Tumor targeted nanohybrid for dual stimuli responsive and NIR amplified photothermal/photo-induced thermodynamic/chemodynamic combination therapy.

The combination of photodynamic (PDT) and chemodynamic therapy (CDT) for cancer treatment has gathered a lot of attention in recent years. However, its efficacy is severely limited by elevated levels of hypoxia and glutathione (GSH) in the tumor microenvironment (TME). Multifunctional nanoparticles that can help remodel the TME while facilitating PDT/CDT combination therapy are the need of the hour. To this effect, we have developed O2self-supplying, free radical generating nanohybrids that exhibit near infra-red (NIR) triggered photothermal (PTT)/photo-induced thermodynamic (P-TDT) and CDT for efficient breast cancer treatment. The surface of nanohybrids has been further modified by biointerfacing with cancer cell membrane. The biomimetic nanohybrids have been comprehensively characterized and found to exhibit high 2,2'-azobis-[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) loading, GSH depletion, oxygen self-supply with TME responsive AIPH release. Biological activity assays demonstrate efficient cellular uptake with homotypic targeting, excellent hemo- and cytocompatibility as well as high intracellular reactive oxygen species generation with synergistic cytotoxicity against tumor cells. The multifunctional nanohybrid proposed in the present study provides an attractive strategy for achieving NIR responsive, tumor targeted PTT/P-TDT/CDT combination therapy for breast cancer treatment.

Quatramer™ encapsulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of breast cancer.

Multiple studies have shown that the progression of breast cancer depends on multiple signaling pathways, suggesting that therapies with multitargeted anticancer agents will offer improved therapeutic benefits through synergistic effects in inhibiting cancer growth. Dual-targeted inhibitors of phosphoinositide 3-kinase (PI3-K) and histone deacetylase (HDAC) have emerged as promising cancer therapy candidates. However, poor aqueous solubility and bioavailability limited their efficacy in cancer. The present study investigates the encapsulation of a PI3-Kδ/HDAC6 dual inhibitor into hybrid block copolymers (polylactic acid-methoxy polyethylene glycol; polylactic acid-polyethylene glycol-polypropylene glycol-polyethylene glycol-polylactic acid) (HSB-510) as a delivery system to target PI3-Kδ and HDAC6 pathways in breast cancer cells. The prepared HSB-510 showed an average diameter of 96 ± 3 nm, a zeta potential of -17 ± 2 mV, and PDI of ˂0.1 with a slow and sustained release profile of PI3-Kδ/HDAC6 inhibitors in a nonphysiological buffer. In vitro studies with HSB-510 have demonstrated substantial growth inhibition of breast cancer cell lines, MDA-MB-468, SUM-149, MCF-7, and Ehrlich ascites carcinoma (EAC) as well as downregulation of phospho-AKT, phospho-ERK, and c-Myc levels. Importantly, bi-weekly treatment of Balb/c wild-type mice harboring EAC cells with HSB-510 at a dose of 25 mg/kg resulted in significant tumor growth inhibition. The treatment with HSB-510 was without any significant effect on the body weights of the mice. These results demonstrate that a novel Quatramer encapsulation of a PI3-Kδ/HDAC6 dual inhibitor (HSB-510) represents an approach for the successful targeting of breast cancer and potentially other cancer types.

Biodegradable implant application: Electrodeposition of HA/TiO2/ZrO2 coating onto Zn-composite substrates.

Zinc has currently emerged as a promising biodegradable metal due to its good biocompatible property and promising degradation behaviour. Additionally, inadequate mechanical strength and a lower cell viability value fall short of what is needed for biodegradable implants. In this work, we used the stir-casting process to create a biodegradable Zn-1Mg-1Cu-1HA (ZHA) and Zn-1Mg-1Cu-1ZrO2 (ZZR) composite onto which ceramics composite coating is done by electrodeposition technique to enhance the biocompatibility. The as-cast sample has uniformly distributed fine MgZn2 and CuZn2 phases in a α-Zn matrix, according to microstructural analysis. The mechanical test confirms that ZZR composite exhibited high tensile and compressive properties, including compressive yield strength of 369.562 MPa, a yield tensile strength of 88.725 MPa and ultimate tensile strength of 116.21 MPa. The result of potentiodynamic polarization test shows that the coated ZZR composite sample gives a corrosion rate value of 0.112 mm/year. From immersion tests, the degradation rate obtained a much lower value after immersing the sample in PBS solution for 55 days (0.067 mm/year). Moreover, an extract of coated ZZR composite shows good cell viability in comparison to the uncoated sample at a concentration of 25%, 50% and 75%. Also, the hemolysis percentage for coated ZZR sample is lower than the other prepared uncoated sample (3.072%) Overall, the result obtained proves that the coated ZZR composite sample can be expected as a capable material for implant application.

