Synergistic Combination Therapy Research Articles

Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook.

Hepatocellular carcinoma (HCC) has emerged the culprit of cancer-related mortality worldwide with its dismal prognosis climbing. In recent years, ground-breaking progress has been made in systemic therapy for HCC. Targeted therapy based on specific signaling molecules, including sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab, has been widely used for advanced HCC (aHCC). Immunotherapies such as pembrolizumab and nivolumab greatly improve the survival of aHCC patients. More recently, synergistic combination therapy has boosted first-line (atezolizumab in combination with bevacizumab) and second-line (ipilimumab in combination with nivolumab) therapeutic modalities for aHCC. This review aims to summarize recent updates of systemic therapy relying on the biological mechanisms of HCC, particularly highlighting the approved agents for aHCC. Adjuvant and neoadjuvant therapy, as well as a combination with locoregional therapies (LRTs), are also discussed. Additionally, we describe the promising effect of traditional Chinese medicine (TCM) as systemic therapy on HCC. In this setting, the challenges and future directions of systemic therapy for HCC are also explored.

Image-guided drug delivery of nanotheranostics for targeted lung cancer therapy.

Enormous efforts have been made to integrate various therapeutic interventions into multifunctional nanoplatforms, resulting in the advance of nanomedicine. Image-guided drug delivery plays a pivotal role in this field by providing specific targeting as well as image navigation for disease prognosis.Methods: We demonstrate image-guided surgery and drug delivery for the treatment of lung cancer using nanotheranostic H-dots loaded with gefitinib and genistein.Results: The surgical margin for lung tumors is determined by image guidance for precise tumor resection, while targeted anti-cancer drugs function simultaneously for synergistic combination therapy. Compared to conventional chemotherapies, H-dot complexes could improve the therapeutic efficacy of drugs while reducing the risk of adverse effects and drug resistance owing to their ideal biodistribution profiles, high targetability, low nonspecific tissue uptake, and fast renal excretion.Conclusions: These H-dot complexes have unlocked a unique framework for integrating multiple therapeutic and diagnostic modalities into one nanoplatform.

Layered double hydroxides-silver-chlorin e6 nanocomposite for photo-chemo combination therapy to efficiently combat both Gram-positive and Gram-negative bacteria

Antibiotics play an important role in the treatment of infectious diseases. However, the growing threat of drug-resistant bacteria has limited the availability and effectiveness of antibiotics. Here, we introduced an antibiotic nanocomposite using biocompatible and biodegradable layered double hydroxides as a matrix, followed by covalent conjugation of a photosensitizer, chlorin e6 (Ce6), and in-situ doping of silver nanoparticles for synergistic photo-chemo combination therapy to effectively kill both Gram-positive and Gram-negative bacteria. This layered double hydroxides-silver-chlorin e6 nanocomposite could be potentially utilized for treating various bacterial infections and overcoming bacterial resistance.

Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney's Bacterial Loads upon Systemic Monotherapy.

We describe the design and attributes of a linear pentapeptide-like derivative (C14(ω5)OOc10O) screened for its ability to elicit bactericidal competences of plasma constituents against Gram-negative bacteria (GNB). In simpler culture media, the lipopeptide revealed high aptitudes to sensitize resilient GNB to hydrophobic and/or efflux-substrate antibiotics, whereas in their absence, C14(ω5)OOc10O only briefly delayed bacterial proliferation. Instead, at low micromolar concentrations, the lipopeptide has rapidly lowered bacterial proton and ATP levels, although significantly less than upon treatment with its bactericidal analog. Mechanistic studies support a two-step scenario providing a plausible explanation for the lipopeptide’s biological outcomes against GNB: initially, C14(ω5)OOc10O permeabilizes the outer membrane similarly to polymyxin B, albeit in a manner not necessitating as much LPS-binding affinity. Subsequently, C14(ω5)OOc10O would interact with the inner membrane gently yet intensively enough to restrain membrane-protein functions such as drug efflux and/or ATP generation, while averting the harsher inner membrane perturbations that mediate the fatal outcome associated with bactericidal peers. Preliminary in vivo studies where skin wound infections were introduced in mice, revealed a significant efficacy in affecting bacterial viability upon topical treatment with creams containing C14(ω5)OOc10O, whereas synergistic combination therapies were able to secure the pathogen’s eradication. Further, capitalizing on the finding that C14(ω5)OOc10O plasma-potentiating concentrations were attainable in mice blood at sub-maximal tolerated doses, we used a urinary tract infection model to acquire evidence for the lipopeptide’s systemic capacity to reduce the kidney’s bacterial loads. Collectively, the data establish the role of C14(ω5)OOc10O as a compelling antibacterial potentiator and suggest its drug-like potential.

