumor tissues, and exhibited good photothermal effect in vivo. More importantly, the CT/PTT group exhibited satisfactory tumor growth inhibition effects with good biocompatibility in vivo. In summary, this oral drug delivery system is an efficient platform for chemotherapy and photothermal combinational therapy of orthotopic colon cancer.

Ultrasound-Enhanced Reactive Oxygen Species Responsive Charge-Reversal Polymeric Nanocarriers for Efficient Pancreatic Cancer Gene Delivery.

Inefficient intracellular gene release and transfection limit nonviral gene delivery applications in cancer therapy. Reactive oxygen species (ROS) responsive nonviral gene delivery is the most widely explored strategy for such applications, yet the development of fast and safe ROS responsive nanocarriers proves to be a challenge because of the intracellular chemical equilibrium of high ROS and glutathione levels. Here, we report an ultrasound-enhanced ROS responsive charge-reversal polymeric nanocarrier (BTIL) for fast and efficient pancreatic cancer gene delivery. The BTIL is composed of B-PDEAEA/DNA polyplex-based cores and IR780-loaded liposome coatings. The IR780 is able to produce an excess of ROS under low intensity ultrasound irradiation, thus disequilibrating the chemical equilibrium of ROS and glutathione, and promoting the ROS-responsive positive-to-negative charge-reversal of the B-PDEAEA polymer. This charge conversion results in fast polyplex dissociation and intracellular gene release, inducing efficient gene transfection and cancer cell apoptosis. Moreover, following the intravenous administration, BTIL maintains a stable and long circulation in the bloodstream, achieves orthotopic pancreatic ductal adenocarcinoma distribution, and exhibits potent antitumor activity with negligible side effects. Our results reveal the proposed strategy to be both promising and universal for the development of fast and safe ROS responsive nonviral gene delivery in cancer therapy.

Clinical Studies Reporting on Vascular Graft Coatings for the Prevention of Aortic Graft Infection: A Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this study was to investigate the efficacy of vascular graft coatings used in the aortic position to prevent vascular graft infection (VGI). METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines using a pre-registered protocol (CRD42020206436). Eligible studies used a vascular graft coating in the aortic position and reported on VGI. A search was performed in MEDLINE (PubMed), Embase, Web of Science, and the Cochrane Library. Primary outcome parameters were VGI, patency, and mortality. Pooled estimates of VGI were calculated using odds ratio (OR) and 95% confidence intervals (CIs) wherever possible. Quality assessment was performed with the Newcastle-Ottawa Assessment Scale and the Revised Cochrane risk of bias tool for randomised trials. RESULTS: In total, 6 873 papers were identified. Only eight studies were included. Six of eight studies (75%) reported on known antimicrobial coating strategies such as antibiotics (n = 3) and silver (n = 3). In the other two studies, polymer coated grafts were used. Only three of eight studies compared coated with uncoated grafts (two antibiotic and one silver). Two randomised controlled trials reported on the effect of rifampicin soaked (1 mg/mL) grafts and showed no significant effect in the early (2 months; OR 0.69, 95% CI 0.29 - 1.62) or late (2 years; OR 0.73, 95% CI 0.23 - 2.32) post-operative periods. A retrospective cohort study focusing on the effect of silver coated grafts did not reveal any advantage (OR 0.19, 95% CI 0.02 - 1.64). Two polymer coated grafts were not considered to have a potential benefit in the prevention of VGIs. CONCLUSION: Clinical studies reporting on the antibacterial effect of vascular graft coatings in the aortic position to prevent VGI are scarce. For silver and antibiotic coatings, no significant protection for VGI was observed. New types of grafts or long acting coating strategies are mandatory to prevent this complication in the future.

Scaffold 3D-Printed from Metallic Nanoparticles-Containing Ink Simultaneously Eradicates Tumor and Repairs Tumor-Associated Bone Defects.

