Targeted delivery of etoposide to cancer cells by folate-modified nanostructured lipid drug delivery system

Abstract

Context: Cardiotoxicity and myelosuppression of etoposide (ETP) limited its clinical application. Targeted drug delivery system could deliver anticancer agents to the target cancerous cells, thus reducing their toxicity.

Objective: In this study, folate (FA) was applied for the construction of nanostructured lipid carriers (NLCs), and used for targeted delivery of ETP to tumors overexpresses the FA receptors.

Methods: FA-poly (ethylene glycol)-distearoylphosphatidylethanolamine was synthesized. FA decorated and ETP-loaded NLCs (FA-ETP-NLCs) were prepared and the formulation was optimized by Box–Behnken design. Their particle size (PS), zeta potential and drug encapsulation efficiency (EE) was evaluated. In vitro cytotoxicity studies of FA-ETP-NLCs were tested in CT26, SGC7901, NCI-H209 cell lines. In vivo antitumor efficacies of the carriers were evaluated on mice bearing CT26 cells xenografts.

Results: The optimum FA-ETP-NLCs formulations had a PS of 120.86?nm. The growth of CT26, SGC790 or NCI-H209 cells in vitro was obviously inhibited. FA-ETP-NLCs also displayed the best antitumor activity than other formulations in vivo.

Conclusion: The results demonstrated that FA-ETP-NLCs were efficient in selective delivery to CT26, SGC790 or NCI-H209 cells overexpressing the FA receptors. Also, FA-ETP-NLCs can sufficiently transfer ETP to the cancer cells, enhance the antitumor capacity. Thus, FA-ETP-NLCs could prove to be a superior nanomedicine to achieve tumor therapeutic efficacy.     

Anti-cancer activity of anti-GLUT1 antibody-targeted polymeric micelles co-loaded with curcumin and doxorubicin

Abstract

Background: Treatment of late stage cancers has proven to be a very difficult task. Targeted therapy and combinatory drug administration may be the solution.

Purpose: The study was performed to evaluate the therapeutic efficacy of PEG-PE micelles, co-loaded with curcumin (CUR) and doxorubicin (DOX), and targeted with anti-GLUT1 antibody (GLUT1) against HCT-116 human colorectal adenocarcinoma cells both in vitro and in vivo.

Methods: HCT-116 cells were treated with non-targeted and GLUT1-targeted CUR and DOX micelles as a single agent or in combination. Cells were inoculated in female nude mice. Established tumors were treated with the micellar formulations at a dose of 4?mg/kg CUR and 0.4?mg/kg DOX every 2?d for a total of 7 injections.

Results: CUR?+?DOX-loaded micelles decorated with GLUT1 had a robust killing effect even at low doses of DOX in vitro. At the doses chosen, non-targeted CUR and CUR?+?DOX micelles did not exhibit any significant tumor inhibition versus control. However, GLUT1-CUR and GLUT1-CUR?+?DOX micelles showed a significant tumor inhibition effect with an improvement in survival.

Conclusion: We showed a dramatic improvement in efficacy between the non-targeted and GLUT1-targeted formulations both in vitro and in vivo. Hence, we confirmed that GLUT1-CUR?+?DOX micelles are effective and deserve further investigation.     

Smilax glabra Roxb targets Aktp-Thr308 and inhibits Akt-mediated signaling pathways in SGC7901 cells

Background: Smilax glabra Roxb (SGR) as a novel anti-tumor agent has been paid attention in several types of cancer cells. However, the effect of SGR on SGC7901 cells has not been investigated.

Purpose: We investigate the effect and potential mechanisms of SGR on SGC7901 cells in this study.

Methods: Three kinds of gastric cancer cell lines (BGC823, SGC7901 and MKN45) and one kind of human embryonic kidney cell line (HEK293) were exposed to varying concentrations of SRG. Then, we observed the effect of SRG on these cell lines and the changes on proliferation, invasion and apoptosis. Finally, we detected the signaling pathway in which SGR may involve.

Results: SGR effectively suppressed the proliferation of SGC7901 cell lines by inhibiting the phosphorylation of Akt (Thr308). Moreover, we found SGR could significantly induce SGC7901 cell lines apoptosis by inhibiting Akt^p-Thr308/Bad pathway and inhibit its migration and invasion partly by inhibiting Akt^p-Thr308/MMPs pathway.