A novel form of immunotherapy using antigen peptides conjugated on PD-L1 antibody

Immune checkpoint inhibitors (ICIs), including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 have shown promising cancer clinical outcomes. However, IC therapy has low patient response rates (10%–15%). Thus, ICIs and sufficient antigen combinations into the tumor microenvironment (TME) is important to produce strong tumor-specific adaptive immune responses. Mice were treated with cisplatin, and human cancer cells were exposed to inflammatory cytokines, to confirm increased PD-L1 and major histocompatibility complex (MHC) I expression by tumor cells or dendritic cells. TC-1, CT26, B16-F1, or B16-F10 tumor cells, and bone marrow-derived dendritic cells, were treated with interferon (IFN)-β, IFN-γ, or tumor necrosis factor-α to identify the molecular mechanisms underlying tumor PD-L1 and MHC I upregulation, and to examine MHC I, CD40, CD80, CD86, or PD-L1 levels, respectively. For synergistic combination therapy, αPD-L1 monoclonal antibody (mAb) covalently linked to the long E7 peptide was generated. Chemotherapy shifted the TME to express high PD-L1 and MHC I, resulting in targeted ICI cargo delivery and enhanced generation and activation of tumor antigen-specific T cells. Synergistic effects of vaccination and IC blockade in the TME were demonstrated using an anti-PD-L1 mAb covalently conjugated to the E7 long peptide.

Synergistic chemo-photothermal cancer therapy of pH-responsive polymeric nanoparticles loaded IR825 and DTX with charge-reversal property

IR825 is a kind of near-infrared (NIR) small molecule cyanine dye and has distinct near-infrared absorbance and excellent thermal conversion performance. Due to poor stability and insufficient therapy efficacy, various nano-systems have been developed as delivery vehicles for NIR dyes to improve their application in tumor treatment. Herein, we developed an intelligent polymer drug vehicle (Mal-PAH-PEG-DMMA/ poly (ethylene imine) – poly(ε-caprolactone) block polymers, MPPD/PEI-PCL) based on pH-responsive charge-reversal to deliver docetaxel (DTX) and photosensitizer (IR825) for chemo-photothermal combination therapy (MPPD@IR825/DTX NPs). MPPD@IR825/DTX NPs could undergo charge conversion in a slightly acidic microenvironment (pH 6.8), resulted in strong electrostatic repulsion to withdraw the shell of the polymer nanoparticles (MPPD), enhanced cellular uptake and increased drug release. MPPD@IR825/DTX NPs demonstrated nanoscale in size with good mono-dispersity and stability, triggered DTX release in response to acid environment and NIR stimulation, in the same time providing excellent photothermal conversion efficiency. In vitro and In vivo experiments confirmed that charge-reversal polymeric nanoparticles improved antitumor efficiency in 4T1 tumor cell modal than non-charge-reversal polymeric nanoparticles. Furthermore, in comparison with chemotherapy or photothermal therapy in a single treatment mode, chemo-photothermal combination therapy of MPPD@IR825/DTX NPs with laser irradiation showed highly efficient tumor ablation. In addition, the polymeric nanoparticles exhibited good biocompatibility and safety. Therefore, the design of charge-reversal polymeric nanoparticles (MPPD@IR825/DTX NPs) provides a new strategy and promising application for targeting and synergistic chemo-photothermal combination therapy.

