本論文以niclosamide做為model compound，設計出一套利用電噴霧系統(Electrospray system)所製備出的微奈米粒子懸浮液。針對所使用的電噴霧系統而言，共可分為兩種裝置：(一)為單噴嘴電噴霧系統，經此系統可製備出奈米尺寸等級之niclosamide (nano-Niclo)微奈米粒子，經掃描式電子顯微鏡(SEM)觀察其表面形態確認，其長軸平均為493±151nm，短軸平均為105±21 nm，此外，我們也將生物可降解高分子PLGA與niclosamide混合互溶後，經單噴嘴電噴霧系統成功製備出平均粒徑為662±121 nm之Single-Niclo/PLGA (matrix type)；(二)為雙噴嘴電噴霧系統，可製備出平均粒徑為584±110 nm之Dual-Niclo/PLGA(core-shell type)。In vitro藥物緩釋試驗顯示，nano-Niclo的釋放速率比原始Niclo powder快1.68倍，Single-Niclo/PLGA於釋放24小時後，開始呈現穩定釋放模式(sustained release)，而Dual-Niclo/PLGA的釋放模式則可細分為三個階段(3 stages)。我們最後以卵巢癌細胞株(SKOV-3及CP70)進行此一微奈米藥物的癌症細胞抑制實驗，並以共軛焦雷射顯微鏡觀察此些載體粒子的細胞吞吐追蹤，證實藥物濃度於最低濃度0.75 μM時仍能比傳統給藥方法提高約兩成的療效，其可能原因為此些載體粒子能更有效的將藥物遞送至細胞內，進而抑制癌症細胞的增殖。

This study describes the use of single- or dual-capillary electrospray (ES) system to produce a series of novel niclosamide suspensions. Our study shows that the ES system can generate a homogeneous suspension of pure niclosamide or niclosamide-encapsulated PLGA particles in phosphate buffer saline (PBS), and the suspension solution can remain stable for several months. SEM images show that the pure niclosamide particles all have a rod-like shape (transversal length:105±21 nm, longitudinal length:493±151nm) and the niclosamide-encapsulated PLGA particles possess a spherical shape with an avg. size of 584~662 nm. UV-vis spectroscopy was used for qualitative and quantitative analysis, revealing 2 characteristic absorption peaks attributed to niclosamide (336 nm and 376 nm, in PBS-PVA solution). This information was subsequently used as an index to establish the standard curve for a quantitative purpose. Our Raman spectra indicate that our generated pure niclosamide or niclosamide-encapsulated PLGA particles are all composed of niclosamide monohydrate instead of niclosamide anhydrous form. According to our in vitro cell studies,we found that this novel suspension of niclosamide with or without PLGA encapsulation shows better anti-proliferative ability against CP70 and SKOV-3 ovarian cancer cells, compared to that of conventional formulation. Specifically, the anti-proliferative ability of niclosamide-encapsulated PLGA particles is better than that of pure niclosamide suspension to CP70 cells, which is likely caused by the more efficient intracellular delivery.

