Srinivas Rao Ganta - Academia.edu (original) (raw)

Papers by Srinivas Rao Ganta

The present age is Information Age, and the pedagogic implications of this age are that people sh... more The present age is Information Age, and the pedagogic implications of this age are that people should learn new skills to use information stored on computers. Libraries and Information Centers have responded by acquiring information technology and encourage computer literacy. ...

International Journal of Pharmaceutics, 2008

Sensors have been developed for noninvasive biomonitoring of the organophosphate pesticide chlorp... more Sensors have been developed for noninvasive biomonitoring of the organophosphate pesticide chlorpyrifos (CPF), and previous studies have suggested consistent partitioning of 3,5,6-trichloro-2-pyridinol (TCPy), a metabolite of CPF, into saliva after exposure to TCPy. The objective of this study was to quantitatively evaluate in vivo pharmacokinetics and pharmacodynamics of CPF and TCPy in saliva after CPF administration. Rats were coadministered CPF (0.5-5 mg/kg) and pilocarpine (~13 mg/kg) iv. Saliva and blood were collected, and levels of CPF, TCPy, and cholinesterase (ChE) activity were quantified. Experimental results suggest that CPF is rapidly metabolized after iv administration. Formation of TCPy from administered CPF at the low dose (0.5 mg/kg) was slower than from higher CPF doses, potentially due to differences in plasma protein binding to CPF. CPF was measured in saliva only at the first time point sampled (0-15 min), indicating low partitioning and rapid metabolism. After formation, TCPy pharmacokinetics were very similar in blood and saliva. Saliva/blood TCPy concentration ratios were not affected by TCPy concentration in blood, saliva flow rate, or salivary pH and were consistent with previous studies. ChE activity in plasma demonstrated a dose-dependent decrease, and ChE activity in saliva was extremely variable and demonstrated no dose relationship. A physiologically based pharmacokinetic and pharmacodynamic model for CPF was modified and predicted the data reasonably well. It is envisioned that a combination of biomonitoring compounds like TCPy in saliva coupled with computational modeling will form an approach to measure pesticide exposure to susceptible human populations such as agricultural workers. Downloaded from FIG. 7. Mean normalized ChE activities (fraction of control) with SD error bars in plasma over time of rats dosed with 0.5-5 mg/kg CPF. Lines represent PBPK/PD model predictions of the data.

Pharmaceutical research, Jan 4, 2015

Purpose Platinum-based therapies are the first line treatments for most types of cancer including... more Purpose Platinum-based therapies are the first line treatments for most types of cancer including ovarian cancer. However, their use is associated with dose-limiting toxicities and resistance. We report initial translational studies of a theranostic nanoemulsion loaded with a cisplatin derivative, myrisplatin and pro-apoptotic agent, C 6 -ceramide. Methods The surface of the nanoemulsion is annotated with an endothelial growth factor receptor (EGFR) binding peptide to improve targeting ability and gadolinium to provide diagnostic capability for image-guided therapy of EGFR overexpressing ovarian cancers. A high shear microfludization process was employed to produce the formulation with particle size below 150 nm.