Vitamin D3/phospholipid complex decorated caseinate nanomicelles for targeted delivery of synergistic combination therapy in breast cancer

Targeted delivery of cytotoxic drugs has shown great potential in cancer therapy. In this light, vitamin D3 (vit.D3)-coated micelles were fabricated to encapsulate the cytotoxic drug; etoposide (ETP). Sodium caseinate micelles were first utilized to encapsulate vit.D3 and ETP within their hydrophobic core, then drug-loaded micelles were further decorated with an envelope of vit.D3/ phospholipid complex to enhance the active targeting potency of fabricated micelles via exploiting vit.D3 receptors (VDRs) overexpressed on the outer surface of breast cancer cells. In vitro cytotoxicity studies showed that fabricated micelles exhibited improved anticancer effect on MDA MB-231 and MCF-7 human breast cancer cell lines in comparison to free vit.D3 + ETP without any significant toxicity on normal human lung fibroblast (Wi-38) cells. In vivo biodistribution and efficacy studies in Ehrlich ascites tumor animal model revealed that fabricated micelles manifested improved accumulation in tumor tissue due to active targeting potential of vit.D3 without any remarkable toxicity. More importantly, fabricated micelles resulted in enhanced tumor apoptosis, reduced angiogenesis, invasion and autophagy, besides a decline in the tumor expression levels of both miR-21 and miR-192. Therefore, vit.D3/ETP micelles could serve as a favorable actively targeted anticancer delivery system having a superior effect over the free combination.

Controlled CRISPR-Cas9 Ribonucleoprotein Delivery for Sensitized Photothermal Therapy.

Manipulation of CRISPR delivery for stimuli-responsive gene editing is crucial for cancer therapeutics through maximizing efficacy and minimizing side-effects. However, realizing controlled gene editing for synergistic combination therapy remains a key challenge. Here, a near-infrared (NIR) light-triggered thermo-responsive copper sulfide (CuS) multifunctional nanotherapeutic platform is constructed to achieve controlled release of CRISPR-Cas9 ribonucleoprotein (RNP) and doxorubicin for tumor synergistic combination therapy involving in gene therapy, mild-photothermal therapy (PTT), and chemotherapy. The semiconductor CuS serves as a "photothermal converter" and can stably convert NIR light (808nm) into local thermal effect to provide photothermal stimulation. The double-strand formed between CuS nanoparticle-linked DNA fragments and single-guide RNA is employed as a controlled element in response to photothermal stimulation for controlled gene editing and drug release. Hsp90α, one subunit of heat shock protein 90 (Hsp90), is targeted by Cas9 RNP to reduce tumor heat tolerance for enhanced mild-PTT effects (≈43°C). Significant synergistic therapy efficacy can be observed by twice NIR light irradiation both in vitro and in vivo, compared to PTT alone. Overall, this exogenously controlled method provides a versatile strategy for controlled gene editing and drug release with potentially synergistic combination therapy.

Combinatorial Anti-Leukemic Activity Of Liposomal Ceramide and Inhibitors Of Autophagy