[1] C.-J. Wu, J.-T. Jan, C.-M. Chen, H.-P. Hsieh, D.-R. Hwang, H.-W. Liu, C.-Y. Liu, H.-W. Huang, S.-C. Chen, C.-F. Hong, R.-K. Lin, Y.-S. Chao, and J. T. A. Hsu, "Inhibition of Severe Acute Respiratory Syndrome Coronavirus Replication by Niclosamide," Antimicrobial Agents and Chemotherapy, Vol. 48, No. 7, pp. 2693-2696 (2004)
[2] T. Osada, M. Chen, X. Y. Yang, I. Spasojevic, J. B. Vandeusen, D. Hsu, B. M. Clary, T. M. Clay, W. Chen, M. A. Morse, and H. K. Lyerly, "Antihelminth Compound Niclosamide Downregulates Wnt Signaling and Elicits Antitumor Responses in Tumors with Activating APC Mutations," Cancer Research, Vol. 71, No. 12, pp. 4172-4182 (2011)
[3] U. Sack, W. Walther, D. Scudiero, M. Selby, D. Kobelt, M. Lemm, I. Fichtner, P. M. Schlag, R. H. Shoemaker, and U. Stein, "Novel Effect of Antihelminthic Niclosamide on S100A4-Mediated Metastatic Progression in Colon Cancer," Journal of the National Cancer Institute, Vol. 103, No. 13, pp. 1018-1036 (2011)
[4] Y.-T. Yo, Y.-W. Lin, Y.-C. Wang, C. Balch, R.-L. Huang, M. W. Y. Chan, H.-K. Sytwu, C.-K. Chen, C.-C. Chang, K. P. Nephew, T. H. M. Huang, M.-H. Yu, and H.-C. Lai, "Growth inhibition of ovarian tumor-initiating cells by niclosamide," Molecular Cancer Therapeutics, DOI: 10.1158/1535-7163.MCT-12-0002, (2012)
[5] P. P. Adiseshaiah, J. B. Hall, and S. E. McNeil, "Nanomaterial standards for efficacy and toxicity assessment," Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, Vol. 2, No. 1, pp. 99-112 (2010)
[6] L. Brannon-Peppas and J. O. Blanchette, "Nanoparticle and targeted systems for cancer therapy," Advanced Drug Delivery Reviews, Vol. 56, No. 11, pp. 1649-1659 (2004)
[7] J. Fang, H. Nakamura, and H. Maeda, "The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect," Advanced Drug Delivery Reviews, Vol. 63, No. 3, pp. 136-151 (2011)
[8] L. E. van Vlerken and M. M. Amiji, "Multi-functional polymeric nanoparticles for tumour-targeted drug delivery," Expert Opinion on Drug Delivery, Vol. 3, No. 2, pp. 205-216 (2006)
[9] R. Duncan, "Polymer conjugates for tumour targeting and intracytoplasmic delivery. The EPR effect as a common gateway?," Pharmaceutical Science & Technology Today, Vol. 2, No. 11, pp. 441-449 (1999)
[10] A. Nori and J. i. Kopeček, "Intracellular targeting of polymer-bound drugs for cancer chemotherapy," Advanced Drug Delivery Reviews, Vol. 57, No. 4, pp. 609-636 (2005)
[11] B. Zebli, A. S. Susha, G. B. Sukhorukov, A. L. Rogach, and W. J. Parak, "Magnetic Targeting and Cellular Uptake of Polymer Microcapsules Simultaneously Functionalized with Magnetic and Luminescent Nanocrystals," Langmuir, Vol. 21, No. 10, pp. 4262-4265 (2005)
[12] J. Zhang and R. D. K. Misra, "Magnetic drug-targeting carrier encapsulated with thermosensitive smart polymer: Core-shell nanoparticle carrier and drug release response," Acta Biomaterialia, Vol. 3, No. 6, pp. 838-850 (2007)
[13] A. C. Balazs, T. Emrick, and T. P. Russell, "Nanoparticle Polymer Composites: Where Two Small Worlds Meet," Science, Vol. 314, No. 5802, pp. 1107-1110 (2006)