PIK-75 is a phosphatidylinositol 3-kinase (PI3K) inhibitor that shows selectivity toward p110-␣ o... more PIK-75 is a phosphatidylinositol 3-kinase (PI3K) inhibitor that shows selectivity toward p110-␣ over the other PI3K class Ia isoforms p110-␤ and p110-␦, but it lacks solubility, stability and other kinase selectivity. The purpose of this study was to develop folate-targeted PIK-75 nanosuspension for tumor targeted delivery and to improve therapeutic efficacy in human ovarian cancer model. High pressure homogenization was used to prepare the non-targeted and targeted PIK-75 nanosuspensions which were characterized for size, zeta potential, entrapment efficiency, morphology, saturation solubility and dissolution velocity. In vitro analysis of drug uptake, cell viability and cell survival was conducted in SKOV-3 cells. Drug pharmacokinetics and pAkt expression were determined in SKOV-3 tumor bearing mice. PIK-75 nanosuspensions showed an improvement in dissolution velocity and an 11-fold increase in saturation solubility over pre-milled PIK-75. In vitro studies in SKOV-3 cells indicated a 2-fold improvement in drug uptake and 0.4-fold decrease in IC 50 value of PIK-75 following treatment with targeted nanosuspension compared to non-targeted nanosuspension. The improvement in cytotoxicity was attributed to an increase in caspase 3/7 and hROS activity. In vivo studies indicated a 5-10-fold increased PIK-75 accumulation in the tumor with both the nanosuspension formulations compared to PIK-75 suspension. The targeted nanosuspension showed an enhanced downregulation of pAkt compared to non-targeted formulation system. These results illustrate the opportunity to formulate PIK-75 as a targeted nanosuspension to enhance uptake and cytotoxicity of the drug in tumor.

Drug Delivery

Objective: Ovarian cancer is a highly lethal disease in which the majority of patients eventually... more Objective: Ovarian cancer is a highly lethal disease in which the majority of patients eventually demonstrate multidrug resistance. Develop a novel active targeted theranostic nanomedicine designed to overcome drug efflux mechanisms, using a Generally Regarded As Safe (GRAS) grade nanoemulsion (NE) as a clinically relevant platform. Materials and methods: The NEs surface-functionalized with folate and gadolinium, were made using GRAS grade excipients and a high-shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3 and SKOV3TR. The NE accumulation in tumors was evaluated in SKOV3 tumor-bearing mice by magnetic resonance imaging (MRI). Results and discussion: The NE with particle size 5150 nm were stable in plasma and parenteral fluids for 24 h. Ovarian cancer cells in vitro efficiently took up the non-targeted and folatetargeted NEs; improved cytotoxicity was observed for the folate-targeted NEs showing a 270fold drop in the IC 50 in SKOV3TR cells as compared to docetaxel alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist Õ . Folate-targeted NEs accumulated in tumors for prolonged period of time compared to Magnevist Õ and showed enhanced contrast compared to non-targeted NEs with MRI in SKOV3 tumor-bearing mice suggesting active targeting of NEs due to folate modification. Conclusions: A folate-targeted, theranostic NE delivers docetaxel by receptor mediated endocytosis that shows enhanced cytotoxicity capable of overcoming ABC transporter mediated taxane resistance. The diagnostic capability of the targeted nanomedicine showed enhanced contrast in tumors compared to clinically relevant MRI contrast agent Magnevist Õ .

Journal of pharmaceutical …, 2010

The aim of this study was to evaluate the effect of curcumin (CUR) in oral bioavailability and th... more The aim of this study was to evaluate the effect of curcumin (CUR) in oral bioavailability and therapeutic efficacy of paclitaxel (PTX) administered in nanoemulsion to SKOV3 tumor-bearing nu/nu mice. Oral administration of the mice with CUR at 50 mg/kg for 3 consecutive days resulted in a down regulation of intestinal P-glycoprotein (Pgp) and cytochrome P450 3A2 (CYP3A2) protein levels. PTX, a Pgp and CYP3A2 substrate, was administered orally at 20 mg/kg in solution or nanoemulsion either as single agent or upon pretreatment with CUR at 50 mg/kg in tumor-bearing mice. Plasma AUC 0-1 of PTX administered in nanoemulsion to CUR pretreated mice showed 4.1-fold increase relative to controls. Similarly, relative PTX bioavailability was increased by 5.2-fold, resulting in a 3.2-fold higher PTX accumulation in the tumor tissue. PTX administered in nanoemulsion to CUR pretreated mice also showed significantly enhanced anti-tumor activity. Preliminary safety evaluation showed that CUR þ PTX combination did not induce any acute toxicity as measured by body weight changes, blood cell counts, liver enzyme levels, and liver histopathology. The results of this study suggest that combination of PTX and CUR, administered in nanoemulsions, could improve oral bioavailability and therapeutic efficacy in ovarian adenocarcinoma. ß

