Mourya Atul, Kumar Sanjeev, Shah Saurabh, Famta Paras, Kanchupalli Vinaykumar, Srivastava Saurabh, Madan Jitender
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research Hyderabad, Hyderabad 500037, India.
Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research Hyderabad, Hyderabad 500037, India.
Mol Pharm. 2025 Jul 7;22(7):3868-3884. doi: 10.1021/acs.molpharmaceut.5c00139. Epub 2025 Jun 6.
Despite exhibiting promising efficacy in managing postmenopausal osteoporosis, hormonal therapy, and breast cancer prevention, the usage of raloxifene hydrochloride (RLX) is limited in clinical settings due to its low aqueous solubility (345.2 ± 15.6 μg/mL) and 2% oral bioavailability. Oral administration of RLX results in the formation of an inactive glucuronide conjugate at free hydroxyl groups in the presence of hepatic and extrahepatic UDP-glucuronosyltransferases (UGTs). To circumvent RLX transformation, lipid-drug-conjugate-based lymphatic targeting may offer a suitable alternative. Therefore, we synthesized a stearic acid-raloxifene hydrochloride (SRC) conjugate and confirmed it using ATR-FT-IR, H NMR, and HR-MS spectral techniques. Further, SRC was amalgamated with optimized lipid nanoparticles (SRC@LNPs4) to improve its stability under simulated physiological conditions. SRC@LNPs4 demonstrated remarkably improved stability of SRC compared to SRC alone when incubated with SGF, SIF, porcine lipoprotein lipase, and lipase-simulated plasma. Furthermore, biocompatibility analysis conducted with HT-29 cells ensured its safety for oral administration. Micrographic evaluation of rat intestines incubated with C6@LNPs indicated improved uptake of LNPs into enteric epithelia. Female Wistar rats orally administered with SRC@LNPs4 (∼10 mg/kg of RLX) exhibited a hike (unpaired -test, < 0.05) of 1.87-fold in the AUC of SRC@LNPs4 (43.04 ± 0.50 h·μg/mL) compared to RLX (22.95 ± 4.30 h·μg/mL) Furthermore, the notable changes observed in the pharmacokinetic parameters of SRC@LNPs4 in rats previously injected with cycloheximide (CHX; 3 mg/kg) suggest that the drug is primarily absorbed into systemic circulation through lymphatic uptake. In conclusion, SRC@LNPs4 presents a valuable strategy to augment oral absorption and bioavailability via lymphatic targeting.
尽管盐酸雷洛昔芬（RLX）在治疗绝经后骨质疏松症、激素疗法和预防乳腺癌方面显示出有前景的疗效，但由于其低水溶性（345.2±15.6μg/mL）和2%的口服生物利用度，其在临床环境中的使用受到限制。口服RLX会在肝脏和肝外尿苷二磷酸葡萄糖醛酸转移酶（UGTs）存在的情况下，在游离羟基处形成无活性的葡萄糖醛酸共轭物。为了规避RLX的转化，基于脂质 - 药物共轭物的淋巴靶向可能提供一种合适的替代方案。因此，我们合成了硬脂酸 - 盐酸雷洛昔芬（SRC）共轭物，并使用衰减全反射傅里叶变换红外光谱（ATR - FT - IR）、核磁共振氢谱（H NMR）和高分辨质谱（HR - MS）光谱技术对其进行了确认。此外，SRC与优化的脂质纳米颗粒（SRC@LNPs4）合并，以提高其在模拟生理条件下的稳定性。当与模拟胃液（SGF）、模拟肠液（SIF）、猪脂蛋白脂肪酶和脂肪酶模拟血浆一起孵育时，SRC@LNPs4与单独的SRC相比，显示出SRC的稳定性显著提高。此外，用HT - 29细胞进行的生物相容性分析确保了其口服给药的安全性。用C6@LNPs孵育的大鼠肠道的显微评估表明脂质纳米颗粒（LNPs）进入肠上皮细胞的摄取有所改善。口服给予SRC@LNPs4（约10mg/kg的RLX）的雌性Wistar大鼠与RLX（22.95±4.30h·μg/mL）相比，SRC@LNPs4的曲线下面积（AUC）（43.04±0.50h·μg/mL）提高了1.87倍（未配对t检验，P<0.05）。此外，在先前注射环己酰亚胺（CHX；3mg/kg）的大鼠中观察到的SRC@LNPs4药代动力学参数的显著变化表明，该药物主要通过淋巴摄取吸收进入体循环。总之，SRC@LNPs4提出了一种通过淋巴靶向增强口服吸收和生物利用度的有价值策略。