BackgroundCeramides are naturally occurring cellular sphingolipids which are increased following various effective cancer therapies. Bioavailable forms of ceramide are under development as therapeutic tools (Anticancer Agents Med Chem. 2011 Nov;11(9):911-9). Short side chain (C6) ceramide has, in pegylated nanoliposomal (NL) formulations, shown excellent cellular uptake and significant anti-tumor activity in a variety of tumor types and models. Cellular autophagy is an active microsomal process implicated in ceramide metabolism and potentially in the detoxification of C6-ceramide. We have previously shown synergistic combination therapy with Lip-C6-ceramide and vinblastine and its association with autophagy dysfunction in hepatocarcinoma and colorectal cancer models (Cancer Lett. 2013 Sep 1;337(2):254-65.). Methods and findingsWe explored the therapeutic activity of nano-liposomally delivered C6-ceramide (Lip-C6) in cell lines and primary human acute myelogenous leukemia (hAML). Lip-C6 cytotoxicity was tested in multiple human and murine AML lines (in short term viability assays) and in multiple cryopreserved primary human AML cases (in clonogenic assays - colony formation in methylcellulose). Lip-C6 demonstrated anti-AML activity in these cells with an EC50 of 2-23uM Lip-C6. In order to enhance this efficacy the interplay between ceramide induced apoptosis and autophagy was explored. The AML line KG1 was found to be relatively resistant to Lip-C6 (EC50 23uM). KGI showed supra-additive sensitivity to the combination of Lip-C6 with either vinblastine (VBL) or vincristine, both microtubule binding agents with the ability to reduce autophageic flux. KG1 sub-clones with knockdown of ATG5 demonstrated increased sensitivity to Lip-C6 relative to control or scrambled knockdown transfectants, consistent with the hypothesis that autophagy “rescues” this line from ceramide cytotoxicity. To further confirm these findings we examined the interaction of Lip-C6 (20uM) with VBL (5uM) or chloroquine (25uM) in a series of 13 fresh, patient derived AML cases (Figure: A-F). After 48 hours of co-culture, cells were examined for apoptosis of whole leukemic(E) and putative leukemia “stem cell” (LSC - F) fractions by flow cytometry. We also studied the in-vivo activity of Ghost (control) NLs, Lip-C6, VBL-NLs and combinatorial Lip-C6+VBL-NLs in NSG xenografts bearing a single poor prognosis (inversion 3) hAML (data are shown in the figure G.) [Display omitted] ConclusionsWe conclude that VBL and chloroquine both yield significant enhancement of Lip-C6 ceramide anti-hAML cytotoxicity. Available evidence suggests that this effect is mediated by inhibition of autophagy in these ceramide stressed cells. These data suggest that the combination of Lip-6 with autophagy inhibitors delivered simultaneously or in combinatorial formulations may prove clinically useful for these disorders. Disclosures:Kester:Keystone Nano Inc.: Membership on an entity's Board of Directors or advisory committees, Penn state research foundation has licensed ceramide nanoliposome technology to keystone nano Inc. For commercialization, MK is co-founder and CMO of Keystone Nano., Penn state research foundation has licensed ceramide nanoliposome technology to keystone nano Inc. For commercialization, MK is co-founder and CMO of Keystone Nano. Patents & Royalties.

Targeting WEE1 Kinase after G2/M Checkpoint Arrest Induces Apoptosis in Chronic Myeloid Leukemia Progenitors

