Synthesis of octadecylamine-retinoic acid conjugate for enhanced cytotoxic effects of 5-FU using LDL targeted nanostructured lipid carriers.
The aim of the present study was to reduce 5-FU side effects by targeted nanostructured lipid carriers (NLCs) to LDL receptors that are over expressed in colorectal carcinoma and also use of a new synthesized conjugate of retinoic acid as a cytotoxic agent. Fatty acyl amide derivative of retinoic acid was synthesized by its conjugation to octadecylamine with the expectation to improve its loading capacity in NLCs of 5-FU. The NLCs were prepared by an emulsification-solvent evaporation method using cholesterol and cholesteryl stearate. Physical properties and drug release were studied in NLCs. The cytotoxicity of NLCs loaded with 5-FU and retinoic acid conjugate was studied on colon cancer cells (HT29) using MTT assay. To confirm that drug targeting has been done through LDL receptors, APO-E was omitted from the cell culture and the MTT assay was repeated. FTIR and (1)H NMR spectra confirmed successful production of the conjugate. Results showed the IC(50) of free 5-FU was about 7.6 μM while in comparable concentration, the cytotoxicity of 5-FU loaded in NLCs containing the retinoic acid conjugate was nearly 2 fold of NLCs just loaded with 5-FU and more than 5 fold of free 5-FU. The retinoic acid conjugate loaded NLCs prepared by cholesterol can target LDL receptors of HT29 cells and seems promising in reducing 5-FU dose in colorectal cancer.
Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. varshosaz@pharm.mui.ac.ir
Jaleh
J
Varshosaz
Farshid
F
Hassanzadeh
Hojjat
H
Sadeghi
Sare
S
Andalib
D000588:Amines / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D005472:Fluorouracil / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D049329:Nanostructures / Q000737:chemistry*; D011973:Receptors, LDL / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000737:chemistry*
D000588:Amines; D000970:Antineoplastic Agents; D004337:Drug Carriers; D011973:Receptors, LDL; D014212:Tretinoin; D002784:Cholesterol; C009317:stearylamine; D005472:Fluorouracil