[14] Y. Jin, Z. Lu, K. Ding, J. Li, X. Du, C. Chen, X. Sun, Y. Wu, J. Zhou, and J. Pan, "Antineoplastic Mechanisms of Niclosamide in Acute Myelogenous Leukemia Stem Cells: Inactivation of the NF-κB Pathway and Generation of Reactive Oxygen Species," Cancer Research, Vol. 70, No. 6, pp. 2516-2527 (2010)
[15] X. Ren, L. Duan, Q. He, Z. Zhang, Y. Zhou, D. Wu, J. Pan, D. Pei, and K. Ding, "Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway," ACS Medicinal Chemistry Letters, Vol. 1, No. 9, pp. 454-459 (2010)
[16] A. Kleindienst, J. G. Dunbar, R. Glisson, K. Okuno, and A. Marmarou, "Effect of dimethyl sulfoxide on blood-brain barrier integrity following middle cerebral artery occlusion in the rat," Acta Neurochirurgica Supplementum, Vol. 96, pp. 258-262 (2006)
[17] S. Leeuwenburgh, J. Wolke, J. Schoonman, and J. Jansen, "Electrostatic spray deposition (ESD) of calcium phosphate coatings," Journal of Biomedical Materials Research Part A, Vol. 66A, No. 2, pp. 330-334 (2003)
[18] T. Yukio, I. Yukio, and Y. Toshio, "Fundamental Studies on An Electrostatic Ink Jet Printer : 1st Report, Electrostatic Drop Formation," Bulletin of JSME, Vol. 29, No. 257, pp. 3737-3743 (1986)
[19] A. R. Jones and K. C. Thong, "The production of charged monodisperse fuel droplets by electrical dispersion," Journal of Physics D: Applied Physics, Vol. 4, No. 8, pp. 1159-1166 (1971)
[20] J. Doshi and D. H. Reneker, "Electrospinning process and applications of electrospun fibers," Journal of Electrostatics, Vol. 35, No. 2–3, pp. 151-160 (1995)
[21] M.-S. Khil, D.-I. Cha, H.-Y. Kim, I.-S. Kim, and N. Bhattarai, "Electrospun nanofibrous polyurethane membrane as wound dressing," Journal of Biomedical Materials Research Part B: Applied Biomaterials, Vol. 67B, No. 2, pp. 675-679 (2003)
[22] K. S. Rho, L. Jeong, G. Lee, B.-M. Seo, Y. J. Park, S.-D. Hong, S. Roh, J. J. Cho, W. H. Park, and B.-M. Min, "Electrospinning of collagen nanofibers: Effects on the behavior of normal human keratinocytes and early-stage wound healing," Biomaterials, Vol. 27, No. 8, pp. 1452-1461 (2006)
[23] N. Bock, M. A. Woodruff, D. W. Hutmacher, and T. R. Dargaville, "Electrospraying, a Reproducible Method for Production of Polymeric Microspheres for Biomedical Applications," Polymers, Vol. 3, No. 1, pp. 131-149 (2011)
[24] S. Guha, M. Li, M. J. Tarlov, and M. R. Zachariah, "Electrospray differential mobility analysis of bionanoparticles," Trends in Biotechnology, Vol. 30, No. 5, pp. 291-300 (2012)
[25] Y. Hong, Y. Li, Y. Yin, D. Li, and G. Zou, "Electrohydrodynamic atomization of quasi-monodisperse drug-loaded spherical/wrinkled microparticles," Journal of Aerosol Science, Vol. 39, No. 6, pp. 525-536 (2008)
[26] A. Jaworek, "Micro- and nanoparticle production by electrospraying," Powder Technology, Vol. 176, No. 1, pp. 18-35 (2007)
[27] A. Jaworek and A. T. Sobczyk, "Electrospraying route to nanotechnology: An overview," Journal of Electrostatics, Vol. 66, No. 3-4, pp. 197-219 (2008)
[28] I. W. Lenggoro, K. Okuyama, J. Fernández de la Mora, and N. Tohge, "Preparation of ZnS nanoparticles by electrospray pyrolysis," Journal of Aerosol Science, Vol. 31, No. 1, pp. 121-136 (2000)
