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Hyaluronan-coated solid nanoemulsions with high payload of paclitaxel for tumor specific delivery
- Subtitle
- Preparation, characterization, In vitro and In vivo evaluation
- Alternative Title
- Hyaluronan-coated solid nanoemulsions with high payload of paclitaxel for tumor specific delivery
- Author(s)
- 김주은
- Alternative Author(s)
- Joo-Eun Kim
- Advisor
- 박영준
- Department
- 일반대학원 약학
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2017-08
- Language
- eng
- Keyword
- Hyaluronan solid-nanoemulsion; Tumor targeting; MTD; Ovarian cancer and non-small cell lung cancer; Paclitaxel.
- Alternative Abstract
- 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.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Pharmacy > 4. Theses(Ph.D)
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