Discussion: SGR could effectively suppress the proliferation and invasion of SGC7901 cell lines by inhibiting the phosphorylation of Akt (Thr308) and its downstream relative pathways.

Conclusion: SGR could effectively suppress the phosphorylation of Akt (Thr308) and then inhibit the proliferation and invasion of SGC7901 cell and enhance its apoptosis through Akt-mediated signaling pathways.     

CPT21, a novel compound with anti-proliferative effect against gastric cancer cell SGC7901

Summary  7-[(3-piperidyl)-1-propinyl]-camptothecin (CPT21) is a novel semi-synthetic water-soluble analogue of camptothecin. In this context, we assessed the anti-tumor activity of CPT21 both in vivo and in vitro and explored its molecular mechanism. We found that CPT21 presented a broad anti-tumor spectrum against ten cancer cell lines in vitro, and the IC₅₀ values ranged from 0.1 to 12.0 μM. CPT21 was also capable to interrupt the DNA topoisemerase I activity and caused DNA double strand breaks during DNA replication. Proportion of apoptotic SGC7901 cells induced by CPT21 showed a time- and concentration-dependent increase accompanied with the decrease in mitochondria membrane potential (ΔΨm). We also observed that CPT21 up-regulated the protein expression of p53, phospho-p53, p21, BAX, phospho-c-Jun NH2-terminal protein kinase (JNK), meanwhile down-regulating the protein expression of Bcl-2, procaspase-9, XIAP, and phospho-ERK1/2. In the study of SGC7901 xenograft model, the results suggested that both 5.0 mg/kg and 10.0 mg/kg CPT21 achieved high anti-tumor activity, and the tumor inhibition rates were 42.5% and 75.1% respectively. Taken together, our study demonstrates that CPT21 displays an extensive anti-tumor spectrum and CPT21 can induce the apoptosis of SGC7901 cells via activating the caspases cascade followed by disrupting mitochondrion function.     

pH triggered delivery of curcumin from Eudragit-coated chitosan microspheres for inflammatory bowel disease: characterization and pharmacodynamic evaluation

Objective: This investigation deals with the development and evaluation (in vitro and in vivo) of pH triggered Eudragit-coated chitosan microspheres of curcumin (CUR) for treating ulcerative colitis.

Methods: CUR-loaded chitosan microspheres were initially prepared by emulsion cross linking method followed by coating with Eudragit S-100. The pharmacodynamics of the developed formulation was analyzed in mice by acetic acid induced colitis model.

Results: The developed microspheres were of uniform spherical shape with high entrapment efficiency. CUR-chitosan microspheres showed less intense peaks compared to free CUR confirming inclusion of drug within microspheres as revealed by X-ray diffractogram. Uncoated CUR-chitosan microspheres exhibited burst release within initial 4?h while microspheres coated with Eudragit S-100 prevented premature release of CUR and showed controlled release up to 12?h following Higuchi model. In vivo organ biodistribution study showed negligible amount of CUR in stomach and small intestine confirming integrity of microsphere in upper gastrointestinal tract (GIT). In vivo study revealed significant reduction in severity and extent of colonic damage with CUR-loaded microspheres as compared to pure CUR which was further confirmed by histopathological study.

Conclusion: In vitro and in vivo studies proved the developed formulations as a promising system for pH-dependent delivery of drug to colon in ulcerative colitis.     

Which one performs better for targeted lung cancer combination therapy: pre- or post-bombesin-decorated nanostructured lipid carriers?

Abstract

Purpose: The co-delivery of gene and drugs has the potential to treat cancer. The aim of this study was to compare post-bombesin decorated nanostructured lipid carriers (NLC) carrying both doxorubicin (DOX) and DNA with pre-bombesin decorated NLC for lung cancer therapy.

Methods: Post-bombesin decorated NLC were prepared by two steps. First, DOX and DNA-loaded NLC (DOX-DNA-NLC) was prepared. Second, Bombesin-NH₂ (BN-NH₂) was added into DOX-DNA-NLC to react with stearic acid-polyethylene glycol-COOH (SA-PEG-COOH) loaded in NLC. Pre-bombesin decorated NLC were prepared by two steps. First, Bombesin (BN)-conjugated ligands were synthesized. Second, DOX and DNA were loaded into BN decorated NLC. Their average size, zeta potential, drug and gene loading were evaluated. NCl-H460 human non-small lung cancer cells (NCl-H460 cells) were used for the testing of in vitro transfection efficiency and in vitro cytotoxicity. In vivo transfection efficiency and anti-tumor effect of NLC were evaluated on mice bearing NCl-H460 cells model.