Mobile Applications to Support Diabetes Self-Management Education: Patient Experiences and Provider Perspectives.

BACKGROUND: Diabetes self-management education and support (DSMES) is a critical component of diabetes care, but time for it is often limited. Digital tools, such as mobile applications (apps), show promise in extending efforts and supporting self-management education, but have not been fully used. Objectives of this multi-phase study were to (1) evaluate an app designed to support patients with insulin therapy and (2) examine provider perspectives on DSMES apps. METHODS: Phase 1: Thirty-two adult patients with type 2 diabetes new to or having difficulties with insulin therapy were introduced to the BDTM Diabetes Care App. Three-month app use and satisfaction and changes in hemoglobin A1c (HbA1c) and diabetes distress were assessed. Phase 2: Sixty diabetes providers completed a survey about their experiences with and perspectives on DSMES apps. RESULTS: Phase 1: Patients reported satisfaction with the app, and significant improvements in HbA1c and diabetes distress were observed. Phase 2: Most providers viewed apps as adjuncts to diabetes education. Only 33% had previous app experience; however, 100% would consider recommending apps to their patients. Most would spend 5-15 minutes introducing apps to patients. All respondents agreed that the following DSMES app features-evidence-based educational content, data logging and tracking features, customizable user experience, digital coaching via goal setting or reminders, and ability to share data with providers-are key components to consider. CONCLUSIONS: Findings suggest DSMES apps can play a role in self-management support and provide guidance on factors to consider when introducing digital tools into clinical practice. TRIAL REGISTRATION: Clinicaltrials.gov, #NCT03999268.

IGF-1 is positively associated with BMI in patients with acromegaly.

PURPOSE: Acromegaly is a disorder characterized by IGF-1 excess due to autonomous GH secretion. In individuals without acromegaly, IGF-1 is not only influenced by GH secretion but is also sensitive to other factors including nutritional status, as evidenced by the inverted U-shaped association between BMI and IGF-1; in low-weight individuals (BMI < 18.5 kg/m2) and those who are obese, IGF-1 levels may be frankly low. It is not known if this same relationship between BMI and IGF-1 is also observed in acromegaly. METHODS: Retrospective study including patients who underwent resection of a pituitary adenoma (n = 197) for either acromegaly (n = 32) or a nonfunctioning adenoma (NFPA, n = 165) at a large academic medical center between 1/1/2015 and 5/31/2021. RESULTS: Median BMI in acromegaly was 30.8 kg/m2 (range 20.9-42.6 kg/m2). Percent upper limit of normal (%ULN) IGF-1 was 228.2% [159.0, 271.4] in acromegaly versus 32.2% [18.5, 50] in NFPA (p < 0.0001). There was a significant positive association between BMI and %ULN IGF-1 (R = 0.35, p < 0.05) in acromegaly. In contrast, there was no association between BMI and %ULN IGF-1 in the NFPA group as a whole (p = 0.22), but a significant inverse association between BMI and %ULN IGF-1 in NFPA patients with a BMI ≥ 35 kg/m2 (rho = - 0.39, p = 0.02). CONCLUSION: In contrast to individuals without acromegaly, BMI is significantly and positively associated with IGF-1 in acromegaly across the weight spectrum. Future studies are needed to determine if obese patients with acromegaly experience more significant symptoms related to their disease, or if patients with a low BMI may require different diagnostic criteria.

Polylactic acid based biodegradable hybrid block copolymeric nanoparticle mediated co-delivery of salinomycin and doxorubicin for cancer therapy.

