Co-Delivery of Curcumin and Paclitaxel by "Core-Shell" Targeting Amphiphilic Copolymer to Reverse Resistance in the Treatment of Ovarian Cancer.

BACKGROUND: Ovarian cancer is a common malignancy in the female reproductive system with a high mortality rate. The most important reason is multidrug resistance (MDR) of cancer chemotherapy. To reduce side effects, reverse resistance and improve efficacy for the treatment of ovarian cancer, a "core-shell" polymeric nanoparticle-mediated curcumin and paclitaxel co-delivery platform was designed. METHODS: Nuclear magnetic resonance confirmed the successful grafting of polyethylenimine (PEI) and stearic acid (SA) (PEI-SA), which is designed as a mother core for transport carrier. Then, PEI-SA was modified with hyaluronic acid (HA) and physicochemical properties were examined. To understand the regulatory mechanism of resistance and measure the anti-tumor efficacy of the treatments, cytotoxicity assay, cellular uptake, P-glycoprotein (P-gp) expression and migration experiment of ovarian cancer cells were performed. In addition, adverse reactions of nanoformulation to the reproductive system were examined. RESULTS: HA-modified drug-loaded PEI-SA had a narrow size of about 189 nm in diameters, and the particle size was suitable for endocytosis. The nanocarrier could target specifically to CD44 receptor on the ovarian cancer cell membrane. Co-delivery of curcumin and paclitaxel by the nanocarriers exerts synergistic anti-ovarian cancer effects on chemosensitive human ovarian cancer cells (SKOV3) and multi-drug resistant variant (SKOV3-TR30) in vitro, and it also shows a good anti-tumor effect in ovarian tumor-bearing nude mice. The mechanism of reversing drug resistance may be that the nanoparticles inhibit the efflux of P-gp, inhibit the migration of tumor cells, and curcumin synergistically reverses the resistance of PTX to increase antitumor activity. It is worth noting that the treatment did not cause significant toxicity to the uterus and ovaries with the observation of macroscopic and microscopic. CONCLUSION: This special structure of targeting nanoparticles co-delivery with the curcumin and paclitaxel can increase the anti-tumor efficacy without increasing the adverse reactions as a promising strategy for therapy ovarian cancer.

Hyaluronic acid reagent functional chitosan-PEI conjugate with AQP2-siRNA suppressed endometriotic lesion formation.

To identify a new drug candidate for treating endometriosis which has fewer side effects, a new polymeric nanoparticle gene delivery system consisting of polyethylenimine-grafted chitosan oligosaccharide (CSO-PEI) with hyaluronic acid (HA) and small interfering RNA (siRNA) was designed. There was no obvious difference in sizes observed between (CSO-PEI/siRNA)HA and CSO-PEI/siRNA, but the fluorescence accumulation in the endometriotic lesion was more significant for (CSO-PEI/siRNA)HA compared with CSO-PEI/siRNA due to the specific binding of HA to CD44. In addition, the (CSO-PEI/siRNA)HA nanoparticle gene therapy significantly decreased the endometriotic lesion sizes with atrophy and degeneration of the ectopic endometrium. The epithelial cells of ectopic endometrium from rat models of endometriosis showed a significantly lower CD44 expression than control after treatment with (CSO-PEI/siRNA)HA. Furthermore, observation under an electron microscope showed no obvious toxic effect on the reproductive organs. Therefore, (CSO-PEI/siRNA)HA gene delivery system can be used as an effective method for the treatment of endometriosis.

Gene therapy of endometriosis introduced by polymeric micelles with glycolipid-like structure.

