Vazda Amina, Pujari-Palmer Michael, Xia Wei, Engqvist Håkan
Department of Materials Science and Engineering, Division of Applied Materials Science, Uppsala University, 75121 Uppsala, Sweden.
Materials (Basel). 2021 Nov 9;14(22):6735. doi: 10.3390/ma14226735.
Controlled drug release and targeted drug delivery can reduce systemic toxicity of chemotherapeutics by restricting drugs to the target organ and increasing the local concentration. As tumors and inflamed tissue are often surrounded by an acidic microenvironment, pH-responsive calcium carbonates (CaCO) are promising vehicles for controlled drug delivery applications. The aim of this study was to evaluate the loading efficacy and release of a chemotherapeutic drug, Hydroxyurea (HU), into the crystal structure of calcite. Incorporation of HU did not alter the crystallinity, crystal size, or morphology of precipitated calcite crystals, as assessed by XRD and SEM. The amount of HU was quantified by High-Pressure Liquid Chromatography (HPLC) and showed that 6.7 ± 0.7 µg of HU could be for each milligram of calcite (0.016 mol% ± 0.002). In cell media, the optimal pH for controlled release was 5 (0.1 mg/mL released after 1 h). However, in vitro, pH below 6.5 was cytotoxic to human breast cancer cells (MCF-7). Direct contact studies, where particles were incubated with MCF-7 cells, showed that the amount of HU release from calcite was not high enough to kill the cell or arrest growth at pH 6.5. Pre-dissolved release studies, where the particles were pre-dissolved in acidic media to simulate complete drug release in vivo, pH neutralized, and exposed to the cells, showed that the amount of loaded HU reduced the survival/proliferation of MCF7. In conclusion, it is possible to integrate HU into the crystal structure of a calcite crystal and release the drug in vitro at concentrations that can slow the growth of cancer cells, without affecting calcite morphology and crystallinity. Further research is needed to investigate the in vivo behavior of the particles and whether the actual tumor pH is low enough to achieve complete drug release in vivo.
可控药物释放和靶向给药可通过将药物限制在靶器官并提高局部浓度来降低化疗药物的全身毒性。由于肿瘤和炎症组织通常被酸性微环境所包围，pH响应性碳酸钙（CaCO）是可控药物递送应用中很有前景的载体。本研究的目的是评估化疗药物羟基脲（HU）在方解石晶体结构中的负载效率和释放情况。通过XRD和SEM评估，HU的掺入并未改变沉淀方解石晶体的结晶度、晶体尺寸或形态。通过高压液相色谱（HPLC）对HU的量进行了定量，结果表明每毫克方解石可负载6.7±0.7μg的HU（0.016 mol%±0.002）。在细胞培养基中，可控释放的最佳pH值为5（1小时后释放0.1 mg/mL）。然而，在体外，pH低于6.5对人乳腺癌细胞（MCF-7）具有细胞毒性。将颗粒与MCF-7细胞孵育的直接接触研究表明，在pH 6.5时，方解石中HU的释放量不足以杀死细胞或阻止其生长。预溶解释放研究中，将颗粒在酸性介质中预溶解以模拟体内药物完全释放，调节pH至中性后再暴露于细胞，结果表明负载的HU量降低了MCF7的存活率/增殖率。总之，有可能将HU整合到方解石晶体结构中，并在体外以能够减缓癌细胞生长的浓度释放药物，而不影响方解石的形态和结晶度。需要进一步研究来探究颗粒在体内的行为以及实际肿瘤pH是否低到足以实现体内药物的完全释放。