BackgroundThe integrity of signaling pathways involved in cell cycle arrest, chromatin remodeling and DNA repair are critical for maintaining the fidelity of replicated DNA. Normal cells repair damaged DNA during G1 arrest; in contrast, leukemic cells often have a deficient G1/S checkpoint and depend on a functional G2/M checkpoint for DNA repair. Aurora Kinase A (AKA) is a key component of centrosome cycle and polar spindle assembly required for regulated progression from G2 to M and throughout M phase. It is frequently overexpressed in cancers, where it correlates with a poor prognosis. Notably, AKA overexpression is associated with genomic instability, one major trait of chronic myeloid leukemia (CML). Our hypothesis is that AKA, together with Polo like kinase 1 (Plk1), cooperates with the constitutive TK activity of the BCR-ABL1 fusion protein by increasing DNA damage, promoting the occurrence of additional genomic alterations and driving TKIs resistance and disease progression to blast crisis.AimsIn this study, the effects of AKA and Plk1 inhibition were evaluated in K562 cells sensitive (K562-S) and resistant (K562-R) to imatinib.MethodsProtein expression and activation was assessed by Western Blotting (WB). Danusertib and Volasertib were used to investigate the effects of AKA and Plk1 inhibition in K562-S and K562-R cells. Both cell lines were incubated with increasing concentrations of Danusertib and Volasertib (0.5-1 µM) or control medium for 24, 48, 72 and 96 hours to perform growth curve experiments and to identify the best sub-lethal drug doses in liquid medium. The percentage of apoptotic cells was quantified by annexin V/propidium iodide staining and flow cytometry. WB experiments were performed to evaluate AKA and Plk1 expression and activation before and after treatment with Danusertib and Volasertib alone or in combination with the Wee1 inhibitor MK1775. Further experiments were performed using polyclonal antibodies against cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 to confirm apoptosis activation. PARP cleavage and γH2AX expression and activation were also tested. The effects of Danusertib and Volasertib on cell cycle progression were evaluated by flow cytometry in K562-S and K562-R cells after incubation in medium containing 0.5 µM of each drugs for 24 h.ResultsBoth Danusertib and Volasertib (0.5 µM for 24h) were effective in cell growth inhibition in K562-S and K562-R by inducing cells to undergo cell cycle arrest and apoptosis. Moreover, they caused a dose- and time-dependent reduction of the G0/G1 cell fraction and an increase of the G2/M fraction. Cell cycle arrest was associated with increased levels of phospho (p)-Chk1 and p-Chk2, p-cyclin B1, p-cdc2 and p-Wee1. Using a Wee1 inhibitor (MK1775) after 24h treatment with Danusertib and Volasertib 0.5 µM, when cells were arrested in G2 phase and Wee1 was overexpressed and hyper-activated, resulted in a synergistic inhibition of cell viability in both K562-S and -R (Figure 1). MK1775 combined with either Danusertib or Volasertib caused a time-dependent increase of annexin-V-positive cells by activating the mitochondrial apoptotic pathway as reflected by an increment of Bax expression and induction of the cleavage of caspase-3, -8 and -9 and PARP. Moreover, both drug combinations induced a significant increase of the DNA double-strand break marker γH2AX, suggesting that Wee1 inhibition promotes mitosis and propagates genomic instability by forcing the cells through successive replication cycles, ultimately resulting in apoptosis from mitotic catastrophe.ConclusionsOur results provide support for MK1775 to be used in synergistic combination therapies to improve the outcomes of patients with CML in blast crisis or resistant to multiple lines of TKI therapy.Supported by ELN, AIL, AIRC, project Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project, HARMONY project, Fondazione del Monte BO e RA project. [Display omitted] DisclosuresCastagnetti:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rosti:Incyte: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Martinelli:Johnson&Johnson: Consultancy; Roche: Consultancy; Ariad/Incyte: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Soverini:Bristol-Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy.

Synergistic combination therapy of lung cancer using lipid-layered cisplatin and oridonin co-encapsulated nanoparticles

Lung cancer treatment using cisplatin (DDP) in combination with other drugs are effective for the treatment of non-small cell lung cancer (NSCLC). The aim of this study was to prepare a layer-by-layer nanoparticles (NPs) for the co-loading of DDP and oridonin (ORI) and to evaluate the antitumor activity of the system in vitro and in vivo. Novel DDP and ORI co-loaded layer-by-layer NPs (D/O-NPs) were constructed. The mean diameter, surface change stability and drug release behavior of NPs were evaluated. In vitro cytotoxicity of D/O-NPs was investigated against DDP resistant human lung cancer cell line (A549/DDP cells), and in vivo anti-tumor efficiency of D/O-NPs was tested on mice bearing A549/DDP cells xenografts. D/O-NPs have a diameter of 139.6 ± 4.4 nm, a zeta potential value of +13.8 ± 1.6 mV. D/O-NPs could significantly enhance in vitro cell toxicity and in vivo antitumor effect against A549/DDP cells and lung cancer animal model compared to the single drug loaded NPs and free drugs. The results demonstrated that the D/O-NPs could be used as a promising lung cancer treatment system.

Extending the lymphoblastoid cell line model for drug combination pharmacogenomics.

