Preparation and Evaluation of Human Serum Albumin Modified Irinotecan Hydrochloride PLGA Nanoparticles
LIU Xi-yanga,b,c, LUO Yu-yinga,b,c, DENG Sheng-qia,b,c*, ZHENG Lina,b,c*, SHEN Xuea,b,c
a. Antibiotics Research and Reevaluation Key Laboratory of Sichuan Province, b. Sichuan Industrial Institute of Antibiotics, c. School of Pharmacy, Chengdu University, Chengdu 610106, China
Abstract：OBJECTIVE To enhance the therapeutic effects in colon cancer, the human serum albumin modified irinotecan hydrochloride PLGA nanoparticles (HSA/PLGA/CPT-11 NPs) were prepared based on the optimized prescription. Then, its pharmaceutical property and anti-tumor activity were evaluated. METHODS The HSA/PLGA/CPT-11 NPs were prepared by emulsification-solvent evaporation method, finally made into freeze-dried powder. The response surface method of Box-Behnken Design was used to optimize the initial prescription. The particle size and distribution were measured by Malvern laser granulometer. Transmission electron microscope (TEM) and Fourier transform infrared spectrometer (FTIR) were used to determine the morphology of nanoparticles and the chemical stability of CPT-11, respectively. The in vitro release behavior was determined by dialysis. The preliminary stability was studied at low temperature and room temperature, respectively. Cytotoxicity assay was employed to evaluate the anti-tumor activity of the prepared NPs. RESULTS The TEM images showed that the optimized freeze-dried HSA/PLGA/CPT-11 NPs were spherical in shape, and exhibited good dispersibility. The average particle size of HSA/PLGA/CPT-11 NPs was 98.73±2.04 nm with a polydispersity index (PDI) of 0.257±0.03, and the zeta potential was -18.30±0.14 mV. The encapsulation efficiency of CPT-11 loaded into HSA/PLGA/CPT-11 NPs was 64.61±0.29%. The results of FTIR showed that CPT-11 was embedded in the nanocarrier and formed a new phase, not a simple physical mixture. The in vitro drug release rate of HSA/PLGA/CPT-11 NPs in 24 h reached 80%. The preliminary stability test demonstrated the good stability of freeze-dried HSA/PLGA/CPT-11 NPs under 4 ℃ and 25 ℃ during 60 days, respectively. The hemolytic test shows that the carrier material is safe and non-toxic, and the prepared HSA / PLGA / CPT-11 NPs freeze-dried preparation is suitable for intravenous injection. The cytotoxicity of HSA/PLGA/CPT-11 NPs on HCT-116 cells (human colon cancer cells) was significantly stronger than that of free irinotecan hydrochloride. CONCLUSION The HSA/PLGA/CPT-11 NPs prepared by emulsification-solvent evaporation method exhibited a relative small and uniform particle size, good dispersibility, high encapsulation efficiency, sustained-drug release behavior, and enhanced cytotoxicity.
刘喜阳, 罗玉莹, 邓盛齐, 郑林, 沈雪. 人血清白蛋白修饰的盐酸伊立替康PLGA纳米粒的制备与评价[J]. 中国药学杂志, 2021, 56(21): 1740-1748.
LIU Xi-yang, LUO Yu-ying, DENG Sheng-qi, ZHENG Lin, SHEN Xue. Preparation and Evaluation of Human Serum Albumin Modified Irinotecan Hydrochloride PLGA Nanoparticles. Chinese Pharmaceutical Journal, 2021, 56(21): 1740-1748.
DENG S Q JIANG F, REN J, et al. New Carrier Materials for Particles Drug Delivery System of Irinotecan Hydrochloride[J]. Chin Pharm J(中国药学杂志), 2018, 53(13):1093-1097.
[2]
PERRONE E, LOPEZ S, ZEYBEK B, et al. Preclinical activity of sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (Trop-2) linked to the active metabolite of irinotecan (SN-38) [J]. Front Oncol, 2020, 10: 118.
[3]
YANG W, YANG Z, LIU J, et al. Development of a method to quantify total and free irinotecan and 7-ethyl-10-hydroxycamptothecin (SN-38) for pharmacokinetic and bio-distribution studies after administration of irinotecan liposomal formulation[J]. Asian J Pharm Sci, 2019, 14(6): 687-697.
