Clinical developments of antitumor polymer therapeutics

Polymer therapeutics encompasses polymer–drug conjugates that are nano-sized, multicomponent constructs already in the clinic as antitumor compounds, either as single agents or in combination with other organic drug scaffolds. Nanoparticle-based polymer-conjugated therapeutics are poised to become a leading delivery strategy for cancer treatments as they exhibit prolonged half-life, higher stability and selectivity, water solubility, longer clearance time, lower immunogenicity and antigenicity and often also specific targeting to tissues or cells. Compared to free drugs, polymer-tethered drugs preferentially accumulate in the tumor sites unlike conventional chemotherapy which does not discriminate between the cancer cells and healthy cells, thereby causing severe side-effects. It is also desirable that the drug reaches its site of action at a particular concentration and the therapeutic dose remains constant over a sufficiently long period of time. This can be achieved by opting for new formulations possessing polymeric systems of drug carriers. However, many challenges still remain unanswered in polymeric drug conjugates which need to be readdressed and therefore, can broaden the scope of this field. This review highlights some of the antitumor polymer therapeutics including polymer–drug conjugates, polymeric micelles, polymeric liposomes and other polymeric nanoparticles that are currently under investigation.

Polymer therapeutics encompasses polymer–drug conjugates that are nano-sized, multicomponent constructs already in the clinic as antitumor compounds, either as single agents or in combination with other organic drug scaffolds.     

Hepatitis C viral heterogeneity based on core gene and an attempt to design small interfering RNA against strains resistant to interferon in rawalpindi, pakistan

Background

Global prevalence of Hepatitis C Virus (HCV) infection corresponds to about 130 million HCV positive patients worldwide. The only drug that effectively reduces viral load is interferon-α (IFN-α) and currently combination of IFN and ribavirin is the choice for treatment.

Objectives

The present study is aimed to resolve the genotypes based on core gene that might affect the response to interferon therapy. Furthermore an attempt was made to propose a powerful therapeutic approach by designing the siRNA from sequences of the same patients who remain resistant to IFN in this study.

Patients and Methods

To achieve the objectives, a sequence analysis was performed in five HCV ELISA positive subjects who have completed IFN treatment. Neighbor Joining (NJ) method was used to study the evolutionary relationship. Atomic models were predicted using online software PROCHECK and i- TASSER.

Results

Two new genotypes were reported for the first time namely 4a from suburban region of Rawalpindi and 6e from all over the Pakistan. According to Ramachandran plot, satisfactory atomic model was considered useful for further studies, i.e. to calculate HCV genotypes conservation at structural level, to find out critical binding sites for drug designing, or to silence those binding sites by using appropriate siRNA. Single siRNA can be used to inhibit HCV RNA synthesis against genotype 3 and 4, as the predicted siRNA were originated from the same domain in studied HCV core region in both genotypes.

Conclusions

We can conclude that any change or mutation in core region might be the cause of HCV strains to resist against IFN therapy. Therefore, further understanding of the complex mechanism involved in disrupting viral response to therapy would facilitate the development of more effective therapeutic regimens. Additionally, a single designed siRNA can be used as an alternative for current therapy against more than one resistant HCV genotypes.     

Observation of phenotypic variation among Indian women with polycystic ovary syndrome (PCOS) from Delhi and Srinagar

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder that demonstrates ethnic and regional differences. To assess the phenotypic variability among Indian PCOS women, we evaluated clinical, biochemical and hormonal parameters of these women being followed in two tertiary care institutions located in Delhi and Srinagar. A total of 299 (210 PCOS diagnosed by Rotterdam 2003 criteria and 89 healthy) women underwent estimation of T4, TSH, LH, FSH, total testosterone, prolactin, cortisol, 17OHP, and lipid profile, in addition to post OGTT, C-peptide, insulin, and glucose measurements. Among women with PCOS, mean age, age of menarche, height, systolic, diastolic blood pressure, and serum LH were comparable. PCOS women from Delhi had significantly higher BMI (26.99?±?5.38 versus 24.77?±?4.32?kg/m²; P?=?0.01), glucose intolerance (36 versus 10%), insulin resistance as measured by HOMA-IR (4.20?±?3.39 versus 3.01?±?2.6; P?=?0.006) and QUICKI (0.140?±?0.013 versus 0.147?±?0.015; P?=?0.03) while PCOS from Srinagar had higher FG score (12.12?±?3.91 versus 10.32?±?2.22; P?=?0.01) and serum total testosterone levels (0.65?±?0.69 versus 0.86?±?0.41?ng/ml; P?=?0.01. Two clear phenotypes, i.e. obese hyperinsulinaemic dysglycemic women from Delhi and lean hyperandrogenic women from Srinagar are emerging. This is the first report on North Indian women with PCOS showing phenotypic differences in clinical, biochemical and hormonal parameters despite being in the same region.     