Combination drug therapies have become an integral part of precision oncology, and while evidence of clinical effectiveness continues to grow, the underlying mechanisms supporting synergy are poorly understood. Immortalized human lymphoblastoid cell lines (LCLs) have been proven as a particularly useful, scalableand low-cost model in pharmacogenetics research, and are suitable for elucidating the molecular mechanisms of synergistic combination therapies. In this review, we cover the advantages of LCLs in synergy pharmacogenomics and consider recent studies providing initial evidence of the utility of LCLs in synergy research. We also discuss several opportunities for LCL-based systems to address gaps in the research through the expansion of testing regimens, assessment of new drug classes and higher-order combinations, and utilization of integrated omics technologies.

19P A synergistic combination therapy for KRAS-driven cancers

19P A synergistic combination therapy for KRAS-driven cancers

Improving Anti-PD-1/PD-L1 Therapy for Localized Bladder Cancer.

In high-risk non-muscle invasive bladder cancer (HR-NMIBC), patient outcome is negatively affected by lack of response to Bacillus-Calmette Guérin (BCG) treatment. Lack of response to cisplatin-based neoadjuvant chemotherapy and cisplatin ineligibility reduces successful treatment outcomes in muscle-invasive bladder cancer (MIBC) patients. The effectiveness of PD-1/PD-L1 immune checkpoint inhibitors (ICI) in metastatic disease has stimulated its evaluation as a treatment option in HR-NMIBC and MIBC patients. However, the observed responses, immune-related adverse events and high costs associated with ICI have provided impetus for the development of methods to improve patient stratification, enhance anti-tumorigenic effects and reduce toxicity. Here, we review the challenges and opportunities offered by PD-1/PD-L1 inhibition in HR-NMIBC and MIBC. We highlight the gaps in the field that need to be addressed to improve patient outcome including biomarkers for response stratification and potentially synergistic combination therapy regimens with PD-1/PD-L1 blockade.

CRISPR-Mediated Kinome Editing Prioritizes a Synergistic Combination Therapy for FGFR1-Amplified Lung Cancer.

Oncogenic activation of the FGFR pathway is frequent in lung and other cancers. However, due to drug resistance, pharmacological blockage of aberrant FGFR signaling has provided little clinical benefit in patients with FGFR-amplified tumors. The determining factors for the limited efficacy of FGFR-targeted therapy remain incompletely understood. In this study, we performed kinome-wide CRISPR/Cas9 loss-of-function screens in FGFR1-amplified lung cancer cells treated with an FGFR inhibitor. These screens identified PLK1 as a potent synthetic lethal target that mediates a resistance mechanism by overriding DNA damage and cell-cycle arrest upon FGFR1 inhibition. Genetic and pharmacological antagonism of PLK1 in combination with FGFR inhibitor therapy synergized to enhance antiproliferative effects and drove cancer cell death in vitro and in vivo through activation of the γH2AX-CHK-E2F1 axis. These findings suggest a previously unappreciated role for PLK1 in modulating FGFR1 inhibitor sensitivity and demonstrate a synergistic drug combination for treating FGFR1-amplified lung cancer. SIGNIFICANCE: The identification of PLK1 as a potent synthetic lethal target for FGFR-targeted therapy provides an innovative rationale for the treatment of lung and other FGFR1-amplified cancers.

Synthesis and design of Ag\u2013Fe bimetallic nanoparticles as antimicrobial synergistic combination therapies against clinically relevant pathogens

The inappropriate use of antibiotics and the inadequate control of infections have led to the emergence of drug-resistant strains. In recent years, metallo-pharmaceutics and metallic nanoparticles have been proposed as potential alternative antimicrobials due to their broad-spectrum antimicrobial properties. Moreover, recent findings have shown that combinations of transition metal compounds can exhibit synergistic antimicrobial properties. Therefore, the synthesis and design of bimetallic nanoparticles is a field worth exploring to harness the interactions between groups of metals and organic complex structures found in different microbial targets, towards the development of more efficient combinatorial antimicrobials composed of synergistic metals. In this study, we present a green synthesis of Ag–Fe bimetallic nanoparticles using an aqueous extract from the leaves of Gardenia jasminoides. The characterization of the nanoparticles demonstrated that the synthesis methodology produces homogenously distributed core–shell Ag–Fe structures with spherical shapes and average diameter sizes of 13 nm (± 6.3 nm). The Ag–Fe bimetallic nanoparticles showed magnetic and antimicrobial properties; the latter were evaluated against six different, clinically relevant multi-drug-resistant microbial strains. The Ag–Fe bimetallic nanoparticles exhibited an antimicrobial (bactericidal) synergistic effect between the two metals composing the bimetallic nanoparticles compared to the effects of the mono-metallic nanoparticles against yeast and both Gram-positive and Gram-negative multidrug-resistant bacteria. Our results provide insight towards the design of bimetallic nanoparticles, synthesized through green chemistry methodologies, to develop synergistic combinatorial antimicrobials with possible applications in both industrial processes and the treatment of infections caused by clinically relevant drug-resistant strains.

