牙周炎是由致病菌群和宿主發炎反應共同貢獻的一種慢性發炎疾病。牙齒的生物膜會引發宿主防禦的系統，並產生細胞激素以及酵素。這些細胞激素進一步刺激局部發炎反應，進而破壞牙周組織。為了控制這樣的惡性循環，我們設計了包含抗菌和免疫調節的長期偕同奈米藥物調控在治療上。薑黃素是從薑黃根部萃取的天然化合物，具有抗發炎性質。然而其低生物可利用度限制了臨床使用。米諾環素，具有良好的抗菌功效且已被廣泛的用於治療致病菌感染。為了解決生物利用度問題，我們選擇聚乳酸共聚甘醇酸作為包覆薑黃素的奈米劑型，並在表面上接合米諾環素，以期改善抗病原體和調節局部發炎的協同作用。結果發現，此奈米粒子在最低抑菌濃度和最低殺菌濃度的測定中表現出對金黃色葡萄球菌、大腸桿菌、伴放線桿菌以及牙齦卟啉菌具有優異的抗菌功效。並且在治療劑量範圍作細胞毒性測試後，發現對人類牙齦成纖維母細胞（HGF）以及人類正常口腔角質細胞(hNOK)皆有良好細胞相容性。在酯多醣(LPS)誘發RAW264.7細胞的發炎模式中，此奈米粒子顯著的抑制發炎後產生的一氧化氮、細胞分化作用以及發炎訊息因子(TNF-α and IL-1β)。結果顯示此奈米劑型在抗細菌功效和局部發炎反應的調節組合中提供良好的協同作用，因此本研究鼓勵未來在牙周病感染控制上的先進應用。

Periodontitis is a chronic inflammation disease co-contributed by pathogenic flora and the host inflammatory responses. Dental biofilms may trigger host’s defense system to produce cytokines and enzymes that subsequently aggravate local inflammation and destruct periodontal tissues. Thus effective disease control may require to break the vicious cycle by long-term synergistic modulation of anti-bacterial and inflammation control in the therapeutic regimen design. Curcumin is a natural compound extracted from the root of turmeric with anti-inflammation property. The low bioavailability render their compromised clinical usage. Minocycline showed good anti-bacterial efficacy over a wide spectra of infectious pathogens. PLGA was selected to co-formulate curcumin and minocycline to resolve the bioavailability issues and to synergize anti-pathogen and immune-modulation functions. This was achieved through surface grafting of minocycline on the particles and embedding of curcumin in the core compartment. The results showed that minocycline grafted curcumin-PLGA nanoparticles presented excellent anti-bacterial efficacy for S. aureus, E. coli, A. actinomycetemcomitans and P. gingivalis in both MIC & MBC tests and 0.1μg /mL f minocycline concentration for the nanoparticles. The MTT assay showed good biocompatibility to human gingival fibroblast (HGF) cell and human normal oral keratinocytes (hNOK) at this therapeutic dose range. Minocycline grafted curcumin-PLGA nanoparticles significantly inhibited the production of the nitric oxide as well as RAW 264.7 differentiation and pro-inflammatory TNF-α and IL-1β signaling in stimulated by lipopolysaccharide (LPS). These results suggest that such formulation may provide synergistic combination of anti-bacterial and local inflammatory response modulation advantages for future applications in periodontitis infection control.

Acharya, S., and Sahoo, S.K. (2011). PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect. Advanced drug delivery reviews 63, 170-183.
Aggarwal, B.B., Yuan, W., Li, S., and Gupta, S.C. (2013). Curcumin-free turmeric exhibits anti-inflammatory and anticancer activities: Identification of novel components of turmeric. Molecular nutrition & food research 57, 1529-1542.
Araujo, N.C., Fontana, C.R., Bagnato, V.S., and Gerbi, M.E. (2012). Photodynamic effects of curcumin against cariogenic pathogens. Photomedicine and laser surgery 30, 393-399.
Araujo, N.C., Fontana, C.R., Bagnato, V.S., and Gerbi, M.E. (2014). Photodynamic antimicrobial therapy of curcumin in biofilms and carious dentine. Lasers in medical science 29, 629-635.
Atsumi, T., Tonosaki, K., and Fujisawa, S. (2006). Induction of early apoptosis and ROS-generation activity in human gingival fibroblasts (HGF) and human submandibular gland carcinoma (HSG) cells treated with curcumin. Archives of Oral Biology 51, 913-921.
