PAMAM-G4 protect the N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) and maintain its antiproliferative effects on MCF-7 (Dataset).

Our work group designed and synthesized a promissory compound N-(2-hydroxyphenyl)-2- propylpentanamide (HO-AAVPA). The HO-AAVPA which is a HDAC1 inhibitor and antiproliferative in cancer cell lines. However, HO-AAVPA is poor water solubility and enzymatically metabolized. In this work, the fourth-generation poly(amidoamine) dendrimer (PAMAM-G4) was used as a drug deliver nanocarrier of HO-AAVPA. Moreover, HO-AAVPA and HO-AAVPA-PAMAM complex were submitted to forced degradation studies (heat, acid, base, oxidation and sunlight). Also, the HO-AAVPA- PAMAM-G4 complex was assayed as antiproliferative in a breast cancer cell line (MCF-7). The HO AAVPA-PAMAM-G4 complex was obtained by docking and experimentally using three pH conditions: acid (pH = 3.0), neutral (pH = 7.0) and basic (pH = 9.0) showing that PAMAM-G4 is captured and protect the HO-AAVPA from forced degradation, it is due to sunlight yielded a by-product from HO-AAVPA. In addition, the PAMAM-G4 favored the HO-AAVPA water solubility under basic and neutral pH conditions with significant difference (F _(2,18) =259.9, p&lt;0.001) between the slopes of the three conditions being the basic condition which solubilizes the greatest amount of HO-AAVPA. Finally, the HO-AAVPA-PAMAM-G4 complex showed better antiproliferative effects on MCF-7 (IC₅₀ = 75.3 μM) than HO-AAVPA (IC₅₀ = 192 μM). These results evidence that PAMAM- G4 complex improve the biological effects of HO-AAVPA.本研究团队设计并合成了极具应用前景的化合物N-(2-羟基苯基)-2-丙基戊酰胺（HO-AAVPA）。该化合物作为组蛋白去乙酰化酶1（HDAC1）抑制剂，对多种癌细胞系具有抗增殖活性。但HO-AAVPA存在水溶性较差且易被酶代谢的缺陷。本研究选用第四代聚酰胺-胺树状大分子（poly(amidoamine) dendrimer, PAMAM-G4）作为HO-AAVPA的药物递送纳米载体。此外，本研究对游离HO-AAVPA及HO-AAVPA-PAMAM复合物开展了强制降解实验，涵盖高温、强酸、强碱、氧化及光照五种条件。同时，针对HO-AAVPA-PAMAM-G4复合物，本研究在乳腺癌细胞系MCF-7中检测了其抗增殖活性。本研究通过分子对接及实验验证的方式，在三种pH条件（强酸pH=3.0、中性pH=7.0、强碱pH=9.0）下制备了HO-AAVPA-PAMAM-G4复合物，实验结果显示PAMAM-G4可包裹并保护HO-AAVPA免受强制降解，而光照条件下HO-AAVPA会生成副产物。此外，PAMAM-G4可显著提升HO-AAVPA在中性及强碱pH条件下的水溶性；三种pH条件下的溶解斜率存在极显著差异（F_(2,18)=259.9，p<0.001），其中强碱条件下HO-AAVPA的溶出量最高。最终实验结果表明，HO-AAVPA-PAMAM-G4复合物在MCF-7细胞中的抗增殖活性优于游离HO-AAVPA，其半数抑制浓度（IC₅₀）为75.3 μM，而游离HO-AAVPA的IC₅₀为192 μM。上述结果证实，PAMAM-G4复合物可有效增强HO-AAVPA的生物学活性。