Results: Post-bombesin decorated NLC has a particle size of 128?nm, DOX encapsulation efficiency (EE) of 85% and DNA EE of 91%. Pre-bombesin decorated NLC has a particle size of 101?nm, DOX EE of 86% and DNA EE of 92%. Post-bombesin decorated NLC displayed more stable and remarkably higher transfection efficiency and better anti-tumor ability than pre-bombesin decorated NLC both in vitro and in vivo.

Conclusion: Post-bombesin decorated NLC could function as better carriers to improve the cell targeting and nuclear targeting ability. The resulting nanomedicine could be a promising active targeting drug/gene therapeutic system for lung cancer therapy.     

High drug payload curcumin nanosuspensions stabilized by mPEG-DSPE and SPC: in vitro and in vivo evaluation

Context: Curcumin (CUR) is a promising drug candidate based on its broad bioactivities and good antitumor effect, but the application of CUR is potentially restricted because of its poor solubility and bioavailability.

Objective: This study aims at developing a simple and effective drug delivery system for CUR to enhance its solubility and bioavailability thus to improve its antitumor efficacy.

Materials and methods: Curcumin nanosuspensions (CUR-NSps) were prepared by precipitation-ultrasonication method using mPEG2000-DSPE and soybean lecithin as a combined stabilizer.

Results: CUR-NSps with a high drug payload of 67.07% were successfully prepared. The resultant CUR-NSps had a mean particle size of 186.33?±?2.73?nm with a zeta potential of ?19.00?±?1.31?mV. In vitro cytotoxicity assay showed that CUR-NSps exhibited enhanced cytotoxicity compared to CUR solution. The pharmacokinetics results demonstrated that CUR-NSps exhibited a significantly greater AUC_0–24 and prolonged MRT compared to CUR injections after intravenous administration. In the biodistribution study, CUR-NSps demonstrated enhanced biodistribution compared with CUR injections in liver, spleen, kidney, brain, and tumor. The CUR-NSps also showed improved antitumor therapeutic efficacy over the injections (70.34% versus 40.03%, p?Conclusions: These results suggest that CUR-NSps might represent a promising drug formulation for intravenous administration of CUR for the treatment of cancer.     

The effective combination therapy against human osteosarcoma: doxorubicin plus curcumin co-encapsulated lipid-coated polymeric nanoparticulate drug delivery system

Objective: To overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) in osteosarcoma (OS), biodegradable lipid-coated polymeric nanoparticles (LPNs) were explored for the loading of doxorubicin (DOX) and curcumin (CUR).

Methods: DOX plus CUR co-encapsulated LPNs (DOX?+?CUR LPNs) of mixed lipid monolayer shell and biodegradable polymer core were prepared. The cytotoxicity effect of DOX?+?CUR LPNs, single drug loaded LPNs, and free drug solutions were evaluated on human OS cell line KHOS cells and mice KHOS cells xenograft in vivo.

Results: DOX?+?CUR LPNs displayed a curative effect on OS cell lines than the free drug counterparts. Also, best anti-OS effects were observed on the animal model compared with other groups tested.

Conclusion: This promising dual drugs co-encapsulated lipid-coated polymeric nanoparticulate drug delivery system enhanced the cell delivery and activity of drugs against human OS cancer cell lines and in cancer bearing mice. This research may offer new options for the treatment of OS.     

Breast cancer targeted chemotherapy based on doxorubicin-loaded bombesin peptide modified nanocarriers

Context: Breast cancer is the most common cancer in female population. Breast cancer chemotherapy using doxorubicin (DOX) is well illustrated. However, a significant obstacle for successful chemotherapy with DOX is multidrug resistant (MDR) in breast cancer cells. Targeted nanocarriers have emerged as frontier research for the improvement of cancer chemotherapy.