Pharmaceutical Research, 2014

Purpose Platinum-based chemotherapy is the treatment of choice for malignant epithelial ovarian c... more Purpose Platinum-based chemotherapy is the treatment of choice for malignant epithelial ovarian cancers, but generalized toxicity and platinum resistance limits its use. Theranostic nanoemulsion with a novel platinum prodrug, myrisplatin, and the pro-apoptotic agent, C 6 -ceramide, were designed to overcome these limitations. Methods The nanoemulsions, including ones with an EGFR binding peptide and gadolinium, were made using generally regarded as safe grade excipients and a high shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3, A2780 and A2780 CP . Results The nanoemulsion with particle size <150 nm were stable in plasma and parenteral fluids for 24 h. Ovarian cancer cells in vitro efficiently took up the non-targeted and EGFRtargeted nanoemulsions; improved cytotoxicity was observed for the these nanoemulsions with the latter showing a 50-fold drop in the IC 50 in SKOV3 cells as compared to cisplatin alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist ® . Conclusion The myrisplatin/C 6 -ceramide nanoemulsion synergistically enhanced in vitro cytotoxicity. An EGFR binding peptide addition further increased in vitro cytotoxicity in EGFR positive cancer cells. The diagnostic version showed MR imaging similar to the clinically relevant Magnevist® and may be suitable as a theranostic for ovarian cancer.

Accounts of Chemical …, 2011

By definition, multifunctional nanosystems include several features within a single construct so ... more By definition, multifunctional nanosystems include several features within a single construct so that these devices can target tumors or other disease tissue, facilitate in vivo imaging, and deliver a therapeutic agent. Investigations of these nanosystems are rapidly progressing and provide new opportunities in the management of cancer. Tumor-targeted nanosystems are currently designed based primarily on the intrinsic physico-chemical properties of off-the-shelf polymers. Following fabrication, the surfaces of these nanoscale structures are functionalized for passive or active targeted delivery to the tumors. In this Account, we describe a novel approach for the construction of multifunctional polymeric nanosystems based on combinatorial design principles. Combinatorial approaches offer several advantages over conventional methods because they allow for the integration of multiple components with varied properties into a nanosystem via self-assembly or chemical conjugation. High-throughput synthesis and screening is required in polymer design because polymer composition directly affects properties including drug loading, retention in circulation, and targeting of the nanosystems. The first approach relies on the self-assembly of macromolecular building blocks with specific functionalities in aqueous media to yield a large variety of nanoparticle systems. These self-assembled nanosystems with diverse functionalities can then be rapidly screened in a high-throughput fashion for selection of ideal formulations, or hits, which are further evaluated for safety and efficacy. In another approach, a library of a large number of polymeric materials is synthesized using different monomers. Each of the formed polymers is screened for the selection of the best candidates for nanoparticle fabrication. The combinatorial design principles allow for the selection of those nanosystems with the most favorable properties based on the type of payload, route of administration, and the desired target for imaging and delivery.