[29] Y.-H. Lee, F. Mei, M.-Y. Bai, S. Zhao, and D.-R. Chen, "Release profile characteristics of biodegradable-polymer-coated drug particles fabricated by dual-capillary electrospray," Journal of Controlled Release, Vol. 145, No. 1, pp. 58-65 (2010)
[30] Y.-H. Lee, M.-Y. Bai, and D.-R. Chen, "Multidrug encapsulation by coaxial tri-capillary electrospray," Colloids and Surfaces B: Biointerfaces, Vol. 82, No. 1, pp. 104-110 (2011)
[31] B. Almería, W. Deng, T. M. Fahmy, and A. Gomez, "Controlling the morphology of electrospray-generated PLGA microparticles for drug delivery," Journal of Colloid and Interface Science, Vol. 343, No. 1, pp. 125-133 (2010)
[32] J. Xie, W. J. Ng, L. Y. Lee, and C.-H. Wang, "Encapsulation of protein drugs in biodegradable microparticles by co-axial electrospray," Journal of Colloid and Interface Science, Vol. 317, No. 2, pp. 469-476 (2008)
[33] H. Valo, L. Peltonen, S. Vehviläinen, M. Karjalainen, R. Kostiainen, T. Laaksonen, and J. Hirvonen, "Electrospray Encapsulation of Hydrophilic and Hydrophobic Drugs in Poly(L-lactic acid) Nanoparticles," Small, Vol. 5, No. 15, pp. 1791-1798 (2009)
[34] Y. Wu and R. L. Clark, "Electrohydrodynamic atomization: a versatile process for preparing materials for biomedical applications," Journal of Biomaterials Science, Polymer Edition, Vol. 19, No. 5, pp. 573-601 (2008)
[35] R. P. A. Hartman, D. J. Brunner, D. M. A. Camelot, J. C. M. Marijnissen, and B. Scarlett, "Jet break-up in electrohydrodynamic atomization in the cone-jet mode," Journal of Aerosol Science, Vol. 31, No. 1, pp. 65-95 (2000)
[36] M. Cloupeau and B. Prunet-Foch, "Electrostatic spraying of liquids in cone-jet mode," Journal of Electrostatics, Vol. 22, No. 2, pp. 135-159 (1989)
[37] S. N. Jayasinghe, "Biojets in regenerative biology & medicine," Materials Today, Vol. 14, No. 5, pp. 202-211 (2011)
[38] L. Rayleigh, "XX. On the equilibrium of liquid conducting masses charged with electricity," Philosophical Magazine Series 5, Vol. 14, No. 87, pp. 184-186 (1882)
[39] G. Taylor, "Electrically Driven Jets," Proceedings of the Royal Society of London. A. Mathematical and Physical Sciences, Vol. 313, No. 1515, pp. 453-475 (1969)
[40] G. Taylor, "Disintegration of Water Drops in an Electric Field," Proceedings of the Royal Society of London. Series A. Mathematical and Physical Sciences, Vol. 280, No. 1382, pp. 383-397 (1964)
[41] M. S. Wilm and M. Mann, "Electrospray and Taylor-Cone theory, Dole's beam of macromolecules at last?," International Journal of Mass Spectrometry and Ion Processes, Vol. 136, No. 2–3, pp. 167-180 (1994)
[42] I. G. Loscertales, A. Barrero, I. Guerrero, R. Cortijo, M. Marquez, and A. M. Gañán-Calvo, "Micro/Nano Encapsulation via Electrified Coaxial Liquid Jets," Science, Vol. 295, No. 5560, pp. 1695-1698 (2002)
[43] K. Kim, W. Kim, S. Hwa Yun, J. Hyun Lee, S. Kim, and B. U. Lee, "Use of an electrospray for the generation of bacterial bioaerosols," Journal of Aerosol Science, Vol. 39, No. 4, pp. 365-372 (2008)
[44] Y. Terada, Y. Suzuki, and S. Tohno, "Synthesis and characterization of TiO2 powders by electrospray pyrolysis method," Materials Research Bulletin, Vol. 47, No. 3, pp. 889-895 (2012)
[45] A. Gholami, H. Tavanai, and A. Moradi, "Production of fibroin nanopowder through electrospraying," Journal of Nanoparticle Research, Vol. 13, No. 5, pp. 2089-2098 (2011)