Bone metastasis occurs in about 70% of breast cancer patients. The surgical resection of metastatic tumors often leads to bone erosion and destruction, which greatly hinders the treatment and prognosis of breast cancer patients with bone metastasis. Herein, a bifunctional scaffold 3D-printed from nanoink is fabricated to simultaneously eliminate the tumor cells and repair the tumor-associated bone defects. The metallic polydopamine (PDA) nanoparticles (FeMg-NPs) may effectively load and sustainably release the metal ions Fe3+ and Mg2+ in situ. Fe3+ exerts a chemodynamic therapy to synergize with the photothermal therapy induced by PDA with effective photothermal conversion under NIR laser, which efficiently eliminates the bone-metastatic tumor. Meanwhile, the sustained release of osteoinductive Mg2+ from the bony porous 3D scaffold enhances the new bone formation in the bone defects. Taken together, the implantation of scaffold (FeMg-SC) 3D-printed from the FeMg-NPs-containing nanoink provides a novel strategy to simultaneously eradicate bone-metastatic tumor and repair the tumor-associated bone defects.

Polymeric long-acting drug delivery systems (LADDS) for treatment of chronic diseases: Inserts, patches, wafers, and implants.

Non-oral long-acting drug delivery systems (LADDS) encompass a range of technologies for precisely delivering drug molecules into target tissues either through the systemic circulation or via localized injections for treating chronic diseases like diabetes, cancer, and brain disorders as well as for age-related eye diseases. LADDS have been shown to prolong drug release from 24 h up to 3 years depending on characteristics of the drug and delivery system. LADDS can offer potentially safer, more effective, and patient friendly treatment options compared to more invasive modes of drug administration such as repeated injections or minor surgical intervention. Whilst there is no single technology or definition that can comprehensively embrace LADDS; for the purposes of this review, these systems include solid implants, inserts, transdermal patches, wafers and in situ forming delivery systems. This review covers common chronic illnesses, where candidate drugs have been incorporated into LADDS, examples of marketed long-acting pharmaceuticals, as well as newly emerging technologies, used in the fabrication of LADDS.

[Design of Synthetic Polymer Nanoparticles That Capture and Neutralize Target Molecules].

Protein affinity reagents that specifically and strongly bind to target molecules are widely used in disease detection, diagnosis, and therapy. Although antibodies and their fragments are the gold standard in protein-protein inhibitors (PPIs), synthetic polymers such as linear polymers, dendrimers, and nanoparticles as cost-effective PPIs have attracted great attention as alternatives to antibodies. These polymers exhibit high affinity to the target by imitating natural protein-protein interactions. However, only a few in vivo applications have been reported. Here, our recent advances in the development of synthetic polymers for in vivo application are reviewed. Poly(N-isopropylacrylamide) (pNIPAm) was used as a model of synthetic affinity reagents. Incorporation of both sulfated carbohydrate and hydrophobic monomers into lightly crosslinked pNIPAm nanoparticles (NPs) captured and neutralized vascular endothelial growth factor (VEGF) and inhibited tumor growth upon intravenous injection into tumor-bearing mice. Modification of a liposome with the pNIPAm-based linear polymer increased the polymer circulation time after intravenous injection and improved the affinity for the target. The pNIPAm-based NPs delivered by oral administration captured the target small molecules and inhibited their absorption from the intestine. Our recent findings provide useful information for the design of synthetic polymers that capture target molecules in vivo.

Co-Delivery of Doxorubicin and Chloroquine by Polyglycerol Functionalized MoS2 Nanosheets for Efficient Multidrug-Resistant Cancer Therapy.

2D MoS2 has shown a great potential in biomedical applications, due to its superior loading capacity, photothermal property, and biodegradation. In this work, polyglycerol functionalized MoS2 nanosheets with photothermal and pH dual-stimuli responsive properties are used for the co-delivery of doxorubicin and chloroquine and treatment of multidrug-resistant HeLa (HeLa-R) cells. The polyglycerol functionalized MoS2 nanosheets with 80 nm average size show a high biocompatibility and loading efficiency (≈90%) for both drugs. The release of drugs from the nanosheets at pH 5.5 is significantly promoted by laser irradiation leading to efficient destruction of incubated HeLa-R cells. In vitro evaluation shows that the designed nanoplatform has a high ability to kill HeLa-R cells. Confocal experiments demonstrate that the synthesized drug delivery system enhances the cellular uptake of DOX via folic acid targeting ligand. Taking advantage of the combined properties including biocompatibility and targeting ability as well as high loading capacity and photothermal release, this multifunctional nanosystem is a promising candidate for anticancer therapy.

