A solid lipid nanoparticle formulation of 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine with increased solubility, stability, and antitumor activity

Publication date: Available online 12 August 2019Source: International Journal of PharmaceuticsAuthor(s): Solange A. Valdes, Riyad F. Alzhrani, Andres Rodriguez, Dharmika S.P. Lansakara-P, Sachin G. Thakkar, Zhengrong CuiAbstractPreviously, we synthesized 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine (DHA-dFdC), a novel lipophilic compound with a potent, broad-spectrum antitumor activity. Herein, we report a solid lipid nanoparticle (SLN) formulation of DHA-dFdC with improved apparent aqueous solubility, chemical stability, as well as efficacy in a mouse model. The SLNs were prepared from lecithin/glycerol monostearate-in-water emulsions emulsified with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and Tween 20. The resultant DHA-dFdC-SLNs were 102.2 ± 7.3 nm in diameter and increased the apparent solubility of DHA-dFdC in water to at least 5.2 mg/mL, more than 200-fold higher than its intrinsic water solubility. DHA-dFdC in a lyophilized powder of DHA-dFdC-SLNs was significantly more stable than the waxy solid of pure DHA-dFdC. DHA-dFdC-SLNs also showed an increased cytotoxicity against certain tumor cells than DHA-dFdC. The plasma concentration of DHA-dFdC in mice intravenously injected with DHA-dFdC-SLNs in dispersion followed a bi-exponential model, with a half-life of ∼44 h. In mice bearing B16-F10 murine melanoma, DHA-dFdC-SLNs were significantly more effective than DHA-dFdC in controlling the tumor growth. In addition, histology evaluation revea...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research