Characterization of 9-nitrocamptothecin-in-cyclodextrin-in-liposomes modified with transferrin for the treating of tumor

• Published in: International journal of pharmaceutics Vol. 490; no. 1-2; pp. 219 - 228
• Main Authors: Chen, Jun, Lu, Shanshan, Gu, Wei, Peng, Pei, Dong, Jie, Xu, Fei, Yang, Xueqin, Xiong, Zheyun, Yang, Xixiong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 25.07.2015
• Subjects: 9-Nitrocamptothecin; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor efficacy; Camptothecin - analogs & derivatives; Camptothecin - chemistry; Camptothecin - pharmacology; Cyclodextrin; Cyclodextrins - chemistry; Drug Carriers - chemistry; Drug Delivery Systems - methods; Drug Stability; Lactones - chemistry; Liposomes; Liposomes - chemistry; Mice; Mice, Inbred ICR; Neoplasms - drug therapy; Rats; Rats, Sprague-Dawley; Stability; Transferrin - chemistry; Transferrin modification; TfR; EDC; CPT; EPR; SPC; IRT; Transferrin modification; MTT; Coumarin-6 (CID: 100334); Tf-C-L; MPS; Tf; 9-NC; PDI; NHS; 9-Nitrocamptothecin (CID: 472335); HSPC; P-9-NC-CL; EE; PBS; BCA; CD; DSPC; Stability; Tf-9-NC-L; 9-Nitrocamptothecin; DSPE-PEG2000; FITC-HP-β-CD; DCL; HP-β-CD; Antitumor efficacy; Cyclodextrin; PC; PEG; P-C-L; Liposomes; PL; DSPE-PEG2000-COOH
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2015.05.047

[Display omitted] Encapsulation of hydrophobic drugs in the form of drug-cyclodextrin (CD) complex in liposomes has been applied as a novel strategy to combine the relative advantages of CDs and liposomes into one system, naming drug-in-CD-in-liposome (DCL). In the present study, soluble 9-NC/hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complexes were prepared using the freeze-drying technique. Then 9-NC inclusion complexes were further encapsulated into liposomes by ethanol injection method and transferrin (Tf) was conjugated to the surface of 9-NC DCL to obtain Tf modified 9-NC DCL (Tf-9-NC-CL). Compared to PEGylated 9-NC DCL (P-9-NC-CL), the lactone stability and vesicle stability of Tf-9-NC-CL were significantly increased. Both 9-NC and HP-β-CD were found to release from the DCL and Tf modification resulted in reduced release of them. The enhanced targeting efficiency of the Tf-modified liposomes was demonstrated by flow cytometry and confocal microscopy. In vivo pharmacokinetics in rats showed improved lactone stability of 9-NC following intravenous injection of Tf-9-NC-CL. The cytotoxicity of Tf-9-NC-CL against tumor cells and normal cells was investigated in vitro and the antitumor efficacy was evaluated in S180 tumor-bearing mice in vivo. Compared with free 9-NC, 9-NC inclusion complexes and P-9-NC-CL, Tf-9-NC-CL demonstrated the strongest cytotoxicity to tumor cells. And the inhibitory rate of tumor (IRT) values were determined to be 43.08%, 56.92%, 67.69% and 80.00% for 9-NC solution, inclusion complexes, P-9-NC-CL and Tf-9-NC-CL, respectively. In conclusion, Tf modification can be useful in increasing vesicle stability, targeting drug delivery efficiency and antitumor efficacy of DCL containing hydrophobic antitumor drugs, such as 9-NC.