Taurine prevents tamoxifen-induced mitochondrial oxidative damage in mice

Tamoxifen is a selective oestrogen receptor modulator widely used in the treatment of breast cancer. Tamoxifen potentially affects mitochondrial functions as it acts as an uncoupling agent and a powerful inhibitor of mitochondrial electron transport chain. There is concern for the deleterious effects of tamoxifen. Taurine is known to have membrane stabilizing and antioxidant properties. We studied effect of taurine pre-treatment on the toxicity of tamoxifen in mouse liver mitochondria focusing specifically on the redox cycle biomarkers. Tamoxifen caused a significant rise in the mitochondrial lipid peroxidation, protein carbonyl content and superoxide radical generation. There was a significant change in the mitochondrial thiol profile in the tamoxifen-treated animals. Pre-treatment of mice with taurine (100 mg/kg) markedly lowered mitochondrial lipid peroxidation, protein carbonyl content and superoxide radical generation. It also restored decreased enzymatic and non-enzymatic antioxidants of mitochondria. It is suggested that taurine has a potential role in ameliorating tamoxifen-induced mitochondrial toxicity, and the protection is afforded either by reversing the decline of antioxidants or by the direct free radical-scavenging activity.     

Association of rs10490924 in ARMS2/HTRA1 with age‐related macular degeneration in the Pakistani population

Age‐related macular degeneration (AMD) is a disease of the elderly in which central vision is lost because of degenerative changes of the macula. The current study investigated the association of single‐nucleotide polymorphisms (SNPs) with AMD in the Pakistani population. Four SNPs were analyzed in this study: rs1061170 in the CFH, rs429608 near CFB, rs2230199 in the C3, and rs10490924 in ARMS2/HTRA1. This case‐control association study was conducted on 300 AMD patients (125 wet AMD and 175 dry AMD) and 200 unaffected age‐ and gender‐matched control individuals. The association of the SNP genotypes and allele frequency distributions were compared between patients and healthy controls, keeping age, gender, and smoking status as covariates. A significant genotype and variant allele association was found of rs10490924 in ARMS2/HTRA1 with wet AMD, while the SNPs in CFH, CFB, and C3 were not associated with AMD in the current Pakistani cohort. The lack of association of CFH, CFB, and C3 may be attributed to limited sample size. This study demonstrates that genetic causative factors of AMD differ among populations and supports the need for genetic association studies among cohorts from various populations to increase our global understanding of the disease pathogenesis.     

Optical scattering as an early marker of apoptosis during chemotherapy and antiangiogenic therapy in murine models of prostate and breast cancer

Monitoring of the in vivo tumor state to track therapeutic response in real time may help to evaluate new drug candidates, maximize treatment efficacy, and reduce the burden of overtreatment. Current preclinical tumor imaging methods have largely focused on anatomic imaging (e.g., MRI, ultrasound), functional imaging (e.g., FDG-PET), and molecular imaging with exogenous contrast agents (e.g., fluorescence optical tomography). Here we utalize spatial frequency domain imaging (SFDI), a noninvasive, label-free optical technique, for the wide-field quantification of changes in tissue optical scattering in preclinical tumor models during treatment with chemotherapy and antiangiogenic agents. Optical scattering is particularly sensitive to tissue micro-architectural changes, including those that occur during apoptosis, an early indicator of response to cytotoxicity induced by chemotherapy, thermotherapy, cryotherapy, or radiation therapy. We utilized SFDI to monitor responses of PC3/2G7 prostate tumors and E0771 mammary tumors to treatment with cyclophosphamide or the antiangiogenic agent DC101 for up to 49 days. The SFDI-derived scattering amplitude was highly correlated with cleaved caspase-3, a marker of apoptosis (ρ_p = 0.75), while the exponent of the scattering wavelength-dependence correlated with the cell proliferation marker PCNA (ρ_p = 0.69). These optical parameters outperformed tumor volume and several functional parameters (e.g., oxygen saturation and hemoglobin concentration) as an early predictive biomarker of treatment response. Quantitative diffuse optical scattering is thus a promising new early marker of treatment response, which does not require radiation or exogenous contrast agents.     

