大麻二酚 (Cannabidiol, CBD) 是大麻植物中提取的成分之一。研究顯示，大麻二酚具有調節細胞凋亡信號來抑制癌細胞增生的抗癌能力，且對於口腔鱗狀細胞癌具有抑制的成效。然而，CBD高疏水性限制了其有效的應用。為了提高藥物的生物可利用度，使用生物可降解及具有良好生物相容性的高分子作為載體包覆CBD，可增加其在臨床上的應用。本研究以逐步聚合的方式合成聚縮酮 (Polyketal-PCADK)及聚硫縮酮 (Polythioketal-PPADT)，並製備具有微米及奈米尺寸之CBD顆粒，研究其對口腔鱗狀上皮癌細胞株(SCC-25)的抑制效果，及對代表正常細胞的牙齦上皮細胞株(S-G cells)的影響。
實驗結果顯示，成功以逐步聚合法合成PCADK及PPADT高分子，並透過測試合成出高分子量之PPADT。透過實驗不同的均質時間，製備具有微米及奈米尺寸之CBD顆粒。Blank PPADT MPs粒徑為2.07 ± 0.07 μm；CBD-PPADT-MPs為2.15 ± 0.11 μm；Blank PPADT-NPs為294 ± 51.1 nm；CBD-PPADT-NPs為320 ± 35.0 nm；Blank-PCADK-MPs為2.19 ± 0.09 μm；CBD-PCADK MPs為2.42 ± 0.18 μm；Blank PCADK NPs為268 ± 35.4 nm；CBD-PCADK NPs為315 ± 52.6 nm。PCADK微米及奈米顆粒的CBD包埋率分別為52.67 ± 5.65%及46.56 ± 1.58%，PPADT MPs及NPs的CBD包埋率為47.83 ± 1.05% 及39.14 ± 6.67%。經體外釋放檢測，CBD-PCADK藥物顆粒於酸性環境(pH 5.0)的累積釋放率(微米為68.37%、奈米為82.97%)高於正常人體環境(pH 7.4) (微米為45.36%、奈米為53.60%)；CBD-PPADT藥物顆粒於ROS環境的累積釋放率(微米為70.52%、奈米為55.79%)高於正常人體環境(微米為38.93%、奈米為36.63%)，可得知其分別為酸鹼敏感及ROS敏感型之高分子。
在體外細胞實驗中，得知 free CBD具有抑制SCC-25癌細胞之效果(IC50為34.46 μM)，但在低濃度5 μM卻已對代表正常細胞的S-G產生毒性(IC50為5.89 μM)。實驗顯示未包覆藥物之Blank PCADK及PPADT顆粒，對癌細胞及正常細胞均具有80%以上的細胞存活率，可作為良好之藥物載體。包埋CBD之PCADK及PPADT藥物顆粒透過藥物24小時的緩慢釋放及細胞的吞噬作用，對於S-G有70%以上的細胞存活率，然而對SCC-25確有抑制的成效，其中CBD-PCADK NPs抑制效果最明顯(IC50為31.61 μM)，次之為CBD-PPADT MPs及CBD-PCADK MPs(IC50為65.41及91.43 μM)，唯CBD-PPADT NPs抑制效果不佳。結果顯示，CBD-PCADK NPs最有潛力用於治療口腔鱗狀上皮癌。

Cannabidiol (CBD) is one of the ingredients in cannabis derived from the hemp plant. In previous studies, cannabidiol has been found to have anti-cancer abilities to modulate apoptotic signaling to inhibit the proliferation of cancer cells and have inhibitory effects on oral squamous cell carcinoma. However, the high hydrophobicity limits the development of effective formulations. To improve drug bioavailability, using biodegradable and biocompatible polymers as drug carriers could be an excellent way to deliver CBD and extend its release for long-term treatments such as anticancer therapy.
In this study, polyketal-PCADK and polythioketal-PPADT were synthesized by step-polymerization and then prepared into CBD-loaded microparticles and nanoparticles respectively. In in vitro cell experiments, we used oral epithelial squamous carcinoma cells (SCC-25) and Smulow-Glickman gingival cells (S-G cells) as models to evaluate the inhibitory effects of different CBD-loaded micro/nanoparticles.
The experimental results showed that PCADK and PPADT were successfully synthesized by step-polymerization, and high molecular weight PPADT was synthesized through testing. By trial-and-error, we prepared the CBD-loaded particles with micrometer and nanometer sizes. The particle size of Blank PPADT MPs was 2.07 ± 0.07 μm; CBD-PPADT-MPs was 2.15 ± 0.11 μm; Blank PPADT-NPs was 294 ± 51.1 nm; CBD-PPADT-NPs was 320 ± 35.0 nm; Blank-PCADK-MPs was 2.19 ± 0.09 μm; CBD-PCADK MPs was 2.42 ± 0.18 μm; Blank PCADK NPs was 268 ± 35.4 nm; CBD-PCADK NPs was 315 ± 52.6 nm. The encapsulation efficiency of CBD-loaded PCADK micro and nanoparticles were 52.67 ± 5.65% and 46.56 ± 1.58% respectively, and CBD-loaded PPADT micro and nanoparticles were 47.83 ± 1.05% and 39.14 ± 6.67% respectively. The in vitro release testing showed that the cumulative release rate of PCADK-CBD particles in an acidic environment (pH 5.0) (CBD-loaded PCADK microparticles: 68.37%; CBD-loaded PCADK nanoparticles: 82.97%) was higher than that in the normal human environment (pH 7.4) (CBD-loaded PCADK microparticles: 45.36%; CBD-loaded PCADK nanoparticles: 53.60%); the cumulative release rate of PPADT drug particles in the ROS environment (CBD-loaded PPADT microparticles: 70.52%; CBD-loaded PPADT nanoparticles: 55.79%) was higher than that in the normal human environment (CBD-loaded PPADT microparticles: 38.93%; CBD-loaded PPADT nanoparticles: 36.63%). The results explained that PCADK is acid-base sensitive and PPADT is a ROS-sensitive polymer.
The in vitro cell experiments showed that CBD has the effect of inhibiting SCC-25 cancer cells (IC50 = 34.46 μM), but it has caused toxicity to S-G cells at lower concentrations of CBD (IC50 = 5.89 μM). PCADK and PPADT blank particles had low toxicity to cancer cells and normal cells (the cell viability were both above 80%), these results evidenced that PPADT and PCADK have good biocompatibility. The CBD-loaded PCADK and PPADT particles can inhibit SCC-25 through the slow release of drugs and the phagocytosis of cells, and also had low toxicity with above 70% of the viability of S-G cells. CBD-loaded PCADK nanoparticles had the most obvious inhibitory effect of SCC-25 (IC50 = 31.61 μM). The second were CBD-loaded PPADT (IC50 = 65.41 μM) and PCADK microparticles (IC50 = 91.43 μM). Only CBD-PPADT NPs had low inhibitory effect. The results showed that CBD-loaded PCADK nanoparticles had the highest potential for the treatment of oral squamous cell carcinoma.

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