Therapeutic delivery of siRNA with polymeric carriers to down-regulate STAT5A expression in high-risk B-cell acute lymphoblastic leukemia (B-ALL).

Overexpression and persistent activation of STAT5 play an important role in the development and progression of acute lymphoblastic leukemia (ALL), the most common pediatric cancer. Small interfering RNA (siRNA)-mediated downregulation of STAT5 represents a promising therapeutic approach for ALL to overcome the limitations of current treatment modalities such as high relapse rates and poor prognosis. However, to effectively transport siRNA molecules to target cells, development of potent carriers is of utmost importance to surpass hurdles of delivery. In this study, we investigated the use of lipopolymers as non-viral delivery systems derived from low molecular weight polyethylenimines (PEI) substituted with lauric acid (Lau), linoleic acid (LA) and stearic acid (StA) to deliver siRNA molecules to ALL cell lines and primary samples. Among the lipid-substituted polymers explored, Lau- and LA-substituted PEI displayed excellent siRNA delivery to SUP-B15 and RS4;11 cells. STAT5A gene expression was downregulated (36-92%) in SUP-B15 and (32%) in RS4;11 cells using the polymeric delivery systems, which consequently reduced cell growth and inhibited the formation of colonies in ALL cells. With regard to ALL primary cells, siRNA-mediated STAT5A gene silencing was observed in four of eight patient cells using our leading polymeric delivery system, 1.2PEI-Lau8, accompanied by the significant reduction in colony formation in three of eight patients. In both BCR-ABL positive and negative groups, three of five patients demonstrated marked cell growth inhibition in both MTT and trypan blue exclusion assays using 1.2PEI-Lau8/siRNA complexes in comparison with their control siRNA groups. Three patient samples did not show any positive results with our delivery systems. Differential therapeutic responses to siRNA therapy observed in different patients could result from variable genetic profiles and patient-to-patient variability in delivery. This study supports the potential of siRNA therapy and the designed lipopolymers as a delivery system in ALL therapy.

Stromal interaction molecule 1 (STIM1) knock down attenuates invasion and proliferation and enhances the expression of thyroid-specific proteins in human follicular thyroid cancer cells.

Stromal interaction molecule 1 (STIM1) and the ORAI1 calcium channel mediate store-operated calcium entry (SOCE) and regulate a multitude of cellular functions. The identity and function of these proteins in thyroid cancer remain elusive. We show that STIM1 and ORAI1 expression is elevated in thyroid cancer cell lines, compared to primary thyroid cells. Knock-down of STIM1 or ORAI1 attenuated SOCE, reduced invasion, and the expression of promigratory sphingosine 1-phosphate and vascular endothelial growth factor-2 receptors in thyroid cancer ML-1 cells. Cell proliferation was attenuated in these knock-down cells due to increased G1 phase of the cell cycle and enhanced expression of cyclin-dependent kinase inhibitory proteins p21 and p27. STIM1 protein was upregulated in thyroid cancer tissue, compared to normal tissue. Downregulation of STIM1 restored expression of thyroid stimulating hormone receptor, thyroid specific proteins and increased iodine uptake. STIM1 knockdown ML-1 cells were more susceptible to chemotherapeutic drugs, and significantly reduced tumor growth in Zebrafish. Furthermore, STIM1-siRNA-loaded mesoporous polydopamine nanoparticles attenuated invasion and proliferation of ML-1 cells. Taken together, our data suggest that STIM1 is a potential diagnostic and therapeutic target for treatment of thyroid cancer.

Injectable non-leaching tissue-mimetic bottlebrush elastomers as an advanced platform for reconstructive surgery.

Current materials used in biomedical devices do not match tissue's mechanical properties and leach various chemicals into the body. These deficiencies pose significant health risks that are further exacerbated by invasive implantation procedures. Herein, we leverage the brush-like polymer architecture to design and administer minimally invasive injectable elastomers that cure in vivo into leachable-free implants with mechanical properties matching the surrounding tissue. This strategy allows tuning curing time from minutes to hours, which empowers a broad range of biomedical applications from rapid wound sealing to time-intensive reconstructive surgery. These injectable elastomers support in vitro cell proliferation, while also demonstrating in vivo implant integrity with a mild inflammatory response and minimal fibrotic encapsulation.