Bansal, S.S., Goel, M., Aqil, F., Vadhanam, M.V., and Gupta, R.C. (2011). Advanced drug delivery systems of curcumin for cancer chemoprevention. Cancer prevention research 4, 1158-1171.
Barbara, R., Belletti, D., Pederzoli, F., Masoni, M., Keller, J., Ballestrazzi, A., Vandelli, M.A., Tosi, G., and Grabrucker, A.M. (2017). Novel Curcumin loaded nanoparticles engineered for Blood-Brain Barrier crossing and able to disrupt Abeta aggregates. International journal of pharmaceutics 526, 413-424.
Basak, S.K., Zinabadi, A., Wu, A.W., Venkatesan, N., Duarte, V.M., Kang, J.J., Dalgard, C.L., Srivastava, M., Sarkar, F.H., Wang, M.B., et al. (2015). Liposome encapsulated curcumin-difluorinated (CDF) inhibits the growth of cisplatin resistant head and neck cancer stem cells. Oncotarget 6, 18504-18517.
Bharti, A.C., Takada, Y., and Aggarwal, B.B. (2004). Curcumin (Diferuloylmethane) Inhibits Receptor Activator of NF-κB Ligand-Induced NF-κB Activation in Osteoclast Precursors and Suppresses Osteoclastogenesis. The Journal of Immunology 172, 5940-5947.
Brouet, I., and Ohshima, H. (1995). Curcumin, an Anti-tumor Promoter and Anti-inflammatory Agent, Inhibits Induction of Nitric Oxide Synthase in Activated Macrophages. Biochemical and Biophysical Research Communications 206, 533-540.
Castangia, I., Nácher, A., Caddeo, C., Valenti, D., Fadda, A.M., Díez-Sales, O., Ruiz-Saurí, A., and Manconi, M. (2014). Fabrication of quercetin and curcumin bionanovesicles for the prevention and rapid regeneration of full-thickness skin defects on mice. Acta Biomaterialia 10, 1292-1300.
Cekici, A., Kantarci, A., Hasturk, H., and Van Dyke, T.E. (2014). Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontology 2000 64, 57-80.
Chakraborty, S., Stalin, S., Das, N., Choudhury, S.T., Ghosh, S., and Swarnakar, S. (2012). The use of nano-quercetin to arrest mitochondrial damage and MMP-9 upregulation during prevention of gastric inflammation induced by ethanol in rat. Biomaterials 33, 2991-3001.
Chen, D., Nie, M., Fan, M.W., and Bian, Z. (2008). Anti-inflammatory activity of curcumin in macrophages stimulated by lipopolysaccharides from Porphyromonas gingivalis. Pharmacology 82, 264-269.
Cheng, A.L., Hsu, C.H., Lin, J.K., Hsu, M.M., Ho, Y.F., Shen, T.S., Ko, J.Y., Lin, J.T., Lin, B.R., Ming-Shiang, W., et al. (2001). Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 21, 2895-2900.
Ciancio, S.G., Mather, M.L., and McMullen, J.A. (1980). An evaluation of minocycline in patients with periodontal disease. Journal of periodontology 51, 530-534.
Gonzalez, D., Tzianabos, A.O., Genco, C.A., and Gibson Iii, F.C. (2003). Immunization with Porphyromonas gingivalis Capsular Polysaccharide Prevents P. gingivalis-Elicited Oral Bone Loss in a Murine Model. Infection and Immunity 71, 2283-2287.
Guimaraes, M.R., Coimbra, L.S., de Aquino, S.G., Spolidorio, L.C., Kirkwood, K.L., and Rossa, C., Jr. (2011). Potent anti-inflammatory effects of systemically administered curcumin modulate periodontal disease in vivo. Journal of periodontal research 46, 269-279.
Haffajee, A.D., and Socransky, S.S. (1994). Microbial etiological agents of destructive periodontal diseases. Periodontology 2000 5, 78-111.
Izui, S., Sekine, S., Maeda, K., Kuboniwa, M., Takada, A., Amano, A., and Nagata, H. (2016). Antibacterial Activity of Curcumin Against Periodontopathic Bacteria. Journal of periodontology 87, 83-90.
Jorgensen, J.H., and Turnidge, J.D. (2015). Susceptibility test methods: dilution and disk diffusion methods. In Manual of Clinical Microbiology, Eleventh Edition (American Society of Microbiology), pp. 1253-1273.