[46] M. J. Pilat, "Collection of aerosol particles by electrostatic droplet spray scrubbers," Journal of the Air Pollution Control Association, Vol. 25, No. 2, pp. 176-178 (1975 )
[47] H.-H. Kim, J.-H. Kim, and A. Ogata, "Time-resolved high-speed camera observation of electrospray," Journal of Aerosol Science, Vol. 42, No. 4, pp. 249-263 (2011)
[48] J.-H. Kim, H.-S. Lee, H.-H. Kim, and A. Ogata, "Electrospray with electrostatic precipitator enhances fine particles collection efficiency," Journal of Electrostatics, Vol. 68, No. 4, pp. 305-310 (2010)
[49] J. Yao, L. Kuang Lim, J. Xie, J. Hua, and C.-H. Wang, "Characterization of electrospraying process for polymeric particle fabrication," Journal of Aerosol Science, Vol. 39, No. 11, pp. 987-1002 (2008)
[50] A. Gomez and K. Tang, "Charge and fission of droplets in electrostatic sprays," Physics of Fluids, Vol. 6, No. 1, pp. 404-414 (1994)
[51] H. Fong, I. Chun, and D. H. Reneker, "Beaded nanofibers formed during electrospinning," Polymer, Vol. 40, No. 16, pp. 4585-4592 (1999)
[52] D. A. Saville, "Electrohydrodynamic stability: effects of charge relaxation at the interface of a liquid jet," Journal of Fluid Mechanics, Vol. 48, No. 4, pp. 815-827 (1971)
[53] A. L. Huebner and H. N. Chu, "Instability and breakup of charged liquid jets," Journal of Fluid Mechanics, Vol. 49, No. 2, pp. 361-372 (1971)
[54] J. Rosell-Llompart and J. Fernández de la Mora, "Generation of monodisperse droplets 0.3 to 4 μm in diameter from electrified cone-jets of highly conducting and viscous liquids," Journal of Aerosol Science, Vol. 25, No. 6, pp. 1093-1119 (1994)
[55] D.-R. Chen, D. Y. H. Pui, and S. L. Kaufman, "Electrospraying of conducting liquids for monodisperse aerosol generation in the 4 nm to 1.8 μm diameter range," Journal of Aerosol Science, Vol. 26, No. 6, pp. 963-977 (1995)
[56] G. A. Valaskovic, J. P. Murphy Iii, and M. S. Lee, "Automated orthogonal control system for electrospray ionization," Journal of the American Society for Mass Spectrometry, Vol. 15, No. 8, pp. 1201-1215 (2004)
[57] I. Brigger, C. Dubernet, and P. Couvreur, "Nanoparticles in cancer therapy and diagnosis," Advanced Drug Delivery Reviews, Vol. 54, No. 5, pp. 631-651 (2002)
[58] T. W. Atkins, B. J. Tighe, and R. L. McCallion, "Incorporation and release of fluorescein isothiocyanate-linked dextrans from a bead-formed macroporous hydrophilic matrix with potential for sustained release," Biomaterials, Vol. 14, No. 1, pp. 16-20 (1993)
[59] X. Huang and C. S. Brazel, "On the importance and mechanisms of burst release in matrix-controlled drug delivery systems," Journal of Controlled Release, Vol. 73, No. 2–3, pp. 121-136 (2001)
[60] N. Ahmed, H. Fessi, and A. Elaissari, "Theranostic applications of nanoparticles in cancer," Drug Discovery Today, http://dx.doi.org/10.1016/j.drudis.2012.03.010 (2012)
[61] Y. Liu, H. Miyoshi, and M. Nakamura, "Nanomedicine for drug delivery and imaging: A promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles," International Journal of Cancer, Vol. 120, No. 12, pp. 2527-2537 (2007)