Development of CD133 Targeting Multi-Drug Polymer Micellar Nanoparticles for Glioblastoma - In Vitro Evaluation in Glioblastoma Stem Cells.

PURPOSE: Glioblastoma (GBM) is a malignant brain tumor with a poor long-term prognosis due to recurrence from highly resistant GBM cancer stem cells (CSCs), for which the current standard of treatment with temozolomide (TMZ) alone will unlikely produce a viable cure. In addition, CSCs regenerate rapidly and overexpress methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to resistance. The objective of this research was to apply the concepts of nanotechnology to develop a multi-drug therapy, TMZ and idasanutlin (RG7388, a potent mouse double minute 2 (MDM2) antagonist), loaded in functionalized nanoparticles (NPs) that target the GBM CSC subpopulation, reduce the cell viability and provide possibility of in vivo preclinical imaging. METHODS: Polymer-micellar NPs composed of poly(styrene-b-ethylene oxide) (PS-b-PEO) and poly(lactic-co-glycolic) acid (PLGA) were developed by a double emulsion technique loading TMZ and/or RG7388. The NPs were covalently bound to a 15-nucleotide base-pair CD133 aptamer to target the CD133 antigen expressed on the surfaces of GBM CSCs. For diagnostic functionality, the NPs were labelled with radiotracer Zirconium-89 (89Zr). RESULTS: NPs maintained size range less than 100 nm, a low negative charge and exhibited the ability to target and kill the CSC subpopulation when TMZ and RG7388 were used in combination. The targeting function of CD133 aptamer promoted killing in GBM CSCs providing impetus for further development of targeted nanosystems for localized therapy in future in vivo models. CONCLUSIONS: This work has provided a potential clinical application for targeting GBM CSCs with simultaneous diagnostic imaging.

Development of Polymeric Nanoparticles for Blood-Brain Barrier Transfer-Strategies and Challenges.

Neurological disorders such as Alzheimer's disease, stroke, and brain cancers are difficult to treat with current drugs as their delivery efficacy to the brain is severely hampered by the presence of the blood-brain barrier (BBB). Drug delivery systems have been extensively explored in recent decades aiming to circumvent this barrier. In particular, polymeric nanoparticles have shown enormous potentials owing to their unique properties, such as high tunability, ease of synthesis, and control over drug release profile. However, careful analysis of their performance in effective drug transport across the BBB should be performed using clinically relevant testing models. In this review, polymeric nanoparticle systems for drug delivery to the central nervous system are discussed with an emphasis on the effects of particle size, shape, and surface modifications on BBB penetration. Moreover, the authors critically analyze the current in vitro and in vivo models used to evaluate BBB penetration efficacy, including the latest developments in the BBB-on-a-chip models. Finally, the challenges and future perspectives for the development of polymeric nanoparticles to combat neurological disorders are discussed.

Formulation and Characterization of Microcapsules Encapsulating PC12 Cells as a Prospective Treatment Approach for Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurological disorder, associated with decreased dopamine levels in the brain. The goal of this study was to assess the potential of a regenerative medicine-based cell therapy approach to increase dopamine levels. In this study, we used rat adrenal pheochromocytoma (PC12) cells that can produce, store, and secrete dopamine. These cells were microencapsulated in the selectively permeable polymer membrane to protect them from immune responses. For fabrication of the microcapsules, we used a modified Buchi spray dryer B-190 that allows for fast manufacturing of microcapsules and is industrially scalable. Size optimization of the microcapsules was performed by systematically varying key parameters of the spraying device. The short- and long-term stabilities of the microcapsules were assessed. In the in vitro study, the cells were found viable for a period of 30 days. Selective permeability of the microcapsules was confirmed via dopamine release assay and micro BCA protein assay. We found that the microcapsules were permeable to the small molecules including dopamine and were impermeable to the large molecules like BSA. Thus, they can provide the protection to the encapsulated cells from the immune cells. Griess's assay confirmed the non-immunogenicity of the microcapsules. These results demonstrate the effective fabrication of microcapsules encapsulating cells using an industrially scalable device. The microcapsules were stable, and the cells were viable inside the microcapsules and were found to release dopamine. Thus, these microcapsules have the potential to serve as the alternative or complementary treatment approach for PD.

