開發包覆靛氰綠全氟碳奈米乳劑和喜樹鹼奈米顆粒之藻酸鹽複合水凝膠用於乳腺癌光/化學治療之研究;Development of Alginate Composite Hydrogel Containing Indocyanine Green-Loaded Perfluorinated Nanoemulsions and Camptothecin-Encapsulated Nanoparticles for Photochemotherapy of Breast Cancer

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Title:	開發包覆靛氰綠全氟碳奈米乳劑和喜樹鹼奈米顆粒之藻酸鹽複合水凝膠用於乳腺癌光/化學治療之研究;Development of Alginate Composite Hydrogel Containing Indocyanine Green-Loaded Perfluorinated Nanoemulsions and Camptothecin-Encapsulated Nanoparticles for Photochemotherapy of Breast Cancer
Authors:	林芝庭;Lin, Chih-Ting
Contributors:	生醫科學與工程學系
Keywords:	乳腺癌;靛氰綠;全氟碳化物;喜樹鹼;海藻酸鹽;可注射型水凝膠;光化學治療
Date:	2022-08-13
Issue Date:	2022-10-04 11:09:09 (UTC+8)
Publisher:	國立中央大學
Abstract:	乳腺癌為我國婦女發生率第一名的癌症，發生高峰約在45-69歲之間，也是全球女性癌症死亡的主要原因。在各類乳癌中，三陰性乳癌抗藥性高，治療過程中具有高復發、高死亡率等問題，而在臨床上容易早期轉移，且治療的選擇較少，目前藥物治療仍以化學治療為主。近年來，水凝膠已廣泛運用於藥物輸送，與全身化療相比，水凝膠藥物載體的副作用更小，且可以在腫瘤部位緩慢釋放藥物，因此我們開發了一種由二價陽離子(Ca2+)和海藻酸鈉製備的可注射型水凝膠。這種水凝膠含有喜樹鹼(CPT)奈米粒子和靛氰綠(ICG)全氟化碳奈米乳劑(Hydrogel contains camptothecin nanoparticles and indocyanine green perfluorocarbon nanoemulsions; HGCNIPNs)，可在光照下同時提供光療及化療。根據DLS分析結果，CPTNPs和ICGNPs的尺寸分別為483.23±113.0 nm和219.76±13.11 nm，電位分別為28.51 ± 3.35 mV和-33.27 ± 4.90 mV，包覆率均高於92%。與ICG水溶液相比，水凝膠中的ICG增強熱穩定性並提供相當的熱療效果，且在近紅外光（NIR；808 nm，6 W/cm2）照射下產生的單線態氧明顯增加。此外，在體外細胞實驗中顯示HGCNIPNs（ICG=160 μM；CPT=300 μM）與相同濃度Free CPT及CPTNPs更具細胞毒性，有顯著差異，存活率分別為23.57%、75.80%及68.12%。而在動物體內試驗中結果表明HGCNIPNs在ICG為160 μM及CPT為300 μM下是有腫瘤抑制效果的，且心、肝、脾、肺及腎重要器官並沒有造成嚴重的傷害。本研究證實了HGCNIPNs在光熱力及光動力療法應用中具有一定潛力，藉由光療先抑制癌細胞，再使藥物緩慢從載體中釋放達到光/化學治療同時並行，達到減少藥劑用量和副作用的目的，且載體只需在水中簡單混合並且無創注射即可治療，在合成、保存、藥物輸送和臨床應用方面都具有相當大的優勢，可望在未來有近一步的發展。;Breast cancer is the most common cancer among women in my country, with a peak incidence between the ages of 45 and 69 and the leading cause of cancer death in women worldwide. Among various types of breast cancer, triple-negative breast cancer has high drug resistance and a high recurrence rate during treatment, which in turn leads to high mortality, and is prone to early metastasis clinically, and there are few treatment options. At present, the drug treatment is still mainly chemotherapy. In recent years, hydrogels have been widely used for tumor drug delivery. A hydrogel drug carrier can cause less side effects than systemic chemotherapy and can achieve sustained delivery of a drug at tumor sites. We have developed an injectable hydrogel which prepared from divalent cations (Ca2+) and sodium alginate. This hydrogel contains camptothecin (CPT) nanoparticles and indocyanine green (ICG) perfluorocarbon nanoemulsions (HGCNIPNs) and can provide photo/chemotherapy at the same time. Through DLS analysis, the size of CPTNPs and ICGNPs are 483.23±113.0 nm and 219.76±13.11 nm, respectively, the potentials are 28.51±3.35 mV and -33.27±4.90 mV, and both of nanoparticles have high encapsulation rate, which are higher than 92%. In comparison to freely dissolved ICG, the ICG in the hydrogel enhances thermal stability and provides a comparable hyperthermia effect, and the production of singlet oxygen under near-infrared (NIR; 808 nm, 6 W/cm2) irradiation is significantly increased. In addition, in vitro cell experiments showed that HGCNIPNs (ICG=160 μM; CPT=300 μM) are more cytotoxic than the same concentration of Free CPT and CPTNPs groups, with significant differences in survival rates of 23.57%, 75.80% and 68.12%, respectively. The results of in vivo animal studies showed that HGCNIPNs are most effective in tumor suppression at ICG of 160 μM and CPT of 300 μM, and don′t cause serious damage to vital organs such as heart, liver, spleen, lung and kidney. This study confirms that HGCNIPNs have great potential in the application of photothermal and photodynamic therapy, through phototherapy to inhibit cancer cells first, and then use the drug to slowly release from the carrier to achieve simultaneous photo/chemotherapy, reducing the dosage and side effects. Alginate hydrogel can be treated by simply mixing in water and noninvasive injection. It has considerable advantages in synthesis, storage, drug delivery, and clinical applications, and HGCNIPNs are expected to have further development in the future.
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