Betulin (Bet), the main component of birch tree bark, has been recently reported to exert antican... more Betulin (Bet), the main component of birch tree bark, has been recently reported to exert anticancer activity in several cell lines; however the underlying mechanisms are only partially elucidated. The aims of the present work were to assess the in vivo effects of betulin administered as nanoemulsion (NE) in two experimental models: (i) the chicken embryo chorioallantoic membrane (CAM) assay for the study of anti-angiogenic effects and (ii) the two-stage model of skin carcinoma induced in mice for the study of anti-tumor and anti-inflammatory effects, respectively. On the CAM of the chicken betulin in nanoemulsion (BetNE) shows a good penetrability at extra-embryonic tissue level, affecting both the chorioallantoic membrane as well as the yolk sac by reducing the capillary density. In the animal model, the potential impact of local application of betulin on the respiratory function of isolated liver mitochondria was further assessed. Topical application of betulin nanoemulsion for 12 weeks together with DMBA (7,12-dimethylbenz[a]anthracene) and TPA (12-O-tetradecanoylphorbol 13-acetate), as tumor initiator and promoter, enhanced the active respiration of isolated liver mitochondria. Betulin also inhibit skin tumor apparition and promotion, proved by histological results and VEGF (vascular endothelial growth factor) expression correlated to non-invasive measurements. Betulin is active in nanoemulsion formulation as a potential inhibitory on the angiogenic process in CAM assay. BetNE can develop a potent anti-inflammatory and anti-carcinogenic activity with a low toxicity at skin level. It can also influence the penetration of carcinogens and reduce damage in main organs (e.g., liver).

... conditions.[61] Apiin has been used as a reducing and stabiliz-ing agent for the production o... more ... conditions.[61] Apiin has been used as a reducing and stabiliz-ing agent for the production of anisotropic gold and roughly spherical silver nanoparticles.[62] Apiin is a biocompatible compound that has known medical applications and can be obtained from the henna leaf via ...

Epithelial ovarian cancer is the leading cause of death from gynecological malignancies and is th... more Epithelial ovarian cancer is the leading cause of death from gynecological malignancies and is the fourth most frequent cause of death from cancer in women. Oxidative stress plays an important role in the pathogenesis of numerous degenerative diseases including cancer. Despite the availability of general knowledge and various data on the fundamental importance of oxidative stress in the development and progression of tumors, studies assessing the superoxide dismutase (SOD) expression and activity in ovarian cancer are limited, and their results are not comprehensive, but rather contradictory. The ultimate goal of this undergoing study is to investigate the alterations of ovarian oxidant/antioxidant parameters including SOD expression and activities in primary epithelial ovarian (serous) tumor patients, and by examining and assessing the correlations between the antioxidant enzyme activities of tissue and red blood cells (RBC) try to find out suitable biomarkers for ovarian cancer. In this communication, we present our preliminary results on SOD activities, as well as the results of the urinary 8-epiprostaglandin-F2á (F2-isoprostan) levels as a marker of oxidative stress. We used three study groups (n = 15/each): (i) patients with confirmed pathology of malign ovarian tumors (M), (ii) healthy subjects (C1), and (iii) ovariectomized patients without benign or malign pathology (C2). Significantly decreased (>50%) activities of SODTotal, SODCu,Zn and SODMn were found in ovarian tissues of Group (M) compared to Group (C2). Except for SODMn, the same trend was also observed for the enzyme activities in RBC of Group (M) compared to both (C1) and (C2) groups. Lipid peroxidation was found to be higher in Group (M) as evidenced by higher urinary F2-isoprostan concentrations.

The present study examined the antimicrobial activity of the peptide ghrelin. Both major forms of... more The present study examined the antimicrobial activity of the peptide ghrelin. Both major forms of ghrelin, acylated ghrelin (AG) and desacylated ghrelin (DAG), demonstrated the same degree of bactericidal activity against Gram-negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa), while bactericidal effects against Gram-positive Staphylococcus aureus (S. aureus) and Enterococcus faecalis (E. faecalis) were minimal or absent, respectively. To elucidate the bactericidal mechanism of AG and DAG against bacteria, we monitored the effect of the cationic peptides on the zeta potential of E. coli. Our results show that AG and DAG similarly quenched the negative surface charge of E. coli, suggesting that ghrelin-mediated bactericidal effects are influenced by charge-dependent binding and not by acyl modification. Like most cationic antimicrobial peptides (CAMPs), we also found that the antibacterial activity of AG was attenuated in physiological NaCl concentration (150 mM). Nonetheless, these findings indicate that both AG and DAG can act as CAMPs against Gram-negative bacteria. (T. Kawai).