Feasibility of spatial frequency domain imaging (SFDI) for optically characterizing a preclinical oncology model

Determination of chemotherapy efficacy early during treatment would provide more opportunities for physicians to alter and adapt treatment plans. Diffuse optical technologies may be ideally suited to track early biological events following chemotherapy administration due to low cost and high information content. We evaluated the use of spatial frequency domain imaging (SFDI) to characterize a small animal tumor model in order to move towards the goal of endogenous optical monitoring of cancer therapy in a controlled preclinical setting. The effects of key measurement parameters including the choice of imaging spatial frequency and the repeatability of measurements were evaluated. The precision of SFDI optical property extractions over repeat mouse measurements was determined to be within 3.52% for move and replace experiments. Baseline optical properties and chromophore values as well as intratumor heterogeneity were evaluated over 25 tumors. Additionally, tumor growth and chemotherapy response were monitored over a 45 day longitudinal study in a small number of mice to demonstrate the ability of SFDI to track treatment effects. Optical scattering and oxygen saturation increased as much as 70% and 25% respectively in treated tumors, suggesting SFDI may be useful for preclinical tracking of cancer therapies.OCIS codes: (170.3880) Medical and biological imaging, (170.5280) Photon migration, (290.1990) Diffusion, (170.0110) Imaging systems, (170.6510) Spectroscopy, tissue diagnostics, (290.5820) Scattering measurements     

Graphene-based nanocomposites: synthesis and their theranostic applications

Graphene, the mother of all carbon materials, has unlocked a new era of biomedical nanomaterials due to its exceptional biocompatibility, physicochemical and mechanical properties. It is a single atom thick, nanosized, two-dimensional structure and provides high surface area with adjustable surface chemistry to form hybrids. The present article provides a comprehensive review of ever-expanding application of graphene nanomaterials with different inorganic and organic materials in drug delivery and theranostics. Methods of preparation of nanomaterials are elaborated and biological and physicochemical characteristics of biomedical relevance are also discussed. Graphene form nanomaterials with metallic nanoparticles offer multiscale application. First, graphene act as a platform to attach nanoparticles and provide excellent mechanical strength. Second, graphene improves efficacy of metallic nanoparticles in diagnostic, biosensing, therapeutic and drug delivery application. Graphene-based polymeric nanocomposites find wider application in drug delivery with flexibility to incorporate hydrophilic, hydrophobic, sensitive and macromolecules. In addition, grapheme quantum dots and graphene hybrids with inorganic nanocrystal and carbon nanotubes hybrids have shown interesting properties for diagnosis and therapy. Finally, we have pointed out research trends that may be more common in future for graphene-based nanomaterials.     

Adjunctive Use of Ketamine for Benzodiazepine-Resistant Severe Alcohol Withdrawal: a Retrospective Evaluation

Introduction

Benzodiazepine (BZD)-resistant alcohol withdrawal remains a challenge for most institutions due to limited evidence with available agents. One published study currently exists utilizing the N-methyl-d-aspartate antagonist, ketamine, for alcohol withdrawal.

Objective

The purpose of our study was to evaluate the effect of adjunctive ketamine continuous infusion on symptom control and lorazepam infusion requirements for BZD-resistant alcohol withdrawal patients in the intensive care unit.

Methods

A retrospective review was conducted of patients receiving ketamine adjunctively with a lorazepam infusion for severe alcohol withdrawal between August 2012 and August 2014. Outcomes included time to symptom control, lorazepam infusion requirements, ketamine initial and maximum daily infusion rates, and adverse effects of ketamine.

Results

Thirty patients were included in the analysis. Mean time to initiation of ketamine after the initiation of a lorazepam infusion was 41.4 h. All patients achieved initial symptom control within 1 h of ketamine initiation. Median initial ketamine infusion rate was 0.75 mg/kg/h and the average maximum daily rate was 1.6 mg/kg/h. Significant decreases in lorazepam infusion rates from baseline were observed at 24 h (??4 mg/h; p?=?0.01) after ketamine initiation. No patients experienced documented CNS adverse effects. Two patients experienced hypertension and no patients experienced tachycardia related to ketamine.

Conclusion

Adjunctive ketamine could provide symptom control for BZD-refractory patients and may potentially reduce lorazepam infusion requirements. Future studies to determine optimal dosing, timing of initiation, and place in therapy for BZD-resistant alcohol withdrawal are needed. The mechanism of action via the NMDA receptor with ketamine may provide benefit for BZD-resistant alcohol withdrawal.