[62] S. Bisht and A. Maitra, "Dextran–doxorubicin/chitosan nanoparticles for solid tumor therapy," Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, Vol. 1, No. 4, pp. 415-425 (2009)
[63] Y. Matsumura and H. Maeda, "A New Concept for Macromolecular Therapeutics in Cancer Chemotherapy: Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs," Cancer Research, Vol. 46, No. 12 Part 1, pp. 6387-6392 (1986)
[64] S. Manchun, C. R. Dass, and P. Sriamornsak, "Targeted therapy for cancer using pH-responsive nanocarrier systems," Life Sciences, Vol. 90, No. 11-12, pp. 381-387 (2012)
[65] J.-C. Olivier, L. Fenart, R. Chauvet, C. Pariat, R. Cecchelli, and W. Couet, "Indirect Evidence that Drug Brain Targeting Using Polysorbate 80-Coated Polybutylcyanoacrylate Nanoparticles Is Related to Toxicity," Pharmaceutical Research, Vol. 16, No. 12, pp. 1836-1842 (1999)
[66] V. Labhasetwar, J. Bonadio, S. A. Goldstein, and R. J. Levy, "Gene transfection using biodegradable nanospheres: results in tissue culture and a rat osteotomy model," Colloids and Surfaces B: Biointerfaces, Vol. 16, No. 1–4, pp. 281-290 (1999)
[67] A. Lamprecht, N. Ubrich, H. Yamamoto, U. Schäfer, H. Takeuchi, P. Maincent, Y. Kawashima, and C.-M. Lehr, "Biodegradable Nanoparticles for Targeted Drug Delivery in Treatment of Inflammatory Bowel Disease," Journal of Pharmacology and Experimental Therapeutics, Vol. 299, No. 2, pp. 775-781 (2001)
[68] S. Wang, R. Gao, F. Zhou, and M. Selke, "Nanomaterials and singlet oxygen photosensitizers: potential applications in photodynamic therapy," Journal of Materials Chemistry, Vol. 14, No. 4, pp. 487-493 (2004)
[69] Y. Masayuki, M. Mizue, Y. Noriko, O. Teruo, S. Yasuhisa, K. Kazunori, and I. Shohei, "Polymer micelles as novel drug carrier: Adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer," Journal of Controlled Release, Vol. 11, No. 1–3, pp. 269-278 (1990)
[70] B. G. Yu, T. Okano, K. Kataoka, and G. Kwon, "Polymeric micelles for drug delivery: solubilization and haemolytic activity of amphotericin B," Journal of Controlled Release, Vol. 53, No. 1–3, pp. 131-136 (1998)
[71] C. Z. Chen and S. L. Cooper, "Interactions between dendrimer biocides and bacterial membranes," Biomaterials, Vol. 23, No. 16, pp. 3359-3368 (2002)
[72] M. Witvrouw, V. Fikkert, W. Pluymers, B. Matthews, K. Mardel, D. Schols, J. Raff, Z. Debyser, E. De Clercq, G. Holan, and C. Pannecouque, "Polyanionic (i.e., Polysulfonate) Dendrimers Can Inhibit the Replication of Human Immunodeficiency Virus by Interfering with Both Virus Adsorption and Later Steps (Reverse Transcriptase/Integrase) in the Virus Replicative Cycle," Molecular Pharmacology, Vol. 58, No. 5, pp. 1100-1108 (2000)
[73] T. C. Yih and M. Al-Fandi, "Engineered nanoparticles as precise drug delivery systems," Journal of Cellular Biochemistry, Vol. 97, No. 6, pp. 1184-1190 (2006)
[74] S. Hamdy, A. Haddadi, R. W. Hung, and A. Lavasanifar, "Targeting dendritic cells with nano-particulate PLGA cancer vaccine formulations," Advanced Drug Delivery Reviews, Vol. 63, No. 10-11, pp. 943-955 (2011)
[75] H. K. Makadia and S. J. Siegel, "Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier," Polymers, Vol. 3, No. 3, pp. 1377-1397 (2011)