To reduce the side effects and improve the lack of clinical treatment countermeasures in endometriosis chemotherapy, a polymeric micelle gene delivery system composed of lipid grafted chitosan micelles (CSO-SA) and the pigment epithelium derived factor (PEDF) was designed. Due to the cationic property, the glycolipid-like micelles could compact the PEDF to form complexes nanoparticles. The complexes nanoparticles with an N/P at 9.6 had 135.6 nm volume average hydrodynamic diameters with a narrow size distribution, and 6.4 ± 0.1 mV surface potential. PEDF can be distributed to endometriotic lesions in a rat model of peritoneal endometriosis mediated by CSO-SA via the intravenous injection. It showed that the CSO-SA/PEDF nanoparticles gene therapy caused decrease in the sizes of the endometriotic lesions and atrophy and degeneration of ectopic endometrium significantly. And it showed no toxicity to the reproductive organs under electron microscope observation. In addition, a reduction in microvessel density labeled by Von Willebrand factor was observed and no decrease in α-Smooth Muscle Actine-positive mature vessels. And the index of apoptotic was increased significantly in endometriotic lesions of CSO-SA/PEDF group. So, glycolipid-like structure micelles mediated PEDF gene delivery system could be used as an effective treatment approach for endometriosis disease.

RGD peptide-mediated chitosan-based polymeric micelles targeting delivery for integrin-overexpressing tumor cells.

BACKGROUND: Solid tumors need new blood vessels to feed and nourish them as well as to allow tumor cells to escape into the circulation and lodge in other organs, which is termed "angiogenesis." Some tumor cells within solid tumors can overexpress integrins α(v)ß(3) and α(v)ß(5), which can specifically recognize the peptide motif Arg-Gly-Asp (RGD). Thus, the targeting of RGD-modified micelles to tumor vasculature is a promising strategy for tumor-targeting treatment. METHODS: RGD peptide (GSSSGRGDSPA) was coupled to poly(ethylene glycol)-modified stearic acid-grafted chitosan (PEG-CS-SA) micelles via chemical reaction in the presence of N,N'-Disuccinimidyl carbonate. The critical micelle concentration of the polymeric micelles was determined by measuring the fluorescence intensity of pyrene as a fluorescent probe. The micelle size, size distribution, and zeta potential were measured by light scattering and electrophoretic mobility. Doxorubicin (DOX) was chosen as a model anticancer drug to investigate the drug entrapment efficiency, in vitro drug-release profile, and in vitro antitumor activities of drug-loaded RGD-PEG-CS-SA micelles in cells that overexpress integrins (α(ν)ß(3) and α(ν)ß(5)) and integrin-deficient cells. RESULTS: Using DOX as a model drug, the drug encapsulation efficiency could reach 90%, and the in vitro drug-release profiles suggested that the micelles could be used as a controlled-release carrier for the hydrophobic drug. Qualitative and quantitative analysis of cellular uptake indicated that RGD-modified micelles could significantly increase the DOX concentration in integrin-overexpressing human hepatocellular carcinoma cell line (BEL-7402), but not in human epithelial carcinoma cell line (Hela). The competitive cellular-uptake test showed that the cellular uptake of RGD-modified micelles in BEL-7402 cells was significantly inhibited in the presence of excess free RGD peptides. In vitro cytotoxicity tests demonstrated DOX-loaded RGD-modified micelles could specifically enhance the cytotoxicity against BEL-7402 compared with DOX-loaded PEG-CS-SA and doxorubicin hydrochlorate. CONCLUSION: This study suggests that RGD-modified PEG-CS-SA micelles are promising drug carriers for integrin-overexpressing tumor active targeting therapy.

[Study on the mechanism of discoloration and the efficacy of bleaching in non-infected traumatically discolored teeth].

OBJECTIVE: To investigate the mechanism of discoloration and the efficacy of bleaching in non-infected traumatically discolored teeth. METHODS: In vitro model of discolored teeth: sample of fresh erythrocytes was placed in the pulp cavity of 20 extracted teeth and centrifuged for 3 consecutive days. These discolored teeth were divided equally and randomly into two groups: group A (control group); group B (bleaching group), bleached with 10% carbamide peroxide gel for 4 weeks. And then all teeth were prepared for histological examination and subjected to a series of histochemical tests to analyze some of the biochemical changes following haemorrhage into the pulp chamber and post-bleaching. RESULTS: Haemoglobin and haematin were detected in the dentinal tubules of discolored teeth from group A and no evidence of ferric or haemosiderin. Specimens from group B demonstrated a negative response to histochemical tests. CONCLUSIONS: In the absence of bacterial invasive, haemoglobin and haematin could cause discoloration of non-infected traumatized teeth. Peroxide bleaching agent can effectively remove haemoglobin and haematin.