Nonionic surfactant vesicles containing celecoxib (CXB) as an anti-inflammatory drug were prepared using, Span 60 or Span 40 and cholesterol in the ratios of 1:0, 1:1 and 1:2. Prepared vesicles were characterized for encapsulation efficiency, particle size and drug release. The drug encapsulation efficiencies varied from 60.55 to 80.35%. The vesicle size ranged from 170 to 235 nm. The high encapsulation was achieved by the ratio 1:1 of span 60: cholesterol and this formula showed significant in vitro release of the drug (80%) as compared to other forms (P 0.05). Among niosomal gels investigated, poloxamer 407 niosomal gel showed significant drug release (72% after 12 h) over the other forms (P 0.05). The results also showed that the release of CXB from the niosomes and niosomal gels obeyed the Higuchi’s diffusion model. The anti-inflammatory activity of the drug from different niosomal gel formulations was also studied using Carrageenan induced rat paw edema method. The results showed that there is significant anti-inflammatory activity (75.45%) of the poloxamer niosomal gel on rat paw edema (P 0.05).

Nonionic surfactant vesicles containing celecoxib (CXB) as an anti-inflammatory drug were prepared using, Span 60 or Span 40 and cholesterol in the ratios of 1:0, 1:1 and 1:2. Prepared vesicles were characterized for encapsulation efficiency, particle size and drug release. The drug encapsulation efficiencies varied from 60.55 to 80.35%. The vesicle size ranged from 170 to 235 nm. The high encapsulation was achieved by the ratio 1:1 of span 60: cholesterol and this formula showed significant in vitro release of the drug (80%) as compared to other forms (P 0.05). Among niosomal gels investigated, poloxamer 407 niosomal gel showed significant drug release (72% after 12 h) over the other forms (P 0.05). The results also showed that the release of CXB from the niosomes and niosomal gels obeyed the Higuchi’s diffusion model. The anti-inflammatory activity of the drug from different niosomal gel formulations was also studied using Carrageenan induced rat paw edema method. The results showed that there is significant anti-inflammatory activity (75.45%) of the poloxamer niosomal gel on rat paw edema (P 0.05).

Multidrug resistance (MDR), a major cause for chemotherapy failure, has been linked to upregulation of ATP-dependent membrane efflux systems that limit intracellular accumulation of cytotoxic anticancer agents. P-glycoprotein (P-gp) encoded by the human ABCB1 gene was the first efflux transporter identified to contribute to MDR. ABCB1 gene expression is correlated with constitutive activation of the NF-κB signaling pathway in tumor cells. The objective of this research is to modulate P-gp activity in colon cancer cells using NF-κB decoy oligodeoxynucleotides (ODNs) that are effectively delivered into the nucleus of colorectal cancer cells by self-assembling nonviral nanoparticles comprising the novel poly[N-(2-hydroxypropyl)methacrylamide]-poly(N,N-dimethylaminoethyl-methacrylate) diblock copolymer (pHPMA-b-pDMAEMA). Ethidium bromide intercalation and gel retardation assays demonstrated high DNA condensation capacity of pHPMA-b-pDMAEMA. Nanoparticles prepared with and without decoy ODNs did not significantly compromise cellular safety at N/P ratios ≤ 4. Transfection efficiency of pHPMA-b-pDMAEMA polyplexes (N/P = 4) in Caco-2 cells was comparable to TurboFect transfection standard, resulting in a 98% reduction in P-gp protein levels. As a pharmacodynamic consequence, intracellular accumulation of the P-gp substrate Rhodamine123 significantly increased by almost twofold. In conclusion, NF-κB ODN polyplexes fabricated with pHPMA-b-pDMAEMA polymer effectively reduced P-gp-mediated efflux activity in Caco-2 cells, suggesting successful interference with NF-κB-binding sites in the promoter region of the ABCB1 gene.