The present age is Information Age, and the pedagogic implications of this age are that people sh... more The present age is Information Age, and the pedagogic implications of this age are that people should learn new skills to use information stored on computers. Libraries and Information Centers have responded by acquiring information technology and encourage computer literacy. ...

International Journal of Pharmaceutics, 2008

Sensors have been developed for noninvasive biomonitoring of the organophosphate pesticide chlorp... more Sensors have been developed for noninvasive biomonitoring of the organophosphate pesticide chlorpyrifos (CPF), and previous studies have suggested consistent partitioning of 3,5,6-trichloro-2-pyridinol (TCPy), a metabolite of CPF, into saliva after exposure to TCPy. The objective of this study was to quantitatively evaluate in vivo pharmacokinetics and pharmacodynamics of CPF and TCPy in saliva after CPF administration. Rats were coadministered CPF (0.5-5 mg/kg) and pilocarpine (~13 mg/kg) iv. Saliva and blood were collected, and levels of CPF, TCPy, and cholinesterase (ChE) activity were quantified. Experimental results suggest that CPF is rapidly metabolized after iv administration. Formation of TCPy from administered CPF at the low dose (0.5 mg/kg) was slower than from higher CPF doses, potentially due to differences in plasma protein binding to CPF. CPF was measured in saliva only at the first time point sampled (0-15 min), indicating low partitioning and rapid metabolism. After formation, TCPy pharmacokinetics were very similar in blood and saliva. Saliva/blood TCPy concentration ratios were not affected by TCPy concentration in blood, saliva flow rate, or salivary pH and were consistent with previous studies. ChE activity in plasma demonstrated a dose-dependent decrease, and ChE activity in saliva was extremely variable and demonstrated no dose relationship. A physiologically based pharmacokinetic and pharmacodynamic model for CPF was modified and predicted the data reasonably well. It is envisioned that a combination of biomonitoring compounds like TCPy in saliva coupled with computational modeling will form an approach to measure pesticide exposure to susceptible human populations such as agricultural workers. Downloaded from FIG. 7. Mean normalized ChE activities (fraction of control) with SD error bars in plasma over time of rats dosed with 0.5-5 mg/kg CPF. Lines represent PBPK/PD model predictions of the data.

Pharmaceutical research, Jan 4, 2015

Purpose Platinum-based therapies are the first line treatments for most types of cancer including... more Purpose Platinum-based therapies are the first line treatments for most types of cancer including ovarian cancer. However, their use is associated with dose-limiting toxicities and resistance. We report initial translational studies of a theranostic nanoemulsion loaded with a cisplatin derivative, myrisplatin and pro-apoptotic agent, C 6 -ceramide. Methods The surface of the nanoemulsion is annotated with an endothelial growth factor receptor (EGFR) binding peptide to improve targeting ability and gadolinium to provide diagnostic capability for image-guided therapy of EGFR overexpressing ovarian cancers. A high shear microfludization process was employed to produce the formulation with particle size below 150 nm.