Objective: Bombesin (Bn)-modified, DOX-loaded solid lipid nanoparticles (Bn-DOX/SLNs) were constructed. Doxorubicin-resistant MCF-7/MDR human breast cancer cells and the cancer animal models were applied for the evaluation of the in vitro and in vivo anti-tumor effect of Bn-DOX/SLNs.

Methods: Bn-conjugated lipids were synthesized. DOX was then loaded into Bn-modified SLNs. The physicochemical properties of the Bn-DOX/SLNs were investigated by particle size and zeta potential measurement, drug loading and drug-entrapment efficiency, and in vitro drug release behavior. In vitro cytotoxicity against MCF-7/MDR cells was investigated, and in vivo anti-tumor of SLNs was evaluated in human breast cancer mice models.

Results: Bn-DOX/SLNs showed an excellent in vitro cytotoxicity and in vivo anti-tumor effect both in MCF-7/MDR breast cancer cells and breast cancer animal model.

Conclusion: The results demonstrated that Bn-DOX/SLNs reversed the resistance of doxorubicin, suggesting that chemotherapy using this kind of targeted nanocarriers may benefit human breast MDR cancer therapy.     

基于miRNAs的知母水提物体外抑制胃癌细胞SGC7901增殖作用机制

目的 从微小核苷酸（miRNAs）的角度研究知母水提物（aqueous extract from Anemarrhenae Rhizoma,ARAE）体外抑制SGC7901细胞增殖的作用机制。方法 采用MTT法检测ARAE对SGC7901细胞增殖的影响;采用流式细胞术检测ARAE对SGC7901细胞凋亡的影响;采用高通量测序法检测细胞中miRNAs的表达丰度差异;采用miranda、mirbase和targetscan 3个数据库信息比对,预测差异miRNAs的靶基因,并通过KEGG分析靶基因的相关功能;采用实时荧光定量PCR法验证主要靶基因的表达变化。结果 ARAE能明显抑制SGC7901细胞的增殖并诱导其凋亡,调节细胞miR-16-5p、miR-20a-5p、miR-26b-5p和miR-15b-5p的表达水平;并提示这些miRNAs所调控的靶基因主要富集于PI3K-Akt、JAK-STAT和MAPK等信号通路。结论 ARAE可能通过调节SGC7901细胞内miRNAs的表达从而抑制SGC7901细胞增殖,并诱导其凋亡。     

Dihydrotanshinone induces apoptosis of SGC7901 and MGC803 cells via activation of JNK and p38 signalling pathways

Context: Dihydrotanshinone (DHT), a natural compound from Salvia miltiorrhiza Bunge (Lamiaceae), showed higher cytotoxic potential compared with other tanshinones. Its effect and mechanism on gastric cancer have not been investigated.

Objective: This study evaluates the effects of DHT on cell proliferation and apoptosis on gastric cancer cells, and elucidates its molecular mechanisms.

Materials and methods: Human gastric cancer MGC803 and SGC7901 cells were treated with various concentrations of DHT (0–15?μM) for 24 and 48?h, and cell growth was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Cell apoptosis was analysed by flow cytometry and DAPI staining. Western blots were performed to investigate changes in the level of apoptosis related genes in gastric cancer cell.

Results: DHT exhibited obvious inhibition of the survival of gastric cancer cells. The IC₅₀ values in SGC7901 and MGC803 cells were 9.14 and 5.39?μM for 24?h, respectively. Cells treated with 6?μM DHT resulted in 41.3% and 35.4% apoptotic cell fractions in SGC7901 and MGC803 cells, respectively, significantly higher than that of the control. Hallmarks of apoptosis were observed in gastric cancer cells after DHT exposure. DHT enhanced the expression levels of cleaved caspase-3, caspase-9 and poly-ADP-ribose polymerases. Furthermore, DHT increased the phosphorylation of JNK and p38 in SGC7901 and MGC803 cells.

Conclusion: DHT induced growth inhibition and apoptosis of gastric cancer cells, involving activation of caspase proteins and the JNK/p38 signaling pathway. The results indicated that DHT has a promising chemotherapeutic potential for human gastric cancer.     