[76] Y.-M. Tsai, C.-F. Chien, L.-C. Lin, and T.-H. Tsai, "Curcumin and its nano-formulation: The kinetics of tissue distribution and blood–brain barrier penetration," International Journal of Pharmaceutics, Vol. 416, No. 1, pp. 331-338 (2011)
[77] A. MUKERJEE and J. K. VISHWANATHA, "Formulation, Characterization and Evaluation of Curcumin-loaded PLGA Nanospheres for Cancer Therapy," Anticancer Research, Vol. 29, No. 10, pp. 3867-3875 (2009)
[78] M. M. Yallapu, B. K. Gupta, M. Jaggi, and S. C. Chauhan, "Fabrication of curcumin encapsulated PLGA nanoparticles for improved therapeutic effects in metastatic cancer cells," Journal of Colloid and Interface Science, Vol. 351, No. 1, pp. 19-29 (2010 )
[79] C. Fonseca, S. Simões, and R. Gaspar, "Paclitaxel-loaded PLGA nanoparticles: preparation, physicochemical characterization and in vitro anti-tumoral activity," Journal of Controlled Release, Vol. 83, No. 2, pp. 273-286 (2002)
[80] F. Danhier, N. Lecouturier, B. Vroman, C. Jérôme, J. Marchand-Brynaert, O. Feron, and V. Préat, "Paclitaxel-loaded PEGylated PLGA-based nanoparticles: In vitro and in vivo evaluation," Journal of Controlled Release, Vol. 133, No. 1, pp. 11-17 (2009)
[81] D. D. Ateh, V. H. Leinster, S. R. Lambert, A. Shah, A. Khan, H. J. Walklin, J. V. Johnstone, N. I. Ibrahim, M. M. Kadam, Z. Malik, M. Gironès, G. J. Veldhuis, G. Warnes, S. Marino, I. A. McNeish, and J. E. Martin, "The intracellular uptake of CD95 modified paclitaxel-loaded poly(lactic-co-glycolic acid) microparticles," Biomaterials, Vol. 32, No. 33, pp. 8538-8547 (2011)
[82] B. K. Kang, S. K. Chon, S. H. Kim, S. Y. Jeong, M. S. Kim, S. H. Cho, H. B. Lee, and G. Khang, "Controlled release of paclitaxel from microemulsion containing PLGA and evaluation of anti-tumor activity in vitro and in vivo," International Journal of Pharmaceutics, Vol. 286, No. 1-2, pp. 147-156 (2004)
[83] E. C. Gryparis, M. Hatziapostolou, E. Papadimitriou, and K. Avgoustakis, "Anticancer activity of cisplatin-loaded PLGA-mPEG nanoparticles on LNCaP prostate cancer cells," European Journal of Pharmaceutics and Biopharmaceutics, Vol. 67, No. 1, pp. 1-8 (2007)
[84] L. Cheng, C. Jin, W. Lv, Q. Ding, and X. Han, "Developing a Highly Stable PLGA-mPEG Nanoparticle Loaded with Cisplatin for Chemotherapy of Ovarian Cancer," Public Library of Science ONE, Vol. 6, No. 9, p. e25433 (2011)
[85] I. Kim, H. J. Byeon, T. H. Kim, E. S. Lee, K. T. Oh, B. S. Shin, K. C. Lee, and Y. S. Youn, "Doxorubicin-loaded highly porous large PLGA microparticles as a sustained- release inhalation system for the treatment of metastatic lung cancer," Biomaterials, Vol. 33, No. 22, pp. 5574-5583 (2012)
[86] H. S. Yoo, K. H. Lee, J. E. Oh, and T. G. Park, "In vitro and in vivo anti-tumor activities of nanoparticles based on doxorubicin–PLGA conjugates," Journal of Controlled Release, Vol. 68, No. 3, pp. 419-431 (2000)
[87] T. Lei, S. Srinivasan, Y. Tang, R. Manchanda, A. Nagesetti, A. Fernandez-Fernandez, and A. J. McGoron, "Comparing cellular uptake and cytotoxicity of targeted drug carriers in cancer cell lines with different drug resistance mechanisms," Nanomedicine: Nanotechnology, Biology and Medicine, Vol. 7, No. 3, pp. 324-332 (2011)