Existence of cancer stem cells (CSCs) are primarily responsible for chemoresistance, cancer reoccurrence and treatment failure in cancer patients. Eliminating CSCs along with bulk tumor is a necessity to achieve complete cancer inhibition. Salinomycin (SAL) has potential to specifically target and kill CSCs through blocking their multiple pathways simultaneously. SAL has also been reported to improve anti-cancer efficacy of numerous chemo-based drugs when used in combination therapy. However, clinical use of SAL is restricted due to its high off targeted toxicity. Herein, we have developed a PLA based hybrid block copolymer for concomitant delivery of SAL and doxorubicin (DOX) with an aim to reduce their adverse side effects and enhance the therapeutic efficacy of the treatment. Designed PLA based nanoplatform showed high encapsulation and sustained release profile for both the drugs. Cytotoxicity evaluation on cancer cell lines confirmed the synergistic effect of SAL:DOX co-loaded NPs. Additionally, prepared SAL NPs were also found to be highly effective against chemo-resistant cancer cells and CSCs derived from cancer patient. Most importantly, encapsulation of SAL in PLA NPs improved its pharmacokinetics and biodistribution profile. Consequently, undesired toxicity with SAL NPs was significantly reduced which in-turn increased the dose tolerability in mice as compared to free SAL. Treatment of EAC tumor bearing mice with SAL:DOX co-loaded NPs resulted in excellent tumor regression and complete inhibition of cancer reoccurrence. These results conclude that concomitant delivery of SAL and DOX using PLA based block copolymeric nano-carrier have a strong potential for cancer therapy.

Polylactic acid based polymeric nanoparticle mediated co-delivery of navitoclax and decitabine for cancer therapy.

Combination chemotherapy with systemic administration of drugs in their free form can be challenging due to non-synchronized pharmacokinetics and sub-optimal tumor accumulation. The present study investigates a PLA-based block copolymeric nanocarrier for the co-delivery of navitoclax and decitabine (NAV/DCB NPs) for combination cancer therapy. NAV/DCB NPs exhibited potent in vitro synergistic cytotoxicity in both acute myeloid leukemia and breast cancer cell lines. Biodistribution studies of NAV/DCB NPs in tumor bearing mice, showed significant drug accumulation in tumor tissue and detectable quantities in plasma even after 48 h. Good hemocompatibility with reduced in vivo platelet toxicity indicated that encapsulation in PLA-based nanocarrier helped ameliorate navitoclax associated thrombocytopenia. In vivo biological activity of NAV/DCB NPs evaluated in xenograft AML and syngeneic breast cancer model, demonstrated potent tumor growth inhibition efficacy. PLA-based NAV/DCB dual NPs present a novel, safe and effective nanoformulation for combination cancer therapy in both solid tumors and hematologic malignancies.

Development and evaluation of PLA based hybrid block copolymeric nanoparticles for systemic delivery of pirarubicin as an anti-cancer agent.

Pirarubicin (PIRA) is a semi-synthetic anthracycline derivative that is reported to have lesser toxicity and better clinical outcomes as compared to its parental form doxorubicin (DOX). However, long term use of PIRA causes bone marrow suppression and severe cardiotoxicity to the recipients. Herein, we have developed a biodegradable polymeric nano platform consisting of amphiphilic di-block copolymer methoxy polyethylene glycol-polylactic acid and a hydrophobic penta-block copolymer polylactic acid-pluronic L-61-polylactic acid as a hybrid system to prepare PIRA (& DOX) encapsulated nanoparticles (NPs) with an aim to reduce its off targeted toxicity and enhance therapeutic efficacy for cancer therapy. Prepared PIRA/DOX NPs showed uniform particle size distribution, high encapsulation efficiency and sustained drug release profile. Cytotoxicity evaluation of PIRA NPs against TNBC cells and mammospheres showed its superior anti-cancer activity over DOX NPs. Anti-cancer efficacy of PIRA/DOX NPs was found significantly enhanced in presence of penta-block copolymer which confirmed chemo-sensitising ability of pluronic L-61. Most importantly, encapsulation of PIRA/DOX in the NPs reduced their off targeted toxicity and increased the maximum tolerated dose in BALB/c mice. Moreover, treatment of EAC tumor harbouring mice with PIRA NPs resulted in higher tumor regression as compared with the groups treated with free PIRA, free DOX or DOX NPs. Altogether, the results conclude that prepared PIRA NPs exhibits an excellent anti-cancer therapeutic efficacy and has a strong potential for cancer therapy.