Khalil, N.M., do Nascimento, T.C., Casa, D.M., Dalmolin, L.F., de Mattos, A.C., Hoss, I., Romano, M.A., and Mainardes, R.M. (2013). Pharmacokinetics of curcumin-loaded PLGA and PLGA-PEG blend nanoparticles after oral administration in rats. Colloids and surfaces B, Biointerfaces 101, 353-360.
Kiemer, A.K., Muller, C., and Vollmar, A.M. (2002). Inhibition of LPS-induced nitric oxide and TNF-alpha production by alpha-lipoic acid in rat Kupffer cells and in RAW 264.7 murine macrophages. Immunology and cell biology 80, 550-557.
Kumari, A., Tyagi, N., Dash, D., and Singh, R. (2015). Intranasal curcumin ameliorates lipopolysaccharide-induced acute lung injury in mice. Inflammation 38, 1103-1112.
Kuncha, M., Naidu, V.G., Sahu, B.D., Gadepalli, S.G., and Sistla, R. (2014). Curcumin potentiates the anti-arthritic effect of prednisolone in Freund's complete adjuvant-induced arthritic rats. The Journal of pharmacy and pharmacology 66, 133-144.
Lalla, E., Lamster, I.B., Hofmann, M.A., Bucciarelli, L., Jerud, A.P., Tucker, S., Lu, Y., Papapanou, P.N., and Schmidt, A.M. (2003). Oral infection with a periodontal pathogen accelerates early atherosclerosis in apolipoprotein E-null mice. Arteriosclerosis, thrombosis, and vascular biology 23, 1405-1411.
Liu, J., Liu, J., Xu, H., Zhang, Y., Chu, L., Liu, Q., Song, N., and Yang, C. (2013). Novel tumor-targeting, self-assembling peptide nanofiber as a carrier for effective curcumin delivery. International journal of nanomedicine 9, 197-207.
Liu, J., Liu, J., Xu, H., Zhang, Y., Chu, L., Liu, Q., Song, N., and Yang, C. (2014). Novel tumor-targeting, self-assembling peptide nanofiber as a carrier for effective curcumin delivery. International journal of nanomedicine 9, 197-207.
Madaric, A., Kadrabova, J., Krajcovicova-Kudlackova, M., Valachovicova, M., Spustova, V., Mislanova, C., Kajaba, I., and Blazicek, P. (2013). The effect of bioactive complex of quercetin, selenium, catechins and curcumin on cardiovascular risk markers in healthy population after a two month consumption. Bratislava Medical Journal 114, 84-87.
Mau, L.-P., Cheng, W.-C., Chen, J.-K., Shieh, Y.-S., Cochran, D.L., and Huang, R.-Y. (2016). Curcumin ameliorates alveolar bone destruction of experimental periodontitis by modulating osteoclast differentiation, activation and function. Journal of Functional Foods 22, 243-256.
Mo, Y., Guo, R., Zhang, Y., Xue, W., Cheng, B., and Zhang, Y. (2017). Controlled Dual Delivery of Angiogenin and Curcumin by Electrospun Nanofibers for Skin Regeneration. Tissue engineering Part A.
Mukerjee, A., and Vishwanatha, J.K. (2009). Formulation, characterization and evaluation of curcumin-loaded PLGA nanospheres for cancer therapy. Anticancer research 29, 3867-3875.
Naksuriya, O., Okonogi, S., Schiffelers, R.M., and Hennink, W.E. (2014). Curcumin nanoformulations: a review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment. Biomaterials 35, 3365-3383.
Pan, J., Xu, T., Xu, F., Zhang, Y., Liu, Z., Chen, W., Fu, W., Dai, Y., Zhao, Y., Feng, J., et al. (2017). Development of resveratrol-curcumin hybrids as potential therapeutic agents for inflammatory lung diseases. European journal of medicinal chemistry 125, 478-491.
Panwar, M., and Gupta, S.H. (2009). Local Drug Delivery with Tetracycline Fiber : An Alternative to Surgical Periodontal Therapy. Medical Journal Armed Forces India 65, 244-246.
Quirynen, M., Teughels, W.I.M., Soete, M.D., and Steenberghe, D.V. (2002). Topical antiseptics and antibiotics in the initial therapy of chronic adult periodontitis: microbiological aspects. Periodontology 2000 28, 72-90.