Assessment of the Potential for Veverimer Drug-Drug Interactions.

Veverimer is a polymer being developed as a potential treatment of metabolic acidosis in patients with chronic kidney disease. Veverimer selectively binds and removes hydrochloric acid from the gastrointestinal tract, resulting in an increase in serum bicarbonate. Veverimer is not systemically absorbed, so potential drug-drug interactions (DDIs) are limited to effects on the absorption of other oral drugs through binding to veverimer in the gastrointestinal tract or increases in gastric pH caused by veverimer binding to hydrochloric acid. In in vitro binding experiments using a panel of 16 test drugs, no positively charged, neutral, or zwitterionic drugs bound to veverimer. Three negatively charged drugs (furosemide, aspirin, ethacrynic acid) bound to veverimer; however, this binding was reduced or eliminated in the presence of normal physiologic concentrations (100-170 mM) of chloride. Veverimer increased gastric pH in vivo by 1.5-3 pH units. This pH elevation peaked within 1 hour and had returned to baseline after 1.5-3 hours. Omeprazole did not alter the effect of veverimer on gastric pH. The clinical relevance of in vitro binding and the transient increase in gastric pH was evaluated in human DDI studies using two drugs with the most binding to veverimer (furosemide, aspirin) and two additional drugs with pH-dependent solubility effecting absorption (dabigatran, warfarin). None of the four drugs showed clinically meaningful DDI with veverimer in human studies. Based on the physicochemical characteristics of veverimer and results from in vitro and human studies, veverimer is unlikely to have significant DDIs. SIGNIFICANCE STATEMENT: Patients with chronic kidney disease, who are usually on many drugs, are vulnerable to drug-drug interactions (DDIs). The potential for DDIs with veverimer was evaluated based on the known site of action and physicochemical structure of the polymer, which restricts the compound to the gastrointestinal tract. Based on the findings from in vitro and human studies, we conclude that veverimer is unlikely to have clinically significant DDIs.

NIR responsive tumor vaccine in situ for photothermal ablation and chemotherapy to trigger robust antitumor immune responses.

BACKGROUND: Therapeutic tumor vaccine (TTV) that induces tumor-specific immunity has enormous potentials in tumor treatment, but high heterogeneity and poor immunogenicity of tumor seriously impair its clinical efficacy. Herein, a novel NIR responsive tumor vaccine in situ (HA-PDA@IQ/DOX HG) was prepared by integrating hyaluronic acid functionalized polydopamine nanoparticles (HA-PDA NPs) with immune adjuvants (Imiquimod, IQ) and doxorubicin (DOX) into thermal-sensitive hydrogel. RESULTS: HA-PDA@IQ NPs with high photothermal conversion efficiency (41.2%) and T1-relaxation efficiency were using HA as stabilizer by the one-pot oxidative polymerization. Then, HA-PDA@IQ loaded DOX via π-π stacking and mixed with thermal-sensitive hydrogel to form the HA-PDA@IQ/DOX HG. The hydrogel-confined delivery mode endowed HA-PDA@IQ/DOX NPs with multiple photothermal ablation performance once injection upon NIR irradiation due to the prolonged retention in tumor site. More importantly, this mode enabled HA-PDA@IQ/DOX NPs to promote the DC maturation, memory T cells in lymphatic node as well as cytotoxic T lymphocytes in spleen. CONCLUSION: Taken together, the HA-PDA@IQ/DOX HG could be served as a theranostic tumor vaccine for complete photothermal ablation to trigger robust antitumor immune responses.

Poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) Amphiphilic Copolymers for Long-Acting Injectables: Synthesis, Non-Acylating Performance and In Vivo Degradation.

This article presents the evaluation of diblock and triblock poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) amphiphilic copolymers (PEG-PTMCs) as excipients for the formulation of long-acting injectables (LAIs). Copolymers were successfully synthesised through bulk ring-opening polymerisation. The concomitant formation of PTMC homopolymer could not be avoided irrespective of the catalyst amount, but the by-product could easily be removed by gel chromatography. Pure PEG-PTMCs undergo faster erosion in vivo than their corresponding homopolymer. Furthermore, these copolymers show outstanding stability compared to their polyester analogues when formulated with amine-containing reactive drugs, which makes them particularly suitable as LAIs for the sustained release of drugs susceptible to acylation.