Peptide-based combination nanoformulations for cancer therapy.

Research in cancer therapy is moving towards the use of biomolecules in combination with conventional approaches for improved disease outcome. Among the biomolecules explored, peptides are strong contenders due to their small size, high specificity, low systemic toxicity and wide inter/intracellular targets. The use of nanoformulations for such combination approaches can lead to further improvement in efficacy by reducing off-target cytotoxicity, increasing circulation time, tumor penetration and accumulation. This review focuses on nanodelivery systems for peptide-based combinations with chemo, immuno, radiation and hormone therapy. It gives an overview of the latest therapeutic research being conducted using combination nanoformulations with anticancer peptides, cell penetrating/tumor targeting peptides, peptide nanocarriers, peptidomimetics, peptide-based hormones and peptide vaccines. The challenges hindering clinical translation are also discussed.

Isolated Langerhans Cell Histiocytosis of Orbit: A Case Report and Review of the Literature.

A 2-year-old male child presented with a painless progressive mass in the inferolateral aspect of right orbit of three-month duration. Differential leucocyte count revealed raised eosinophil count (13%). On radiological examination, CT scan showed 25 × 27 mm round well-defined smooth-outlined homogenously enhancing extraconal mass arising from the zygomatic bone at the inferotemporal periorbital area of right orbit with bone erosion. Histopathological examination of the incision biopsy revealed characteristic Langerhans cells and immunohistochemical studies were positive for S-100 protein and adenosine deaminase. A diagnosis of Langerhans Cell Histiocytosis (LCH) was made and PET-CT revealed no other foci of uptake anywhere else in the body. The patient received 12 cycles of vinblastine, 0.2 mg/kg body weight, along with oral prednisolone, 1 mg/kg body weight. On completion of three cycles of chemotherapy, a reduction in size of the mass was noticed. A repeat PET scan was done 3 months after completion of chemotherapy did not reveal any activity noted previously.

Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer.

B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family of anti-apoptotic proteins that confers resistance to treatment with anti-cancer drugs; however, there are presently no agents that target BCL2A1. The MUC1-C oncoprotein is aberrantly expressed in triple-negative breast cancer (TNBC) cells, induces the epithelial-mesenchymal transition (EMT) and promotes anti-cancer drug resistance. The present study demonstrates that targeting MUC1-C genetically and pharmacologically in TNBC cells results in the downregulation of BCL2A1 expression. The results show that MUC1-C activates the BCL2A1 gene by an NF-κB p65-mediated mechanism, linking this pathway with the induction of EMT. The MCL-1 anti-apoptotic protein is also of importance for the survival of TNBC cells and is an attractive target for drug development. We found that inhibiting MCL-1 with the highly specific MS1 peptide results in the activation of the MUC1-C→NF-κB→BCL2A1 pathway. In addition, selection of TNBC cells for resistance to ABT-737, which inhibits BCL-2, BCL-xL and BCL-W but not MCL-1 or BCL2A1, is associated with the upregulation of MUC1-C and BCL2A1 expression. Targeting MUC1-C in ABT-737-resistant TNBC cells suppresses BCL2A1 and induces death, which is of potential therapeutic importance. These findings indicate that MUC1-C is a target for the treatment of TNBCs unresponsive to agents that inhibit anti-apoptotic members of the BCL-2 family.

Disseminated cryptococcosis in HIV negative patient.

A 52-year-old white diabetic male with 4-weeks history of persistent cough followed by headache, drenching night sweats, low-grade fever, worsening photophobia, nausea and vomiting was presented. Examination was significant for photophobia and diminution of vision. His spinal fluid and blood cultures were positive for Cryptococcus neoformans Intravenous fluconazole were given for 2 weeks followed by oral fluconazole. There was significant improvement in systemic and ocular symptoms. HIV serology was negative, but his CD4 counts were low with inverted CD4:CD8 ratio.

Catalytic Degradation of Dichlorvos Using Biosynthesized Zero Valent Iron Nanoparticles.

