Varshosaz Jaleh, Enteshari Saeedeh, Hassanzadeh Farshid, Hashemi-Beni Batool, Minaiyan Mohsen, Sadeghian-Rizi Sedighe
Department of Pharmaceutics, School of Pharmacy and Novel Drug Delivery Systems Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran.
Department of Pharmaceutical Chemistry, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.
Anticancer Agents Med Chem. 2018;18(14):2017-2031. doi: 10.2174/1871520618666180905155901.
To reduce the nonspecifically distribution of chemotherapeutic agents throughout the whole body, which causes severe toxicity in normal tissues, targeting them towards a receptor overexpressed on tumor tissue, is a promising method for cancer therapy.
The aim of the present study was development of novel copolymeric micelles of raloxifene targeted Styrene Maleic Acid-Poly Amide Ether Ester Imide-Poly Ethylene Glycol (SMA-PAEEI-PEG-RA) and loading them with Docetaxel (DTX).
Successful synthesis of the targeted copolymer was confirmed by FTIR and C-NMR spectroscopy. The micelles physicochemical properties like morphology, particle size, poly dispersity index, zeta potential, drug loading, release, stability, cytotoxicity and cellular uptake were analyzed. The antitumor activity of DTX-loaded micelles were assessed and compared with free DTX and non-targeted micelles in breast cancer bearing Balb-c mice.
Particle sizes, zeta potentials and the encapsulation efficiency of the drug in targeted micelles were 115.9- 142.8 nm, -4.9 to -12.9 mV, and 54.1-67.8%, respectively. Cell toxicity tests showed that IC of DTX-loaded SMAPAEEI- PEG-RA micelles increased five-fold as compared with free DTX. Survival rate of the mice improved more effectively than free DTX so that, the percentage of increase in lifespan (ILS%) and the tumor inhibition ratio (TIR) changed from 41.66% and 51.19% in free drug to 83.33% and 78.57% in the targeted micelles, respectively.
Therefore, the raloxifene conjugated PEG-derived micelles may provide a novel and effective delivery system for DTX in breast cancer.
为减少化疗药物在全身的非特异性分布，这种分布会导致正常组织出现严重毒性，将它们靶向肿瘤组织上过度表达的受体是一种很有前景的癌症治疗方法。
本研究旨在开发新型的雷洛昔芬靶向苯乙烯马来酸 - 聚酰胺醚酯酰亚胺 - 聚乙二醇（SMA - PAEEI - PEG - RA）共聚物胶束，并将多西他赛（DTX）负载于其中。
通过傅里叶变换红外光谱（FTIR）和碳核磁共振光谱（C - NMR）确认靶向共聚物的成功合成。分析胶束的物理化学性质，如形态、粒径、多分散指数、zeta电位、载药量、释放、稳定性、细胞毒性和细胞摄取。评估负载DTX的胶束的抗肿瘤活性，并与游离DTX和非靶向胶束在荷乳腺癌的Balb - c小鼠中进行比较。
靶向胶束的粒径、zeta电位和药物包封率分别为115.9 - 142.8 nm、 - 4.9至 - 12.9 mV和54.1 - 67.8％。细胞毒性试验表明，负载DTX的SMA - PAEEI - PEG - RA胶束的半数抑制浓度（IC）与游离DTX相比增加了五倍。小鼠的存活率比游离DTX更有效地提高，因此，寿命延长百分比（ILS％）和肿瘤抑制率（TIR）分别从游离药物的41.66％和51.19％变为靶向胶束的83.33％和78.57％。
因此，雷洛昔芬共轭聚乙二醇衍生的胶束可能为乳腺癌中的DTX提供一种新型有效的递送系统。
