Baines Daniel K, Wright Karen, Douglas Timothy E L
School of Engineering, Lancaster University, Gillow Avenue, Lancaster LA1 4YW, UK.
Biomedical and Life Sciences, Lancaster University, Gillow Avenue, Lancaster LA1 4YW, UK.
Polymers (Basel). 2024 Nov 24;16(23):3273. doi: 10.3390/polym16233273.
Colorectal cancer (CRC) is the second global cause of cancer morbidity. Often, potent CRC drugs fail to reach the market, due to the molecule having low solubility levels. Therefore, there is a need to develop a viable, targeted delivery system for hydrophobic drugs. Whey protein isolate (WPI), in the form of hydrogels, has demonstrated loadability with hydrophobic molecules. Hydrophobic cannabidiol (CBD) has demonstrated potential in inhibiting and suppressing CRC tumour growth. Therefore, in this study, WPI hydrogels were assessed as a novel oral hydrophobic drug delivery vehicle, using CBD as a model drug. The hydrogels were analysed in conditions consistent with the alimentary tract. The investigation was performed at pH 2 (stomach), pH 7 (small intestines) and pH 9 (large intestines) and using the enzymes pepsin (stomach) and protease (small and large intestines) to simulate the digestive environment. Polymer swelling assays demonstrated that the swelling potential of the hydrogels was strongly dependent on pH. At pH 2, hydrogels decreased in mass, losing around 10% of their initial mass, while hydrogels in a pH 9 environment increased in mass by approximately 50%. However, the enzymatic degradation of the hydrogels at pH 2 (pepsin, stomach), pH 7 (protease, small intestines) and pH 9 (protease, large intestines) was more pronounced in the neutral-alkaline pH range. Pepsin at pH 2 had no significant effect on the hydrogels. In contrast, protease at pH 9 significantly degraded the hydrogels, resulting in a mass loss of 30-40% from the initial mass. The results suggesting a higher rate of degradation in the intestines rather than in the stomach. Furthermore, CBD release, analysed with U.V. spectroscopy, demonstrated a higher release rate in pH conditions associated with the intestines (pH 7 and pH 9) rather than the stomach (pH 2), suggesting a higher rate of CBD release in regions of the digestive tract affected by CRC. Significantly, the hydrogels significantly reduced the viability of HT29 CRC cells. This study demonstrates the potential of the utilisation of WPI hydrogels as an oral hydrophobic drug delivery system.
结直肠癌（CRC）是全球癌症发病的第二大原因。通常，由于分子溶解度低，有效的CRC药物往往无法进入市场。因此，需要开发一种可行的、针对疏水性药物的靶向递送系统。乳清蛋白分离物（WPI）以水凝胶的形式，已证明具有负载疏水分子的能力。疏水性大麻二酚（CBD）已显示出抑制和抑制CRC肿瘤生长的潜力。因此，在本研究中，以CBD为模型药物，评估了WPI水凝胶作为一种新型口服疏水性药物递送载体。在与消化道一致的条件下对水凝胶进行分析。研究在pH 2（胃）、pH 7（小肠）和pH 9（大肠）条件下进行，并使用胃蛋白酶（胃）和蛋白酶（小肠和大肠）来模拟消化环境。聚合物溶胀试验表明，水凝胶的溶胀潜力强烈依赖于pH值。在pH 2时，水凝胶质量下降，损失约10%的初始质量，而在pH 9环境中的水凝胶质量增加约50%。然而，水凝胶在pH 2（胃蛋白酶，胃）、pH 7（蛋白酶，小肠）和pH 9（蛋白酶，大肠）条件下的酶促降解在中性至碱性pH范围内更为明显。pH 2的胃蛋白酶对水凝胶没有显著影响。相比之下，pH 9的蛋白酶显著降解水凝胶，导致质量从初始质量损失30-40%。结果表明在肠道中的降解速率高于在胃中的降解速率。此外，用紫外光谱分析CBD的释放，结果表明在与肠道相关的pH条件（pH 7和pH 9）下的释放速率高于胃（pH 2），这表明在受CRC影响的消化道区域CBD的释放速率更高。值得注意的是，水凝胶显著降低了HT29 CRC细胞的活力。本研究证明了利用WPI水凝胶作为口服疏水性药物递送系统的潜力。
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