Mahjoub Mohammad Ali, Dadashzadeh Simin, Haeri Azadeh, Shahhosseini Soraya, Abbasian Zahra, Nowroozi Fatemeh
Department of Pharmaceutics and Nanotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Iran J Pharm Res. 2023 Feb 26;21(1):e134190. doi: 10.5812/ijpr-134190. eCollection 2022 Dec.
Despite the advantages of direct intratumoral (IT) injection, the relatively rapid withdrawal of most anti-cancer drugs from the tumor due to their small molecular size limits the effectiveness of this method of administration. To address these limitations, recently, increasing attention has been directed to using slow-release biodegradable delivery systems for IT injection.
This study aimed to develop and characterize a doxorubicin-loaded DepoFoam system as an efficient controlled-release carrier to be employed for locoregional drug delivery in cancer treatment.
Major formulation parameters, including the molar ratio of cholesterol to the main lipid [Chol/egg phosphatidylcholine (EPC)], triolein (TO) content, and lipid-to-drug molar ratio (L/D), were optimized using a two-level factorial design approach. The prepared batches were evaluated for encapsulation efficiency (EE) and percentage of drug release (DR) after 6 and 72 hours as dependent variables. The optimum formulation (named DepoDOX) was further evaluated in terms of particle size, morphology, zeta potential, stability, Fourier-transform infrared spectroscopy, in vitro cytotoxicity, and hemolysis.
The analysis of factorial design indicated that TO content and L/D ratio had a negative effect on EE; between these two, TO content had the greatest effect. The TO content was also the most significant component, with a negative effect on the release rate. The ratio of Chol/EPC showed a dual effect on the DR rate. Using a higher percentage of Chol slowed down the initial release phase of the drug; nevertheless, it accelerated the DR rate in the later slow phase. DepoDOX were spherical and honeycomb-like structures (≈ 9.81 μm) with a desired sustained release profile, as DR lasted 11 days. Its biocompatibility was confirmed by the results of cytotoxicity and hemolysis assays.
The in vitro characterization of optimized DepoFoam formulation demonstrated its suitability for direct locoregional delivery. DepoDOX, as a biocompatible lipid-based formulation, showed appropriate particle size, high capability for encapsulating doxorubicin, superior physical stability, and a markedly prolonged DR rate. Therefore, this formulation could be considered a promising candidate for locoregional drug delivery in cancer treatment.
尽管瘤内直接注射有诸多优势，但大多数抗癌药物因分子尺寸小，在肿瘤内相对快速地清除，限制了这种给药方式的有效性。为解决这些局限性，近来，将缓释可生物降解给药系统用于瘤内注射受到越来越多的关注。
本研究旨在开发并表征一种载有多柔比星的DepoFoam系统，作为一种高效的控释载体，用于癌症治疗中的局部区域给药。
使用两水平析因设计方法优化主要配方参数，包括胆固醇与主要脂质[胆固醇/蛋黄卵磷脂（EPC）]的摩尔比、三油酸甘油酯（TO）含量以及脂质与药物的摩尔比（L/D）。将制备的批次作为因变量，评估其包封率（EE）以及6小时和72小时后的药物释放百分比（DR）。进一步从粒径、形态、zeta电位、稳定性、傅里叶变换红外光谱、体外细胞毒性和溶血等方面对最佳配方（命名为DepoDOX）进行评估。
析因设计分析表明，TO含量和L/D比对EE有负面影响；在这两者之间，TO含量的影响最大。TO含量也是最显著的成分，对释放速率有负面影响。胆固醇/EPC的比例对药物释放速率有双重影响。使用较高百分比的胆固醇会减缓药物的初始释放阶段；然而，它会加速后期缓慢阶段的药物释放速率。DepoDOX呈球形和蜂窝状结构（≈9.81μm），具有理想的缓释曲线，因为药物释放持续了11天。细胞毒性和溶血试验结果证实了其生物相容性。
优化后的DepoFoam配方的体外表征证明其适用于直接局部区域给药。DepoDOX作为一种生物相容性脂质基配方，显示出合适的粒径、高载多柔比星能力、优异的物理稳定性和显著延长的药物释放速率。因此，该配方可被认为是癌症治疗中局部区域给药的有前景的候选者。