High-level Gentamicin Resistance among Clinical Isolates of Enterococci in Iran: a Systematic Review and Meta-analysis.

Enterococci have been considered as one of the most common causes of nosocomial infections. The spread of antibiotic resistance has posed a serious challenge to treating the enterococcal infections. High-level aminoglycosides resistance leads to failure in the synergistic combination therapy.This study aimed to estimate the prevalence of high-level gentamicin resistance (HLGR) among clinical isolates of enterococci in Iran.Systematic literature search was conducted in the Web of Science, PubMed, Scopus and Google Scholar electronic databases from ar-ticles which were published from April 2000 to September 2018. Literature search yielded 918 studies. Eligible studies were selected ac-cording to the defined inclusion and exclusion criteria. Statistical heterogeneity was estimated by Q statistic and the I2 index. The Begg's rank correlation test and Egger's weighted regression tests were used to evaluate possible publication bias.Nineteen studies were included in this review. According to the meta-analysis results, the prevalence of HLGR among Enterococcus spp. was 49.4% (95% CI: 42.2%-56.6%). It was estimated 44.3% (95% CI: 38.1%-50.8%) and 66.3% (95% CI: 51.4%-78.6%) for E. faecalis and E. faecium, respectively.Since notable rate of HLGR in enterococci was seen in this analysis, improving the implementation of all aspects of the infection control programmes is required. Accurate and regular monitoring of infection control procedures are necessary for reducing the dissemination of such infections.

Final results of a phase I/II prospective dose escalation trial evaluating safety and efficacy of combination 177Lu PSMA 617 and NOX66 in men with end-stage metastatic castration-resistant prostate cancer (LuPIN trial).

103 Background: 177LuPSMA – 617 is a promising therapy for metastatic castrate-resistant prostate cancer (mCRPC). However, treatment resistance occurs frequently and synergistic combination therapy may improve outcomes. We combined 177LuPSMA – 617 with idronoxil (NOX66), an inhibitor of external NADH oxidase type 2 with radio-sensitizing properties. We present the final safety and efficacy results. Methods: Men with progressive mCRPC after androgen signalling inhibition (ASI) and taxane chemotherapy were enrolled. Key inclusion criteria were: PSMA PET/CT intensity SUV max > 15 with no discordant disease on FDG PET/CT, haemoglobin > 100g/L, platelets > 100x109/L and eGFR > 40mls/min. Enrolled patients received up to six doses of 177 Lu-PSMA 617 (7.5Gbq) day 1 every 6 weeks in combination with NOX66 days 1-10 each cycle. Cohort 1 (n = 8) received 400mg NOX66. Following safety reviews the doses were escalated in cohorts 2 (n = 24) and 3 (n = 24) to 800mg and 1200mg of NOX66, respectively. Blood samples were prospectively collected for androgen receptor splice variant 7 (ARV7) expression. PSMA and FDG PET/CT were performed at study entry and on progression. The primary outcomes were safety and tolerability; the secondary outcomes evaluated were efficacy, pain scores, and quality of life. Results: Of the 56 men enrolled, all had received prior treatment with ASI and docetaxel, and 95% (53/56) had prior cabazitaxel. 96% (54/56) patients received ≥2 cycles and 46% (26/56) completed six cycles of treatment. Adverse events are summarized in the table below. PSA responses were as follows: 86% (48/56) had any PSA reduction and 61% (34/56) had > 50% PSA reduction. 84% (47/56) have had PSA progression to date with median follow up 18.9 months (95% CI 11.9-25.8). Median PSA PFS was 7.5 months (95% CI 6.0-9.0). 55% (31/56) have died and median overall survival was 19.7 months (95% CI 10.7-28.7). 34/56 men had baseline pain scores ≥3, of whom 53% (18/34) had significant reduction in pain indicators. There was no correlation between quantitative PET results and either PSA > 50% response, PSA PFS or OS. Conclusions: The combination of 177 Lu-PSMA 617 + NOX66 appears safe and efficacious in men with heavily pre-treated mCRPC. Exploratory analysis of ARV7 expression and quantitative PET imaging markers of treatment response and resistance is in progress. Clinical trial information: ACTRN12618001073291. [Table: see text]

