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Hyaluronan-coated solid nanoemulsions with high payload of paclitaxel for tumor specific delivery
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.advisor | 박영준 | - |
| dc.contributor.author | 김주은 | - |
| dc.date.accessioned | 2018-11-08T08:22:53Z | - |
| dc.date.available | 2018-11-08T08:22:53Z | - |
| dc.date.issued | 2017-08 | - |
| dc.identifier.other | 25562 | - |
| dc.identifier.uri | https://dspace.ajou.ac.kr/handle/2018.oak/13391 | - |
| dc.description | 학위논문(박사)--아주대학교 일반대학원 :약학,2017. 8 | - |
| dc.description.tableofcontents | 1. Introduction 1 1.1. Background 1 1.2. Direction of research 5 1.3. Objective 5 2. Materials and methods 6 2.1. Materials 6 2.2. Preparation of SNs and HSNs 7 2.3. Preparation of PTX-SNs and PTX-HSNs 9 2.4. HPLC analysis 10 2.5. Drug loading efficiency (LE) and encapsulation efficiency (EE) 10 2.6. HA content 11 2.7. Physicochemical properties 12 2.8. Stability studies 13 2.9. In vitro cell affinity studies 14 2.10. In vitro release studies 15 2.11. In vivo toxicity studies 16 2.12. Antitumor efficacy for ovarian cancer 17 2.13. Antitumor efficacy for non-small cell lung cancer 19 2.14. Change in body weight and tissue weight 21 2.15. In vivo pharmacokinetics study 21 2.16. Tissue distribution 22 3. Results and Discussion 24 3.1. Preparation and characterization of SNs and HSNs 24 3.2. Preparation and characterization of PTX-SNs and PTX-HSNs 31 3.3. HA content 35 3.4. Stability of lyophilized PTX-SN and PTX-HSN formulations and reconstituted solutions 37 3.5. In vitro cell affinity studies 42 3.6. In vitro release studies 47 3.7. In vivo toxicity studies 49 3.8. Antitumor efficacy for ovarian cancer 52 3.9. Antitumor efficacy for non-small cell lung cancer 56 3.10. Change in body weight and Tissue weight 60 3.11. In vivo pharmacokinetic study 64 3.12. Tissue distribution 68 4. Conclusion 75 5. References 78 Appendix 82 국문초록 85 감사의 글 87 | - |
| dc.language.iso | eng | - |
| dc.publisher | The Graduate School, Ajou University | - |
| dc.rights | 아주대학교 논문은 저작권에 의해 보호받습니다. | - |
| dc.title | Hyaluronan-coated solid nanoemulsions with high payload of paclitaxel for tumor specific delivery | - |
| dc.title.alternative | Hyaluronan-coated solid nanoemulsions with high payload of paclitaxel for tumor specific delivery | - |
| dc.type | Thesis | - |
| dc.contributor.affiliation | 아주대학교 일반대학원 | - |
| dc.contributor.alternativeName | Joo-Eun Kim | - |
| dc.contributor.department | 일반대학원 약학 | - |
| dc.date.awarded | 2017. 8 | - |
| dc.description.degree | Doctoral | - |
| dc.identifier.localId | 788442 | - |
| dc.identifier.url | http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000025562 | - |
| dc.subject.keyword | Hyaluronan solid-nanoemulsion | - |
| dc.subject.keyword | Tumor targeting | - |
| dc.subject.keyword | MTD | - |
| dc.subject.keyword | Ovarian cancer and non-small cell lung cancer | - |
| dc.subject.keyword | Paclitaxel. | - |
| dc.description.alternativeAbstract | Paclitaxel-loaded hyaluronan solid-nanoemulsions (PTX-HSNs) were successfully fabricated for the delivery of PTX with a high MTD to improve ovarian cancer and non-small cell lung cancer treatment via active tumor targeting and low toxicity. PTX-HSNs were fabricated using high-pressure homogenization with a microfluidizer and were lyophilized with D-mannitol. Hyaluronan was coated on the outside of the PTX-HSN sphere. The mean size of the PTX-HSNs was maintained below 100 nm, with a relatively narrow size distribution. The PTX loading content was 3 mg/mL(Maximum 6 mg/mL) and encapsulation efficiency (EE) was close to 100 %. The HSNs were coated with HA on the outer surface of the sphere and the amount of HA was 0.82 ± 0.10% (w/w). The lyophilized formulation was stable at 4°C for 12 months and the reconstituted HSN solution was stable for at least 96 h, even though Taxol® can be maintained for only 72 h. The in vitro paclitaxel release by PTX-SNs and PTX-HSNs lasted more than 6 days without showing a release burst, and was more sustained than that of Taxol®, suggesting a more constant effect on cancer cells at the tumor site than was observed for Taxol®. Further, In in vitro cell affinity studies using SK-OV-3 (CD44+) and OVCAR-3 (CD44-) cells, PTX-HSNs had a targeting capability ten-fold higher than that of PTX-loaded solid-nanoemulsions (PTX-SNs) without hyaluronan. The in vivo toxicity, in vivo antitumor effects, and pharmacokinetics of PTX-HSNs and Taxol® were evaluated in nude mice and rats. The maximum tolerated dose (MTD) for PTX-HSNs, PTX-SNs, and Taxol® was determined by measuring changes in clinical symptoms after administering 20–50 mg/kg PTX via the caudal vein. The MTD of PTX-HSNs had a dosing capacity greater than 50 mg PTX/kg, which was 2.5-fold higher than that of Taxol® when administered as a PTX injection. We assessed the in vivo antitumor efficacy of the PTX-HSNs by measuring changes in tumor volume and body weight in nude mice transplanted with CD44-overexpressing NCI-H460 xenografts and SK-OV-3 xenografts, and treated with a bolus dose of saline, Taxol®, PTX-SNs, or PTX-HSNs at a dose of 20-50 mg/kg. Suppression of cancer cell growth was higher in the PTX-SNs and PTX-HSNs-treated groups than in the Taxol® group. In particular, PTX-HSNs treatment dramatically inhibited tumor growth, likely because of less toxicity, high MTD and the specific tumor-targeting affinity of HA for CD44-overexpressed cancer cells. The loss of body weight and organ weight did not vary significantly between the groups. The pharmacokinetic parameters of PTX-HSNs were more desirable than those of Taxol®. After PTX-HSNs treatment, the circulation time of PTX prolonged and retention of PTX in ovarian tumor tissues and non-small cell lung tumor tissues increased. Therefore, PTX-HSNs is an effective nanocarrier with a high MTD and solubilizing capacity for delivering PTX to ovarian and non-small cell lung cancers characterized by CD44 overexpression, enhanced active tumor targeting. | - |
| dc.title.subtitle | Preparation, characterization, In vitro and In vivo evaluation | - |
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- Graduate School of Ajou University > Department of Pharmacy > 4. Theses(Ph.D)
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