PIK-75 is a phosphatidylinositol 3-kinase (PI3K) inhibitor that shows selectivity toward p110-␣ o... more PIK-75 is a phosphatidylinositol 3-kinase (PI3K) inhibitor that shows selectivity toward p110-␣ over the other PI3K class Ia isoforms p110-␤ and p110-␦, but it lacks solubility, stability and other kinase selectivity. The purpose of this study was to develop folate-targeted PIK-75 nanosuspension for tumor targeted delivery and to improve therapeutic efficacy in human ovarian cancer model. High pressure homogenization was used to prepare the non-targeted and targeted PIK-75 nanosuspensions which were characterized for size, zeta potential, entrapment efficiency, morphology, saturation solubility and dissolution velocity. In vitro analysis of drug uptake, cell viability and cell survival was conducted in SKOV-3 cells. Drug pharmacokinetics and pAkt expression were determined in SKOV-3 tumor bearing mice. PIK-75 nanosuspensions showed an improvement in dissolution velocity and an 11-fold increase in saturation solubility over pre-milled PIK-75. In vitro studies in SKOV-3 cells indicated a 2-fold improvement in drug uptake and 0.4-fold decrease in IC 50 value of PIK-75 following treatment with targeted nanosuspension compared to non-targeted nanosuspension. The improvement in cytotoxicity was attributed to an increase in caspase 3/7 and hROS activity. In vivo studies indicated a 5-10-fold increased PIK-75 accumulation in the tumor with both the nanosuspension formulations compared to PIK-75 suspension. The targeted nanosuspension showed an enhanced downregulation of pAkt compared to non-targeted formulation system. These results illustrate the opportunity to formulate PIK-75 as a targeted nanosuspension to enhance uptake and cytotoxicity of the drug in tumor.

Drug Delivery

Objective: Ovarian cancer is a highly lethal disease in which the majority of patients eventually... more Objective: Ovarian cancer is a highly lethal disease in which the majority of patients eventually demonstrate multidrug resistance. Develop a novel active targeted theranostic nanomedicine designed to overcome drug efflux mechanisms, using a Generally Regarded As Safe (GRAS) grade nanoemulsion (NE) as a clinically relevant platform. Materials and methods: The NEs surface-functionalized with folate and gadolinium, were made using GRAS grade excipients and a high-shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3 and SKOV3TR. The NE accumulation in tumors was evaluated in SKOV3 tumor-bearing mice by magnetic resonance imaging (MRI). Results and discussion: The NE with particle size 5150 nm were stable in plasma and parenteral fluids for 24 h. Ovarian cancer cells in vitro efficiently took up the non-targeted and folatetargeted NEs; improved cytotoxicity was observed for the folate-targeted NEs showing a 270fold drop in the IC 50 in SKOV3TR cells as compared to docetaxel alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist Õ . Folate-targeted NEs accumulated in tumors for prolonged period of time compared to Magnevist Õ and showed enhanced contrast compared to non-targeted NEs with MRI in SKOV3 tumor-bearing mice suggesting active targeting of NEs due to folate modification. Conclusions: A folate-targeted, theranostic NE delivers docetaxel by receptor mediated endocytosis that shows enhanced cytotoxicity capable of overcoming ABC transporter mediated taxane resistance. The diagnostic capability of the targeted nanomedicine showed enhanced contrast in tumors compared to clinically relevant MRI contrast agent Magnevist Õ .

Journal of pharmaceutical …, 2010

The aim of this study was to evaluate the effect of curcumin (CUR) in oral bioavailability and th... more The aim of this study was to evaluate the effect of curcumin (CUR) in oral bioavailability and therapeutic efficacy of paclitaxel (PTX) administered in nanoemulsion to SKOV3 tumor-bearing nu/nu mice. Oral administration of the mice with CUR at 50 mg/kg for 3 consecutive days resulted in a down regulation of intestinal P-glycoprotein (Pgp) and cytochrome P450 3A2 (CYP3A2) protein levels. PTX, a Pgp and CYP3A2 substrate, was administered orally at 20 mg/kg in solution or nanoemulsion either as single agent or upon pretreatment with CUR at 50 mg/kg in tumor-bearing mice. Plasma AUC 0-1 of PTX administered in nanoemulsion to CUR pretreated mice showed 4.1-fold increase relative to controls. Similarly, relative PTX bioavailability was increased by 5.2-fold, resulting in a 3.2-fold higher PTX accumulation in the tumor tissue. PTX administered in nanoemulsion to CUR pretreated mice also showed significantly enhanced anti-tumor activity. Preliminary safety evaluation showed that CUR þ PTX combination did not induce any acute toxicity as measured by body weight changes, blood cell counts, liver enzyme levels, and liver histopathology. The results of this study suggest that combination of PTX and CUR, administered in nanoemulsions, could improve oral bioavailability and therapeutic efficacy in ovarian adenocarcinoma. ß

