Preparation of lipid membrane-wrapped nanoparticles loaded with metformin polymer and doxorubicin and evaluation of their therapeutic effect on breast cancer
10.16438/j.0513-4870.2019-0626
- VernacularTitle:共载新型二甲双胍聚合物和多柔比星的核膜型脂质纳米粒制备及治疗乳腺癌的研究
- Author:
Shuang ZHENG
1
;
Jian-dong YU
1
,
2
;
Li-ying CHEN
1
;
Lu-hui FAN
1
;
Lu-jia ZHU
1
,
3
;
Chao-yuan TANG
1
;
Ke QIAN
1
;
Yang XIONG
1
Author Information
1. College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311402, China
2. Carbiogene Therapeutics Co., Ltd., Hangzhou 310051, China
3. Affiliated Hospital of Shaoxing University, Shaoxing 312000, China
- Publication Type:Research Article
- Keywords:
metformin polymer;
oxorubicin;
nanoparticle;
breast neoplasm;
metformin
- From:
Acta Pharmaceutica Sinica
2019;54(12):2316-2325
- CountryChina
- Language:Chinese
-
Abstract:
In this study, the lipid membrane-wrapped nanoparticles loaded with metformin polymer (PolyMet) and doxorubicin (DOX) was prepared and then evaluated therapeutic effect on breast cancer. An anionic chain PGA-DOX based on γ-polyglutamic acid (PGA) with DOX was synthesized via amidation reaction and characterized by 1H NMR. The PGA-DOX and PolyMet were loaded via electrostatic attraction to prepare the co-delivery nanoparticles system (PolyMet-DOX-NPs). Then, PolyMet-DOX-NPs were coated with cationic liposome membrane to form the core-membrane structural system (PolyMet-DOX-lipid-nanoparticles, PolyMet-DOX-LNPs). The structure and morphology of PolyMet-DOX-LNPs were observed by transmission electron microscope. The particle size, zeta potential, encapsulation efficiency (EE), drug loading (DL), release behavior in vitro of PolyMet-DOX-LNPs were investigated. The MTT assay was used to examine the cytotoxicity of PolyMet combined with DOX on 4T-1 cells. The 4T1Fluc tumor-bearing mice model was used to evaluate the therapeutic efficacy of PolyMet-DOX-LNPs in vivo. All animal experiments were performed in line with ethical standards and approved by the Animal Experiments Ethical Committee of Zhejiang Chinese Medical University. 1H NMR spectrum showed that PGA-DOX was successfully synthesized with DOX grafting rate of (72.03 ± 1.29) %. The EE and DL of PolyMet-DOX-LNPs was (72.76 ± 1.92) % and (1.16 ± 0.12) %, respectively. PolyMet-DOX-LNPs exhibited a suitable size of (159.3 ± 7.4) nm and positive charge of (+36.3 ± 1.9) mV with good spheroidal morphology and dispersibility. The release profiles in vitro showed that PolyMet-DOX-LNPs exhibited a slowly and maintained release behavior at physiological pH value (pH 7.4) within 48 h. Further studies showed that PolyMet combined with DOX could synergistically enhance the cytotoxicity on 4T-1 cells. Bioluminescence imaging (BLI) result showed that the luminescence signal intensity of 4T-1Fluc cells was reduced after treatment with PolyMet-DOX-LNPs and the tumor volume growth was also inhibited. Additionally, the H&E staining and changes of body weight showed that PolyMet could reduce the toxicity of DOX. To sum up, PolyMet has a good synergistic effect with DOX in the treatment of breast cancer, which provide the foundation for this novel metformin polymer on the anti-tumor application.