The removal of dichlorvos contamination from water is a challenging task because of the presence of direct carbon to phosphorous covalent bond, which makes them resistant to chemical and thermal degradation. Although there have been reports in the literature for degradation of dichlorvos using nanomaterials, those are based on photocatalysis. In this paper, we report a simple and rapid method for catalytic degradation of dichlorvos using protein-capped zero valent iron nanoparticles (FeNPs). We have developed an unprecedented reliable, clean, nontoxic, eco-friendly, and cost-effective biological method for the synthesis of uniformly distributed FeNPs. Yeast extract was used as reducing and capping agent in the synthesis of FeNPs, and synthesized particles were characterized by the UV-visible spectroscopy, X -ray diffraction, Fourier transform infrared spectroscopy (FTIR), and transmission electron microscopy (TEM). TEM micrographs reveal that the nanoparticles size is distributed in the range of 2-10 nm. Selected area electron diffraction pattern shows the polycrystalline rings of FeNPs. The mean size was found to be 5.006 nm from ImageJ. FTIR spectra depicted the presence of biomolecules, which participated in the synthesis and stabilization of nanoparticles. As synthesized, FeNPs were used for the catalytic degradation of dichlorvos in aqueous medium. The degradation activity of the FeNPs has been investigated by the means of incubation time effect, oxidant effect, and nanoparticle concentration effect. The ammonium molybdate test was used to confirm the release of phosphate ions during the interaction of dichlorvos with FeNPs.

Efficacy of Natural and Allopathic Antimicrobial Agents Incorporated onto Guided Tissue Regeneration Membrane Against Periodontal Pathogens: An in vitro Study.

INTRODUCTION: Periodontal disease is one of the most prevalent afflictions worldwide. It is an infection of the periodontium as a result of subgingival colonization of the specific microbiota, leading to loss of attachment, which requires optimal care for regeneration to its pre-disease state. Guided Tissue Regeneration (GTR) is one of the successful treatment modalities in Periodontal Regenerative Therapy, but is vulnerable to bacterial colonization. The conflict between usage of classical antibiotics and plant origin antimicrobial agents has recently been in the limelight. AIM: The aim of this study was to assess the in vitro antimicrobial activity of amoxicillin, metronidazole and green coffee extract loaded onto GTR membrane against periodonto-pathogens. MATERIALS AND METHODS: Pure form of amoxicillin, metronidazole and green coffee extract were obtained. One percent concentration of each antimicrobial agent was prepared by appropriate dilution with distilled water. GTR membrane was cut into a size of 1x0.5 cm under sterile conditions and was coated with the antimicrobial agents respectively and with distilled water as the negative control. Antimicrobial activity was checked against Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) and Porphyromonas gingivalis (P. gingivalis) using agar disc diffusion method. The statistical analysis was done using Kruskal Wallis ANOVA and Mann-Whitney U test. RESULTS: One percent amoxicillin showed level of significance (p>0.05) against both A. actinomycetemcomitans and P. gingivalis. Green coffee extract showed no zone of inhibition against both the bacterial species. CONCLUSION: Loading of commercially available antimicrobial agents onto GTR membrane can prevent its bacterial colonization leading to better treatment outcomes for periodontal regeneration.

Short interfering RNA therapeutics: nanocarriers, prospects and limitations.

Since the first experiment depicting gene inhibition using RNA interference mechanism, extensive research has been carried out to design targeted delivery systems that use short interfering RNAs (siRNAs) for gene expression regulation. Although several siRNAs loaded nanoparticle systems have reached clinical trial stage, cellular uptake, reticuloendothelial entrapment and endosomal escape still limit the efficacy of these drugs considerably. This review discusses about the RNA interference mechanism, nanostructures being used as non-viral vectors for targeted delivery, limitations of the common delivery systems and the current siRNA-loaded nanoparticle formulations undergoing clinical testing.

Actinomycosis of eye: Forgotten but not uncommon.

Actinomyces species are known to cause a variety of human infections. Ocular actinomycosis is a rare disease. We report an unusual case of bilateral actinomycotic blepharoconjunctivitis in the absence of canaliculitis that presented with forniceal masses in eye. The case report is discussed here along with Indian literature.