Pharmaceutical Research, 2014

Purpose Platinum-based chemotherapy is the treatment of choice for malignant epithelial ovarian c... more Purpose Platinum-based chemotherapy is the treatment of choice for malignant epithelial ovarian cancers, but generalized toxicity and platinum resistance limits its use. Theranostic nanoemulsion with a novel platinum prodrug, myrisplatin, and the pro-apoptotic agent, C 6 -ceramide, were designed to overcome these limitations. Methods The nanoemulsions, including ones with an EGFR binding peptide and gadolinium, were made using generally regarded as safe grade excipients and a high shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3, A2780 and A2780 CP . Results The nanoemulsion with particle size <150 nm were stable in plasma and parenteral fluids for 24 h. Ovarian cancer cells in vitro efficiently took up the non-targeted and EGFRtargeted nanoemulsions; improved cytotoxicity was observed for the these nanoemulsions with the latter showing a 50-fold drop in the IC 50 in SKOV3 cells as compared to cisplatin alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist ® . Conclusion The myrisplatin/C 6 -ceramide nanoemulsion synergistically enhanced in vitro cytotoxicity. An EGFR binding peptide addition further increased in vitro cytotoxicity in EGFR positive cancer cells. The diagnostic version showed MR imaging similar to the clinically relevant Magnevist® and may be suitable as a theranostic for ovarian cancer.

Accounts of Chemical …, 2011

By definition, multifunctional nanosystems include several features within a single construct so ... more By definition, multifunctional nanosystems include several features within a single construct so that these devices can target tumors or other disease tissue, facilitate in vivo imaging, and deliver a therapeutic agent. Investigations of these nanosystems are rapidly progressing and provide new opportunities in the management of cancer. Tumor-targeted nanosystems are currently designed based primarily on the intrinsic physico-chemical properties of off-the-shelf polymers. Following fabrication, the surfaces of these nanoscale structures are functionalized for passive or active targeted delivery to the tumors. In this Account, we describe a novel approach for the construction of multifunctional polymeric nanosystems based on combinatorial design principles. Combinatorial approaches offer several advantages over conventional methods because they allow for the integration of multiple components with varied properties into a nanosystem via self-assembly or chemical conjugation. High-throughput synthesis and screening is required in polymer design because polymer composition directly affects properties including drug loading, retention in circulation, and targeting of the nanosystems. The first approach relies on the self-assembly of macromolecular building blocks with specific functionalities in aqueous media to yield a large variety of nanoparticle systems. These self-assembled nanosystems with diverse functionalities can then be rapidly screened in a high-throughput fashion for selection of ideal formulations, or hits, which are further evaluated for safety and efficacy. In another approach, a library of a large number of polymeric materials is synthesized using different monomers. Each of the formed polymers is screened for the selection of the best candidates for nanoparticle fabrication. The combinatorial design principles allow for the selection of those nanosystems with the most favorable properties based on the type of payload, route of administration, and the desired target for imaging and delivery.