Raja, M., Ummer, F., and Dhivakar, C.P. (2014). Aggregatibacter actinomycetemcomitans - a tooth killer? Journal of clinical and diagnostic research : JCDR 8, ZE13-16.
Rao, J.P., and Geckeler, K.E. (2011). Polymer nanoparticles: Preparation techniques and size-control parameters. Progress in Polymer Science 36, 887-913.
Safavy, A., Raisch, K.P., Mantena, S., Sanford, L.L., Sham, S.W., Krishna, N.R., and Bonner, J.A. (2007). Design and development of water-soluble curcumin conjugates as potential anticancer agents. Journal of medicinal chemistry 50, 6284-6288.
Sharma, R.A., McLelland, H.R., Hill, K.A., Ireson, C.R., Euden, S.A., Manson, M.M., Pirmohamed, M., Marnett, L.J., Gescher, A.J., and Steward, W.P. (2001). Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 7, 1894-1900.
Shoba, G., Joy, D., Joseph, T., Majeed, M., Rajendran, R., and Srinivas, P.S. (1998). Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta medica 64, 353-356.
Sundaram, K., Nishimura, R., Senn, J., Youssef, R.F., London, S.D., and Reddy, S.V. (2007). RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Experimental cell research 313, 168-178.
Swarnakar, S., Ganguly, K., Kundu, P., Banerjee, A., Maity, P., and Sharma, A.V. (2005). Curcumin regulates expression and activity of matrix metalloproteinases 9 and 2 during prevention and healing of indomethacin-induced gastric ulcer. The Journal of biological chemistry 280, 9409-9415.
Tajbakhsh, A., Hasanzadeh, M., Rezaee, M., Khedri, M., Khazaei, M., Sales, S.S., Ferns, G.A., Hassanian, S.M., and Avan, A. (2017). Therapeutic potential of novel formulated forms of curcumin in the treatment of breast cancer by the targeting of cellular and physiological dysregulated pathways. Journal of cellular physiology.
Thangapazham, R.L., Sharad, S., and Maheshwari, R.K. (2013). Skin regenerative potentials of curcumin. Biofactors 39, 141-149.
Tomita, S., Komiya-Ito, A., Imamura, K., Kita, D., Ota, K., Takayama, S., Makino-Oi, A., Kinumatsu, T., Ota, M., and Saito, A. (2013). Prevalence of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Tannerella forsythia in Japanese patients with generalized chronic and aggressive periodontitis. Microbial pathogenesis 61-62, 11-15.
Wang, L., Xu, X., Zhang, Y., Zhang, Y., Zhu, Y., Shi, J., Sun, Y., and Huang, Q. (2013). Encapsulation of curcumin within poly(amidoamine) dendrimers for delivery to cancer cells. Journal of Materials Science: Materials in Medicine 24, 2137-2144.
Wang, S., Su, R., Nie, S., Sun, M., Zhang, J., Wu, D., and Moustaid-Moussa, N. (2014). Application of nanotechnology in improving bioavailability and bioactivity of diet-derived phytochemicals. The Journal of nutritional biochemistry 25, 363-376.
Whyte, M.P. (2006). The long and the short of bone therapy. The New England journal of medicine 354, 860-863.
Xie, M., Fan, D., Zhao, Z., Li, Z., Li, G., Chen, Y., He, X., Chen, A., Li, J., Lin, X., et al. (2015). Nano-curcumin prepared via supercritical: Improved anti-bacterial, anti-oxidant and anti-cancer efficacy. International journal of pharmaceutics 496, 732-740.
Yallapu, M.M., Gupta, B.K., Jaggi, M., and Chauhan, S.C. (2010). Fabrication of curcumin encapsulated PLGA nanoparticles for improved therapeutic effects in metastatic cancer cells. Journal of colloid and interface science 351, 19-29.
Yang, H.W., Huang, Y.F., and Chou, M.Y. (2004). Occurrence of Porphyromonas gingivalis and Tannerella forsythensis in periodontally diseased and healthy subjects. Journal of periodontology 75, 1077-1083.
Young, N.A., Bruss, M.S., Gardner, M., Willis, W.L., Mo, X., Valiente, G.R., Cao, Y., Liu, Z., Jarjour, W.N., and Wu, L.C. (2014). Oral administration of nano-emulsion curcumin in mice suppresses inflammatory-induced NFkappaB signaling and macrophage migration. PloS one 9, e111559.