Topical microbicides for preventing sexually transmitted infections.

BACKGROUND: This is a updated version of our Cochrane Review published in Issue 6, 2012. Sexually-transmitted infections (STIs) continue to rise worldwide, imposing an enormous morbidity and mortality burden. Effective prevention strategies, including microbicides, are needed to achieve the goals of the World Heath Organization (WHO) global strategy for the prevention and control of these infections. OBJECTIVES: To determine the effectiveness and safety of topical microbicides for preventing acquisition of STIs, including HIV. SEARCH METHODS: We undertook a comprehensive search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, CLIB, Web of Science, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and reference lists of relevant articles up to August 2020. In addition, we contacted relevant organisations and experts. SELECTION CRITERIA: We included randomised controlled trials of vaginal microbicides compared to placebo (except for nonoxynol-9 because it is covered in related Cochrane Reviews). Eligible participants were sexually-active non-pregnant, WSM and MSM, who had no laboratory confirmed STIs. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and selected studies, extracted data, and assessed risks of bias in duplicate, resolving differences by consensus. We conducted a fixed-effect meta-analysis, stratified by type of microbicide, and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included eight trials from the earlier version of the review and four new trials, i.e. a total of 12 trials with 32,464 participants (all WSM). We did not find any eligible study that enrolled MSM or reported fungal STI as an outcome. We have no study awaiting assessment. All 12 trials were conducted in sub-Saharan Africa, with one having a study site in the USA, and another having a site in India. Vaginal microbicides tested were BufferGel and PRO 2000 (1 trial, 3101 women), Carraguard (1 trial, 6202 women), cellulose sulphate (2 trials, 3069 women), dapivirine (2 trials, 4588 women), PRO 2000 (1 trial, 9385 women), C31G (SAVVY) (2 trials, 4295 women), and tenofovir (3 trials, 4958 women). All microbicides were compared to placebo and all trials had low risk of bias. Dapivirine probably reduces the risk of acquiring HIV infection: risk ratio (RR) 0.71, (95% confidence interval (CI) 0.57 to 0.89, I2 = 0%, 2 trials, 4588 women; moderate-certainty evidence). The other microbicides may result in little to no difference in the risk of acquiring HIV (low-certainty evidence); including tenofovir (RR 0.83, 95% CI 0.68 to 1.02, cellulose sulphate (RR 1.20, 95% CI 0.74 to 1.95, BufferGel (RR 1.05, 95% CI 0.73 to 1.52), Carraguard (RR 0.89, 95% CI 0.71 to 1.11), PRO 2000 (RR 0.93, 95% CI 0.77 to 1.14), and SAVVY (RR 1.38, 95% CI 0.79 to 2.41). Existing evidence suggests that cellulose sulphate (RR 0.99, 95% CI 0.37 to 2.62, 1 trial, 1425 women), and PRO 2000 (RR 0.95, 95% CI 0.73 to 1.23) may result in little to no difference in the risk of getting herpes simplex virus type 2 infection (low-certainty evidence). Two studies reported data on tenofovir's effect on this virus. One suggested that tenofovir may reduce the risk (RR 0.55, 95% CI 0.36 to 0.82; 224 participants) while the other did not find evidence of an effect (RR 0.94, 95% CI 0.85 to 1.03; 1003 participants). We have not reported the pooled result because of substantial heterogeneity of effect between the two studies (l2 = 85%). The evidence also suggests that dapivirine (RR 1.70, 95% CI 0.63 to 4.59), tenofovir (RR 1.27, 95% CI 0.58 to 2.78), cellulose sulphate (RR 0.69, 95% CI 0.26 to 1.81), and (Carraguard (RR 1.07, 95% CI 0.75 to 1.52) may have little or no effect on the risk of acquiring syphilis (low-certainty evidence). In addition, dapivirine (RR 0.97, 95% CI 0.89 to 1.07), tenofovir (RR 0.90, 95% CI 0.71 to 1.13), cellulose sulphate (RR 0.70, 95% CI 0.49 to 0.99), BufferGel (RR 0.97, 95% CI 0.65 to 1.45), Carraguard (RR 0.96, 95% CI 0.83 to 1.12), and PRO 2000 (RR 1.01, 95% CI 0.84 to 1.22) may result in little to no difference in the risk of acquiring chlamydia infection (low-certainty evidence). The evidence also suggests that current topical microbicides may not have an effect on the risk of acquiring gonorrhoea, condyloma acuminatum, trichomoniasis, or human papillomavirus infection (low-certainty evidence). Microbicide use in the 12 trials, compared to placebo, did not lead to any difference in adverse event rates. No study reported on acceptability of the intervention.  AUTHORS' CONCLUSIONS: Current evidence shows that vaginal dapivirine microbicide probably reduces HIV acquisition in women who have sex with men. Other types of vaginal microbicides have not shown evidence of an effect on acquisition of STIs, including HIV. Further research should continue on the development and testing of new microbicides.