Multidrug resistance (MDR), a major cause for chemotherapy failure, has been linked to upregulation of ATP-dependent membrane efflux systems that limit intracellular accumulation of cytotoxic anticancer agents. P-glycoprotein (P-gp) encoded by the human ABCB1 gene was the first efflux transporter identified to contribute to MDR. ABCB1 gene expression is correlated with constitutive activation of the NF-κB signaling pathway in tumor cells. The objective of this research is to modulate P-gp activity in colon cancer cells using NF-κB decoy oligodeoxynucleotides (ODNs) that are effectively delivered into the nucleus of colorectal cancer cells by self-assembling nonviral nanoparticles comprising the novel poly[N-(2-hydroxypropyl)methacrylamide]-poly(N,N-dimethylaminoethyl-methacrylate) diblock copolymer (pHPMA-b-pDMAEMA). Ethidium bromide intercalation and gel retardation assays demonstrated high DNA condensation capacity of pHPMA-b-pDMAEMA. Nanoparticles prepared with and without decoy ODNs did not significantly compromise cellular safety at N/P ratios ≤ 4. Transfection efficiency of pHPMA-b-pDMAEMA polyplexes (N/P = 4) in Caco-2 cells was comparable to TurboFect transfection standard, resulting in a 98% reduction in P-gp protein levels. As a pharmacodynamic consequence, intracellular accumulation of the P-gp substrate Rhodamine123 significantly increased by almost twofold. In conclusion, NF-κB ODN polyplexes fabricated with pHPMA-b-pDMAEMA polymer effectively reduced P-gp-mediated efflux activity in Caco-2 cells, suggesting successful interference with NF-κB-binding sites in the promoter region of the ABCB1 gene.

Multidrug resistance (MDR), a major cause for chemotherapy failure, has been linked to upregulation of ATP-dependent membrane efflux systems that limit intracellular accumulation of cytotoxic anticancer agents. P-glycoprotein (P-gp) encoded by the human ABCB1 gene was the first efflux transporter identified to contribute to MDR. ABCB1 gene expression is correlated with constitutive activation of the NF-κB signaling pathway in tumor cells. The objective of this research is to modulate P-gp activity in colon cancer cells using NF-κB decoy oligodeoxynucleotides (ODNs) that are effectively delivered into the nucleus of colorectal cancer cells by self-assembling nonviral nanoparticles comprising the novel poly[N-(2-hydroxypropyl)methacrylamide]-poly(N,N-dimethylaminoethyl-methacrylate) diblock copolymer (pHPMA-b-pDMAEMA). Ethidium bromide intercalation and gel retardation assays demonstrated high DNA condensation capacity of pHPMA-b-pDMAEMA. Nanoparticles prepared with and without decoy ODNs did not significantly compromise cellular safety at N/P ratios ≤ 4. Transfection efficiency of pHPMA-b-pDMAEMA polyplexes (N/P = 4) in Caco-2 cells was comparable to TurboFect transfection standard, resulting in a 98% reduction in P-gp protein levels. As a pharmacodynamic consequence, intracellular accumulation of the P-gp substrate Rhodamine123 significantly increased by almost twofold. In conclusion, NF-κB ODN polyplexes fabricated with pHPMA-b-pDMAEMA polymer effectively reduced P-gp-mediated efflux activity in Caco-2 cells, suggesting successful interference with NF-κB-binding sites in the promoter region of the ABCB1 gene.

Multidrug resistance (MDR), a major cause for chemotherapy failure, has been linked to upregulation of ATP-dependent membrane efflux systems that limit intracellular accumulation of cytotoxic anticancer agents. P-glycoprotein (P-gp) encoded by the human ABCB1 gene was the first efflux transporter identified to contribute to MDR. ABCB1 gene expression is correlated with constitutive activation of the NF-κB signaling pathway in tumor cells. The objective of this research is to modulate P-gp activity in colon cancer cells using NF-κB decoy oligodeoxynucleotides (ODNs) that are effectively delivered into the nucleus of colorectal cancer cells by self-assembling nonviral nanoparticles comprising the novel poly[N-(2-hydroxypropyl)methacrylamide]-poly(N,N-dimethylaminoethyl-methacrylate) diblock copolymer (pHPMA-b-pDMAEMA). Ethidium bromide intercalation and gel retardation assays demonstrated high DNA condensation capacity of pHPMA-b-pDMAEMA. Nanoparticles prepared with and without decoy ODNs did not significantly compromise cellular safety at N/P ratios ≤ 4. Transfection efficiency of pHPMA-b-pDMAEMA polyplexes (N/P = 4) in Caco-2 cells was comparable to TurboFect transfection standard, resulting in a 98% reduction in P-gp protein levels. As a pharmacodynamic consequence, intracellular accumulation of the P-gp substrate Rhodamine123 significantly increased by almost twofold. In conclusion, NF-κB ODN polyplexes fabricated with pHPMA-b-pDMAEMA polymer effectively reduced P-gp-mediated efflux activity in Caco-2 cells, suggesting successful interference with NF-κB-binding sites in the promoter region of the ABCB1 gene.