Betulin (Bet), the main component of birch tree bark, has been recently reported to exert antican... more Betulin (Bet), the main component of birch tree bark, has been recently reported to exert anticancer activity in several cell lines; however the underlying mechanisms are only partially elucidated. The aims of the present work were to assess the in vivo effects of betulin administered as nanoemulsion (NE) in two experimental models: (i) the chicken embryo chorioallantoic membrane (CAM) assay for the study of anti-angiogenic effects and (ii) the two-stage model of skin carcinoma induced in mice for the study of anti-tumor and anti-inflammatory effects, respectively. On the CAM of the chicken betulin in nanoemulsion (BetNE) shows a good penetrability at extra-embryonic tissue level, affecting both the chorioallantoic membrane as well as the yolk sac by reducing the capillary density. In the animal model, the potential impact of local application of betulin on the respiratory function of isolated liver mitochondria was further assessed. Topical application of betulin nanoemulsion for 12 weeks together with DMBA (7,12-dimethylbenz[a]anthracene) and TPA (12-O-tetradecanoylphorbol 13-acetate), as tumor initiator and promoter, enhanced the active respiration of isolated liver mitochondria. Betulin also inhibit skin tumor apparition and promotion, proved by histological results and VEGF (vascular endothelial growth factor) expression correlated to non-invasive measurements. Betulin is active in nanoemulsion formulation as a potential inhibitory on the angiogenic process in CAM assay. BetNE can develop a potent anti-inflammatory and anti-carcinogenic activity with a low toxicity at skin level. It can also influence the penetration of carcinogens and reduce damage in main organs (e.g., liver).

... conditions.[61] Apiin has been used as a reducing and stabiliz-ing agent for the production o... more ... conditions.[61] Apiin has been used as a reducing and stabiliz-ing agent for the production of anisotropic gold and roughly spherical silver nanoparticles.[62] Apiin is a biocompatible compound that has known medical applications and can be obtained from the henna leaf via ...

Epithelial ovarian cancer is the leading cause of death from gynecological malignancies and is th... more Epithelial ovarian cancer is the leading cause of death from gynecological malignancies and is the fourth most frequent cause of death from cancer in women. Oxidative stress plays an important role in the pathogenesis of numerous degenerative diseases including cancer. Despite the availability of general knowledge and various data on the fundamental importance of oxidative stress in the development and progression of tumors, studies assessing the superoxide dismutase (SOD) expression and activity in ovarian cancer are limited, and their results are not comprehensive, but rather contradictory. The ultimate goal of this undergoing study is to investigate the alterations of ovarian oxidant/antioxidant parameters including SOD expression and activities in primary epithelial ovarian (serous) tumor patients, and by examining and assessing the correlations between the antioxidant enzyme activities of tissue and red blood cells (RBC) try to find out suitable biomarkers for ovarian cancer. In this communication, we present our preliminary results on SOD activities, as well as the results of the urinary 8-epiprostaglandin-F2á (F2-isoprostan) levels as a marker of oxidative stress. We used three study groups (n = 15/each): (i) patients with confirmed pathology of malign ovarian tumors (M), (ii) healthy subjects (C1), and (iii) ovariectomized patients without benign or malign pathology (C2). Significantly decreased (>50%) activities of SODTotal, SODCu,Zn and SODMn were found in ovarian tissues of Group (M) compared to Group (C2). Except for SODMn, the same trend was also observed for the enzyme activities in RBC of Group (M) compared to both (C1) and (C2) groups. Lipid peroxidation was found to be higher in Group (M) as evidenced by higher urinary F2-isoprostan concentrations.

The present study examined the antimicrobial activity of the peptide ghrelin. Both major forms of... more The present study examined the antimicrobial activity of the peptide ghrelin. Both major forms of ghrelin, acylated ghrelin (AG) and desacylated ghrelin (DAG), demonstrated the same degree of bactericidal activity against Gram-negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa), while bactericidal effects against Gram-positive Staphylococcus aureus (S. aureus) and Enterococcus faecalis (E. faecalis) were minimal or absent, respectively. To elucidate the bactericidal mechanism of AG and DAG against bacteria, we monitored the effect of the cationic peptides on the zeta potential of E. coli. Our results show that AG and DAG similarly quenched the negative surface charge of E. coli, suggesting that ghrelin-mediated bactericidal effects are influenced by charge-dependent binding and not by acyl modification. Like most cationic antimicrobial peptides (CAMPs), we also found that the antibacterial activity of AG was attenuated in physiological NaCl concentration (150 mM). Nonetheless, these findings indicate that both AG and DAG can act as CAMPs against Gram-negative bacteria. (T. Kawai).