Enhanced tumor targeting effects of a novel paclitaxel-loaded polymer: PEG–PCCL-modified magnetic iron oxide nanoparticles

Background: Multifunctional magnetic nanoparticles (MNP) have been newly developed for tumor-targeted drug carriers. To address challenges including biocompatibility, stability, nontoxicity, and targeting efficiency, here we report the novel drug deliverer poly(ethylene glycol) carboxyl–poly(?-caprolactone) modified MNP (PEG–PCCL-MNP) suitable for magnetic targeting based on our previous studies.

Methods: Their in vitro characterization and cytotoxicity assessments, in vivo cytotoxicity assessments, and antitumor efficacy study were elaborately investigated.

Results: The size of PEG–PCCL-MNP was 79.6?±?0.945?nm. PEG–PCCL-MNP showed little in vitro or in vivo cytotoxicity and good biocompatibility, as well as effective tumor-specific cell targeting for drug delivery with the presence of external magnetic field.

Discussion: PEG–PCCL-MNP is a potential candidate of biocompatible and tumor-specific targeting drug vehicle for hydrophobic drugs.     

Development and optimization of curcumin-loaded mannosylated chitosan nanoparticles using response surface methodology in the treatment of visceral leishmaniasis

Objective: The study aims at formulation and optimization of macrophage-targeted curcumin-loaded mannosylated chitosan nanoparticles (Cur-MCNPs) of curcumin (CUR) to improve its therapeutic potential in the treatment of visceral leishmaniasis (VL).

Methods: Response surface methodology (RSM) using central composite design was employed to study the effect of formulation factors on physicochemical-dependent characteristics. Chitosan was coupled with d-mannose, by reductive amination, to prepare a mannosylated chitosan, a conjugate polymer and a subsequent formulation of Cur-MCNPs. Optimized formulation prepared using RSM was evaluated for in vitro release kinetics at physiological pH 7.4 and endosomal macrophage pH 4.5; in vivo pharmacokinetic profile and targeting potential were evaluated by fluorescence microscopy.

Results: Optimized Cur-MCNPs exhibited spherical and smooth surface with a mean particle size of 215 nm, polydispersity index of 0.381, zeta potential of + 24.37 mV and % entrapment efficiency of 82.12%. The pharmacokinetic study of optimized Cur-MCNPs showed significant improvement in the value of mean resident time (39.38 h) compared to free CUR solution (0.30 h) (p < 0.05). In vivo uptake study indicated that endocytosis took place effectively within the macrophages of reticuloendothelial system.

Conclusions: Thus, Cur-MCNPs could be considered as a promising delivery strategy towards active targeting of CUR to macrophages for the effective treatment of VL.     

Cerenkov luminescence imaging on evaluation of early response to chemotherapy of drug-resistant gastric cancer

Apoptosis imaging enables a timely and specific assessment of treatment response in cancer patients. In this study, we applied a probe for positron emission tomography (PET), which served as an optical biomaterial emitting Cerenkov photons, to in vivo optical imaging of tumor apoptosis, in order to evaluate early response to chemotherapy of drug-resistant gastric cancer. ⁶⁸Ga-DOTA-Annexin V was prepared as the apoptosis targeting probe. Wild type human gastric adenocarcinoma cell line SGC7901/WT and drug vincristine-resistant variant SGC7901/VCR were used to establish normal and vincristine-resistant xenografts to simulate treatment decision situation. Vincristine-resistance of SGC7901/VCR and apoptosis-induction ability of vincristine and cisplatin were verified. In vitro and in vivo CLI of apoptosis was performed. Stronger signals of apoptosis of CLI correlated with confirmed higher levels of apoptosis and subsequent changes in tumor sizes. Our study suggests that CLI is a promising technique for in vivo imaging of apoptosis with radiopharmaceutical-labeled biomaterials.     

A promising targeted gene delivery system: Folate-modified dexamethasone-conjugated solid lipid nanoparticles

Context: Non-viral gene delivery could deliver drugs/genes through cellular membranes and nuclear membranes by some modification of materials.

Objective: This study develops a kind of vector to target the cells through receptor-mediated pathways. Nuclear localization signal (NLS) was also used to increase the nuclear uptake of genetic materials.