Even with the use of double-emulsion technique for preparation, the hydrophobic nature of solid lipid nanoparticles (SLNs) limits their encapsulation efficiency (EE%) for peptides such as insulin. In this study, we hypothesize that inclusion of Methocel into SLN to form Methocel-lipid hybrid nanocarriers (MLNs) will significantly enhance insulin EE% without compromising the various characteristics of SLN favorable for oral drug delivery. Our data show that incorporation of 2% wt/wt of Methocel A15C had doubled insulin EE% (around 40%) versus conventional SLN prepared using standard double emulsion technique. MLN significantly protected the entrapped insulin against chymotrypsin degradation at gastrointestinal pH. Using intestinal epithelial cells Caco2 as a model, it was shown that MLN could be extensively taken up by Caco2 cells while demonstrating low cytotoxicity. The results indicate that MLN have preserved the key advantages of SLN (biocompatibility, low cytotoxicity, good drug protection, and good interaction with cells) while overcoming their key limitation for efficient peptide entrapment. Based on this, MLN may serve as a promising nanocarrier for oral delivery of peptides.

Even with the use of double-emulsion technique for preparation, the hydrophobic nature of solid lipid nanoparticles (SLNs) limits their encapsulation efficiency (EE%) for peptides such as insulin. In this study, we hypothesize that inclusion of Methocel into SLN to form Methocel-lipid hybrid nanocarriers (MLNs) will significantly enhance insulin EE% without compromising the various characteristics of SLN favorable for oral drug delivery. Our data show that incorporation of 2% wt/wt of Methocel A15C had doubled insulin EE% (around 40%) versus conventional SLN prepared using standard double emulsion technique. MLN significantly protected the entrapped insulin against chymotrypsin degradation at gastrointestinal pH. Using intestinal epithelial cells Caco2 as a model, it was shown that MLN could be extensively taken up by Caco2 cells while demonstrating low cytotoxicity. The results indicate that MLN have preserved the key advantages of SLN (biocompatibility, low cytotoxicity, good drug protection, and good interaction with cells) while overcoming their key limitation for efficient peptide entrapment. Based on this, MLN may serve as a promising nanocarrier for oral delivery of peptides.

Even with the use of double-emulsion technique for preparation, the hydrophobic nature of solid lipid nanoparticles (SLNs) limits their encapsulation efficiency (EE%) for peptides such as insulin. In this study, we hypothesize that inclusion of Methocel into SLN to form Methocel-lipid hybrid nanocarriers (MLNs) will significantly enhance insulin EE% without compromising the various characteristics of SLN favorable for oral drug delivery. Our data show that incorporation of 2% wt/wt of Methocel A15C had doubled insulin EE% (around 40%) versus conventional SLN prepared using standard double emulsion technique. MLN significantly protected the entrapped insulin against chymotrypsin degradation at gastrointestinal pH. Using intestinal epithelial cells Caco2 as a model, it was shown that MLN could be extensively taken up by Caco2 cells while demonstrating low cytotoxicity. The results indicate that MLN have preserved the key advantages of SLN (biocompatibility, low cytotoxicity, good drug protection, and good interaction with cells) while overcoming their key limitation for efficient peptide entrapment. Based on this, MLN may serve as a promising nanocarrier for oral delivery of peptides.

Two series, a and b, of 3-cyclopentyl or (3-cyclohexyl)-5-substituted-3,4,5,6-tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTT) 2a-9a and 3b, 4b, 6b-9b, were synthesized to develop new cell cycle inhibitors. Variable and promising in vitro antiproliferative activities were shown with the synthesized THTT derivatives. Compound 5a with a 5-cyclopentyl group on position-3 and a glutamine residue on position-5 of the THTT moiety showed maximum activity (IC50 = 8.98 μM). Compound 5a possessed notable cell cycle disrupting and apoptotic activities with enhanced selectivity against cancer cells, suggesting the potential for the development of new selective cell cycle inhibitors. There is no evident relationship between the cytotoxic activity of the tested compounds and their lipophilicity. In addition, a pharmacophore based study was performed to explain the biological activity on structural bases. A successful model was generated with a good correlation with the observed activity.