Liu Dandan, Su Yupei, Chen Jixuan, Pan Hao, Pan Weisan
School of Biomedical & Chemical Engineering, Liaoning Institute of Science and Technology, Benxi, 117004, People's Republic of China.
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
AAPS PharmSciTech. 2023 Mar 25;24(4):86. doi: 10.1208/s12249-023-02545-4.
Oral administration of doxorubicin (DOX) is preferred but challenged owing to poor permeability in the gastrointestinal tract (GIT), efflux of P-glycoprotein, short residence time in the intestine, and rapid hydrolysis. Herein, folic acid-chitosan oligosaccharide conjugate (FA-COS)-modified hydroxylated nanodiamond (ND-OH) was designed to enhance the oral bioavailability of DOX. The carboxyl surface of ND was modified into hydroxyl terminal group to increase the colloidal stability of the system under different pH conditions in GIT. FA-COS modification could prolong retention time, endow the drug with sustained release properties, and actively target intestinal FA receptors. In contrast to DOX/ND-OH, the particle size of DOX/ND-OH/FA-COS increased from 189.5 ± 2.8 to 224.5 ± 1.4 nm, and the zeta potential reversed from - 9.1 ± 0.2 to 14.8 ± 0.4 mV. At 48 h, DOX/ND-OH and DOX/ND-OH/FA-COS released 69.07 ± 5.70% and 35.87 ± 5.64%, respectively. FA-COS modification effectively enhanced the cytotoxicity and intracellular uptake of ND-OH/DOX by Caco-2 cells and prolonged intestinal retention in rats. The internalization of DOX/ND-OH and DOX/ND-OH/FA-COS was mainly mediated by energy-dependent clathrin- and caveolae-mediated endocytosis pathways. Pharmacokinetic study demonstrated that the AUC of DOX/ND-OH and DOX/ND-OH/FA-COS was enhanced by 3.94- and 6.08-fold compared to DOX solution, respectively. These results illustrated that DOX/ND-OH/FA-COS could be an effective strategy to enhance the oral bioavailability of DOX.
口服阿霉素（DOX）是首选给药方式，但由于其在胃肠道（GIT）中渗透性差、P-糖蛋白外排、在肠道内停留时间短以及快速水解等问题而面临挑战。在此，设计了叶酸-壳寡糖缀合物（FA-COS）修饰的羟基化纳米金刚石（ND-OH）以提高DOX的口服生物利用度。将ND的羧基表面修饰为羟基末端基团，以提高该体系在GIT不同pH条件下的胶体稳定性。FA-COS修饰可延长保留时间，赋予药物缓释特性，并主动靶向肠道叶酸受体。与DOX/ND-OH相比，DOX/ND-OH/FA-COS的粒径从189.5±2.8增加到224.5±1.4nm，zeta电位从-9.1±0.2反转至14.8±0.4mV。在48小时时，DOX/ND-OH和DOX/ND-OH/FA-COS分别释放69.07±5.70%和35.87±5.64%。FA-COS修饰有效地增强了Caco-2细胞对ND-OH/DOX的细胞毒性和细胞内摄取，并延长了大鼠肠道内的保留时间。DOX/ND-OH和DOX/ND-OH/FA-COS的内化主要通过能量依赖的网格蛋白和小窝介导的内吞途径介导。药代动力学研究表明，与DOX溶液相比，DOX/ND-OH和DOX/ND-OH/FA-COS的AUC分别提高了3.94倍和6.08倍。这些结果表明，DOX/ND-OH/FA-COS可能是提高DOX口服生物利用度的有效策略。