Materials and methods: A lipid containing dexamethasone (Dexa) was synthesized as the material of the preparation of solid lipid nanoparticles (SLNs) and folate (Fa)-conjugated PEG-PE (Fa-PEG-PE) ligands were used to modify the SLNs. The in vitro cytotoxicity of the carriers at various concentrations (10, 20, 50, 100, and 200?μg/ml) were evaluated in KB human carcinoma cells (KB cells). In vivo transfection efficiency of the novel modified vectors was evaluated in disseminated peritoneal tumors on mice bearing KB cells.

Results: Fa-PEG-PE modified SLNs/enhanced green fluorescence protein plasmid (pEGFP) has a particle size of 258?nm, and the gene loading quantity of the vector was 90%. The in vitro cytotoxicity of Fa-PEG-PE-modified SLNs/pEGFP (Fa-SLNs/pEGFP) was low (cell viabilities were between 80% and 100% compared with controls). Fa-SLNs/pEGFP displayed remarkably higher transfection efficiency (40%) than non-modified SLNs/pEGFP (24%) and the vectors not containing Dexa (30%) in vivo.

Conclusion: The results demonstrate that Fa and Dexa could function as excellent active targeting ligands to improve the cell targeting and nuclear targeting ability of the carriers and the resulting vectors could be promising active targeting drug/gene delivery systems.     

Cisplatin and paclitaxel co-delivered by folate-decorated lipid carriers for the treatment of head and neck cancer

Context: For head and neck cancer therapy, co-delivery of two drugs, cisplatin (DDP) plus paclitaxel (PTX), are more effective than single drug therapy. Lipid carriers are promising drug carriers for anti-cancer delivery.

Objective: The aim of this study is to construct a folate (FA) decorated nanostructured lipid carriers (NLCs) as nanocarriers for DDP and PTX delivery.

Materials and methods: In this study, DDP and PTX were incorporated into NLCs. Folate-PEG-DSPE (FA-PEG-DSPE) was synthesized and decorated the drugs-loaded NLCs (FA-DDP/PTX NLCs). Their average size, zeta potential, drug encapsulation efficiency, drug loading capacity, and in vitro drug release were evaluated. Head and neck cancer cells (FaDu cells) were used for the testing of in vitro cytotoxicity, and in vivo transfection efficiency of NLC was evaluated on mice bearing FaDu cells model.

Results: The size of FA-DDP/PTX NLCs was around 127?nm, with a positive zeta potential of 26.7?mV. FA-DDP/PTX NLCs showed the highest cytotoxicity and synergistic effect of two drugs in head and neck cancer cells (FaDu cells) in vitro. The in vivo study revealed the greatest anti-tumor activity than all the other formulations in murine-bearing head and neck cancer model.

Discussion and conclusion: FA-DDP/PTX NLCs effectively improves anticancer efficiency for head and neck cancer in vitro and in vivo. The constructed NLCs could be used as a novel carrier to co-delivery DDP and PTX for head and neck cancer therapy.     

Nanostructured lipid carriers,solid lipid nanoparticles,and polymeric nanoparticles: which kind of drug delivery system is better for glioblastoma chemotherapy?

Context: Glioblastoma is a malignant brain tumor originating in the central nervous system. Successfully therapy of this disease required the efficient delivery of therapeutic agents to the tumor cells and tissues. Delivery of anticancer drugs using novel nanocarriers is promising in glioma treatment.

Objective: Polymeric nanoparticles (PNPs), solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) were constructed for the delivery of temozolomide (TMZ). The anti-tumor effects of the three kinds of nanocarriers were compared to provide the optimum choice for gliomatosis cerebri treatment.

Methods: TMZ-loaded PNPs (T-PNPs), SLNs (T-SLNs), and NLCs (T-NLCs) were formulated. Their particle size, zeta potential, drug encapsulation efficiency (EE), and drug loading (DL) capacity were evaluated. Anti-tumor efficacies of the three kinds of nanocarriers were evaluated on U87 malignant glioma cells (U87?MG cells) and mice-bearing malignant glioma model.

Results: T-NLCs displayed the best anti-tumor activity than other formulations in vivo and in vitro. The most significantly glioma inhibition was observed on NLCs formulations than PNPs and SLNs.

Conclusion: This work demonstrates that NLCs can deliver TMZ into U87MG cells more efficiently, with higher inhibition efficacy than PNPs and SLNs. T-NLCs could be an excellent drug delivery system for glioblastoma chemotherapy.     