Supramolecular metal-based nanoparticles for drug delivery and cancer therapy.

Although conventional cancer therapies such as chemotherapy and radiotherapy prevail in clinic, they tend to have narrow therapeutic windows. Many chemotherapies have unfavorable pharmacokinetics while radiotherapy incurs radiotoxicity to normal tissues surrounding tumors. The chemical tunability of supramolecular metal-based nanoparticles (SMNPs) enables the incorporation of various therapeutics, including hydrophilic and hydrophobic chemotherapeutic drugs, photosensitizers, radiosensitizers, and biological therapeutics for more effective delivery to tumors. In this mini-review, we highlight recent advances in SMNPs, namely nanoscale coordination polymers and nanoscale metal-organic frameworks, for drug delivery and cancer therapy. We particularly focus on innovative uses of metal clusters, ligands, pores, and surface modifications to load various therapeutics into SMNPs and critical evaluations of the anticancer efficacies of SMNPs.

Biomineralized iron oxide-polydopamine hybrid nanodots for contrast-enhanced T1-weighted magnetic resonance imaging and photothermal tumor ablation.

Iron oxide nanoparticles (IO NPs) have become the focus of molecular imaging probes for contrast enhanced magnetic resonance (MR) imaging due to their intrinsic magnetic and biodegradable properties, as well as long blood half-lives and low toxicity. Massive efforts have been made to explore the IO NPs as T2-weighted MR contrast agents, which have high susceptibility to induce a long-range magnetic field that interferes with diagnosis. Thus, the development of IO NPs with potent T1 relaxivity might help in providing an alternative for clinically applied gadolinium chelates. Herein, biomineralized iron oxide-polydopamine hybrid nanodots (IO/PDA-NDs) have been constructed using albumin as the nanoreactors to induce nanoprecipitation and polymerization simultaneously, facilitating T1-weighted contrast-enhancement as well as photothermal therapeutic capability. The IO nanoclusters in IO/PDA-NDs have an r1 relaxivity of 5.79 mM-1 s-1 with a relatively low r2/r1 ratio of 1.71, demonstrating the preferable iron oxide based T1 contrast agents. The high photothermal conversion coefficient and tumor targeting effect of the hybrid nanodots could result in complete tumor ablation efficacy. The biomineralization method provides a promising approach for the integration of tumor diagnosis and treatment to achieve efficient cancer theranostics.

Prolonged activation of innate immune pathways by a polyvalent STING agonist.

The stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that is a target of therapeutics for infectious diseases and cancer. However, early-phase clinical trials of small-molecule STING agonists have shown limited antitumour efficacy and dose-limiting toxicity. Here, we show that a polyvalent STING agonist-a pH-sensitive polymer bearing a seven-membered ring with a tertiary amine (PC7A)-activates innate-immunity pathways through the polymer-induced formation of STING-PC7A condensates. In contrast to the natural STING ligand 2',3'-cyclic-GMP-AMP (cGAMP), PC7A stimulates the prolonged production of pro-inflammatory cytokines by binding to a non-competitive STING surface site that is distinct from the cGAMP binding pocket. PC7A induces antitumour responses that are dependent on STING expression and CD8+ T-cell activity, and the combination of PC7A and cGAMP led to synergistic therapeutic outcomes (including the activation of cGAMP-resistant STING variants) in mice bearing subcutaneous tumours and in resected human tumours and lymph nodes. The activation of the STING pathway through polymer-induced STING condensation may offer new therapeutic opportunities.