[4]
LI Z, TAN B, ZHANG Z Q, et al. The effect of liposomes on the lactone ring of irinotecan and the effect of drug release in vitro[J]. Chin Pharm J(中国药学杂志), 2008, 43(13):1003-1007.
[5]
WANG X, RAO Z, QIN H, et al. Effect of hesperidin on the pharmacokinetics of CPT-11 and its active metabolite SN-38 by regulating hepatic Mrp2 in rats[J]. Biopharm Drug Dispos, 2016, 37(7): 421-432.
[6]
PARK D J, WON J H, CHO A R, et al. Determination of irinotecan and its metabolite SN-38 in rabbit plasma and tumors using a validated method of tandem mass spectrometry coupled with liquid chromatography[J]. J Chromatogr B, 2014, 962: 147-152.
[7]
DAVID C A W, OWEN A, LIPTROTT N J, et al. Determining the relationship between nanoparticle characteristics and immunotoxicity: key challenges and approaches[J]. Nanomedicine, 2016, 11(11): 1447-1464.
[8]
ISHIHARA T, KANEKO K, ISHIHARA T, et al. Biodegradable nanoparticles for drug delivery and targeting[J]. J Pharm Sci, 2014, 103(12): 4005-4011.
[9]
XU Y, KIM C S, SAYLOR D M, et al. Polymer degradation and drug delivery in PLGA-based drug–polymer applications: A review of experiments and theories[J]. J Biomed Mater Res B, 2017, 105(6): 1692-1716.
[10]
SOPPIMATH K S, AMINABHAVI T M, KULKARNI A R, et al. Biodegradable polymeric nanoparticles as drug delivery devices[J]. J Controlled Release, 2001, 70(1-2): 1-20.
[11]
PANYAM J, ZHOU W Z, PRABHA S, et al. Rapid endo-lysosomal escape of poly (DL-lactide-coglycolide) nanoparticles: implications for drug and gene delivery[J]. FASEB J, 2002, 16(10): 1217-1226.
[12]
SILVA-ABREU M, CALPENA A C, ESPINA M, et al. Optimization, biopharmaceutical profile and therapeutic efficacy of pioglitazone-loaded PLGA-PEG nanospheres as a novel strategy for ocular inflammatory disorders[J]. Pharm Res, 2018, 35(1): 1-14.
[13]
NOBS L, BUCHEGGER F, GURNY R, et al. Poly(lactic acid) nanoparticles labeled with biologically activeNeutravidin for active targeting[J]. Eur J Pharm Biopharm, 2004, 58(3): 483-490.
[14]
ZELPHATI O, UYECHI LS, BARRON LG, et al. Effect of serum components on the physico-chemical properties of cationic lipid/oligonucleotide complexes and on their interactions with cells[J]. BBA Lipids Metab, 1998, 1390(2): 119-133.
[15]
KRATZ F. Albumin as a drug carrier: Design of prodrugs, drug conjugates and nanoparticles[J]. J Controlled Release, 2008, 132(3):171-183.
[16]
HASHAD R A, ISHAK R A H, GENEIDI A S, et al. Surface functionalization of methotrexate-loaded chitosan nanoparticles with hyaluronic acid/human serum albumin: Comparative characterization and in vitro cytotoxicity[J]. Int J Pharm, 2017, 522(1-2): 128-136.
[17]
WANG J Z, BING Y P, LI F, et al. Preparation of bovine serum albumin-modified PLGA nanoparticles loaded with naringenin[J]. Chin Tradit Pat Med(中成药), 2019, 41(11):2566-2571.
[18]
JIN W Z, TAN H J, WANG K K, et al. Construction of Matrine Solid Lipid Nanoparticle and Determination of the Entrapment Efficiency[J]. Chin Pharm J(中国药学杂志), 2020, 55(12):1015-1020.
[19]
HUANG W Z, CAI Z F, ZHANG Q M. Study on Spectrophometry Determination of Injection hemolysis[J]. Pharm Today(今日药学), 2016, 26(10):713-716,720.
[20]
DENG L, LI L, YANG H, et al. Development and optimization of doxorubicin loaded poly (lactic-co-glycolic acid) nanobubbles for drug delivery into HeLa cells[J]. J Nanosci Nanotechnol, 2014, 14(4): 2947-2954.
2021, Vol. 56 