Thermosensitive in situ nanogel as ophthalmic delivery system of curcumin: development,characterization, in vitro permeation and in vivo pharmacokinetic studies

Context: The nanogel combining cationic nanostructured lipid carriers (CNLC) and thermosensitive gelling agent could enhance preocular retention and ocular permeation capacity of curcumin (CUR).

Objective: The purpose of the study was to develop and characterize a thermosensitive ophthalmic in situ nanogel of CUR-CNLC (CUR-CNLC-GEL) and evaluate in vitro and in vivo properties of the formulations.

Materials and methods: The physicochemical properties, in vitro release and corneal permeation, were evaluated. Ocular irritation and preocular retention capacity were also conducted. Finally, pharmacokinetic study in the aqueous humor was investigated by microdialysis technique.

Results: The solution–gel transition temperature of the optimized formulation diluted by simulated tear fluid was 34?±?1.0?°C. The CUR-CNLC-GEL displayed zero-order release kinetics. The apparent permeability coefficient (P_app) and the area under the curve (AUC_0→∞) of CUR-CNLC-GEL were 1.56-fold and 9.24-fold, respectively, than those of curcumin solution (CUR-SOL, p?<?0.01). The maximal concentration (C_max) was significantly improved (p?<?0.01). The prolonged mean residence time (p?<?0.01) indicated that CUR-CNLC-GEL is a controlled release formulation.

Discussion and conclusion: Those results demonstrated that CUR-CNLC-GEL could become a potential formulation for increasing the bioavailability of CUR in the aqueous humor by enhancing corneal permeation and retention capacity.     

Folate-modified doxorubicin-loaded nanoparticles for tumor-targeted therapy

Context: Polymeric nanoparticles (NPs) have been used frequently as drug delivery vehicles. Surface modification of polymeric NPs with specific ligands defines a new biological identity, which assists in targeting of the nanocarriers to specific cancers cells.

Objective: The aim of this study is to develop a kind of modified vector which could target the cancer cells through receptor-mediated pathways to increase the uptake of doxorubicin (DOX).

Methods: Folate (FA)-conjugated PEG–PE (FA–PEG–PE) ligands were used to modify the polymeric NPs. The modification rate was optimized and the physical–chemical characteristics, in vitro release, and cytotoxicity of the vehicle were evaluated. The in vivo therapeutic effect of the vectors was evaluated in human nasopharyngeal carcinoma KB cells baring mice by giving each mouse 100?µl of 10?mg/kg different solutions.

Results: FA–PEG–PE-modified NPs/DOX (FA-NPs/DOX) have a particle size of 229?nm, and 86% of drug loading quantity. FA-NPs/DOX displayed remarkably higher cytotoxicity (812?mm³ tumor volume after 13?d of injection) than non-modified NPs/DOX (1290?mm³) and free DOX solution (1832?mm³) in vivo.

Conclusion: The results demonstrate that the modified drug delivery system (DDS) could function comprehensively to improve the efficacy of cancer therapy. Consequently, the system was shown to be a promising carrier for delivery of DOX, leading to the efficiency of antitumor therapy.     

In vivo comparison of wound healing and scar treatment effect between curcumin–oligochitosan nanoparticle complex and oligochitosan-coated curcumin-loaded-liposome

This study aimed to compare the in vivo effectiveness between curcumin–oligochitosan nanoplexes (CUR–OCH nanoplexes) and oligochitosan-coated curcumin-encapsulated liposomes (OCH-Lip-CUR) with respect to wound healing and scar treatment. Firstly, CUR-OCH nanoplexes was prepared by drug-polysaccharide complexation method and OCH-Lip-CUR was prepared by a combining method of lipid-film hydration and sonication. Their in vitro cytotoxicity and in vivo wound healing and scar treatment effectiveness were evaluated using 3T3 cells and mice Mus musculus var. Albino, respectively. The resutls indicated that both of them were in nanosize with a moderate PDI (less than 0.3), and exhibited negligible cytotoxicity at low CUR concentration (0.01?mg/mL). Moreover, their application onto wounds resulted in faster healing and higher scar treatment effectiveness than control samples. Interestingly, OCH-Lip-CUR exhibited higher in vivo effectiveness than CUR-OCH nanoplexes. However, based on their own advantages, both of them were good candidates for a commercial formulation for wound healing and scar treatment.