Mechanism of Drug Resistance in Enterococci and Therapeutic Options - A Review

Enterococci exhibit an array of ways for constitutional and extrinsic resistance to primary antimicrobial agents available for clinical use. Susceptibility of these agents to β lactams, aminoglycosides or glycopeptides antibiotics or low susceptibility to combination of these agents, monomicrobial or polymicrobial nature of the infection, the involvement of heart valves or other endovascular structures affects therapy of Enterococcal infection. Vancomycin-resistant phenotypes A and B are most prevalent among medically important Enterococci isolates. Due to poor uptake of aminoglycosides, moderate level inherent resistance was reported in Enterococci. Gentamicin and Streptomycin are among the aminoglycoside antibiotics recommended for synergistic combination therapy with a cell wall acting agent. Enterococci isolates display inherent resistance to beta-lactam antibiotics due to less affinity penicillin-binding proteins, class B. Resistance to macrolides, due to erm B genotype and efflux proteins are common in Enterococci. Fluoroquinolone resistance due to genetic changes in chromosomal resistance determining regions has been observed in Enterococci isolates. Despite studies on good invitro action of Daptomycin, Linezolid and Tigecycline on Enterococci, their use may be limited due to shortage of clinical data and emergence of drug resistance. Thus optimal therapeutic option for Multidrug-resistant Enterococci infection is based on empirical observation, higher doses and combination therapies. This article reviews the antimicrobial resistance mechanism in Enterococci and available therapeutic options.

Combination prostate cancer therapy: Prostate-specific membranes antigen targeted, pH-sensitive nanoparticles loaded with doxorubicin and tanshinone

Prostate cancer is the second most frequently diagnosed cancer in the men population. Combination anticancer therapy using doxorubicin (DOX) and another extract of traditional Chinese medicine is one nano-sized drug delivery system promising to generate synergistic anticancer effects, maximize the treatment effect, and overcome multi-drug resistance. The purpose of this study is to construct a drug delivery system for the co-delivery of DOX and tanshinones (TAN). Lipid nanoparticles loaded with DOX and TAN (N-DOX/TAN) were prepared by emulsification and solvent-diffusion method. PSMA targeted nanoparticles loaded with DOX and TAN (P-N-DOX/TAN) were synthesized by conjugating a PSMA targeted ligand to N-DOX/TAN. We evaluate the performance of this system in vitro and in vivo. P-N-DOX/TAN has a size of 139.7 ± 4.1 nm and a zeta potential of 11.2 ± 1.6 mV. The drug release of DOX and TAN from P-N-DOX/TAN was much faster than that of N-DOX/TAN. N-DOX/TAN presented more inhibition effect on tumor growth than N-DOX and N-TAN, which is consistent with the synergistic results and successfully highlighting the advantages of combing the DOX and TAN in one system. P-N-DOX/TAN achieved higher uptake by LNCaP cells (58.9 ± 1.9%), highest tumor tissue distribution, and the most significant tumor inhibition efficiency. The novel nanomedicine offers great promise for the dual drug delivery to prostate cancer cells, showing the potential of synergistic combination therapy for prostate cancer.