[88] C. C. DeMerlis and D. R. Schoneker, "Review of the oral toxicity of polyvinyl alcohol (PVA)," Food and Chemical Toxicology, Vol. 41, No. 3, pp. 319-326 (2003)
[89] D. C. G. Muir and N. P. Grift, "Determination of Niclosamide (Bayer 2353) in Water and Sediment Samples," International Journal of Environmental Analytical Chemistry, Vol. 8, No. 1, pp. 1-14 (1980)
[90] F. Onur and N. Tekin, "Spectrophotometric Determination of Niclosamide and Thiabendazole in Tablets," Analytical Letters, Vol. 27, No. 12, pp. 2291-2301 (1994)
[91] L. H. Emara, "Rapid and accurate method for determination of niclosamide released from molluscidical formulations," Journal of AOAC International, Vol. 76, No. 4, pp. 847-850 (1993)
[92] M. Sardo, A. M. Amado, and P. J. A. Ribeiro-Claro, "Pseudopolymorphic transitions of niclosamide monitored by Raman spectroscopy," Journal of Raman Spectroscopy, Vol. 39, No. 12, pp. 1915-1924 (2008)
[93] S. D’Souza and P. DeLuca, "Development of a dialysis in vitro release method for biodegradable microspheres," AAPS PharmSciTech, Vol. 6, No. 2, pp. 323-328 (2005)
[94] H. Xie and J. Smith, "Fabrication of PLGA nanoparticles with a fluidic nanoprecipitation system," Journal of Nanobiotechnology, Vol. 8, No. 1, pp. 18-24 (2010)
[95] W. Abdelwahed, G. Degobert, and H. Fessi, "A pilot study of freeze drying of poly(epsilon-caprolactone) nanocapsules stabilized by poly(vinyl alcohol): Formulation and process optimization," International Journal of Pharmaceutics, Vol. 309, No. 1–2, pp. 178-188 (2006)
[96] X. Wang, M. Shao, G. Shao, Z. Wu, and S. Wang, "A facile route to ultra-long polyaniline nanowires and the fabrication of photoswitch," Journal of Colloid and Interface Science, Vol. 332, No. 1, pp. 74-77 (2009)
[97] D. R. Lide, CRC Handbook of Chemistry and Physics, 87 ed. Florida: CRC Press Inc., pp. 6-137-6-139 (2006).
[98] A. Geze, F. Boury, J.-P. Benoit, I. Chourpa, and P. Dubois, "Direct qualitative and quantitative characterization of a radiosensitizer, 5-iodo-2 '-deoxyuridine within biodegradable polymeric microspheres by FT-Raman spectroscopy," Analyst, Vol. 124, No. 1, pp. 37-42 (1999)
[99] L. Lu, C. A. Garcia, and A. G. Mikos, "In vitro degradation of thin poly(DL-lactic-co-glycolic acid) films," Journal of Biomedical Materials Research, Vol. 46, No. 2, pp. 236-244 (1999)
[100] A. M. Reed and D. K. Gilding, "Biodegradable polymers for use in surgery — poly(glycolic)/poly(Iactic acid) homo and copolymers: 2. In vitro degradation," Polymer, Vol. 22, No. 4, pp. 494-498 (1981)
[101] B. S. Zolnik and D. J. Burgess, "Effect of acidic pH on PLGA microsphere degradation and release," Journal of Controlled Release, Vol. 122, No. 3, pp. 338-344 (2007)
[102] A. H. Cory, T. C. Owen, J. A. Barltrop, and J. G. Cory, "Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture," Cancer communications, Vol. 3, No. 7, pp. 207-212 (1991)
[103] E. C. Cho, Y. Liu, and Y. Xia, "A Simple Spectroscopic Method for Differentiating Cellular Uptakes of Gold Nanospheres and Nanorods from Their Mixtures," Angewandte Chemie International Edition, Vol. 49, No. 11, pp. 1976-1980 (2010)