Abstract
Liposome (LP) encapsulation of doxorubicin (DOX) is a clinically validated method for cancer drug delivery, but its cellular uptake is actually lower than the free DOX. Therefore, we modified DOX-LP with a cationic polymer (Eudragit RL100; ER) to improve its cellular uptake and antitumor activity. The resulting DOX-ERLP was a 190 nm nanoparticle that was absorbed efficiently and caused cancer cell death in 5 hrs. Growth as measured by the MTT assay or microscopic imaging demonstrated that DOX-ERLP has at least a two-fold greater potency than the free DOX in inhibiting the growth of a DOX resistant (MCF7/adr) cell and an aggressive liver cancer H22 cell. Further, its in vivo efficacy was tested in H22-bearing mice, where four injections of DOX-ERLP reduced the tumor growth by more than 60% and caused an average of 60% tumor necrosis, which was significantly better than the DOX and DOX-LP treated groups. Our work represents the first use of polymethacrylate derivatives for DOX liposomal delivery, demonstrating the great potential of cationic polymethacrylate modified liposomes for improving cancer drug delivery.
Highlights
The gH625 peptide modification provided DOX liposomes with targeted drug delivery and greatly overcame DOX resistance in lung adenocarcinoma cell lines[16]
DOX-Eudragit RL Liposome (ERLP) was prepared by soaking DOX into the ERLP liposome prepared using a (NH4)2SO4 gradient method
Our preliminary results demonstrated that DOX-LP was not absorbed rapidly by MCF7 cells and showed no improved efficacy towards the DOX-resistant strain (MCF7-adr)
Summary
The gH625 peptide modification provided DOX liposomes with targeted drug delivery and greatly overcame DOX resistance in lung adenocarcinoma cell lines[16]. Eudragit EPO (containing 1:2:1 ratio of butyl-, dimethyl aminyl ethyl-, methyl polymethacrylate) was used to modify acyclovir and minoxidil liposomes, and found that it significantly improved the stability of the liposomes and enhanced the percutaneous penetration of the drug[20]. The amino-bisphosphonate Zoledronic acid (ZOL) has potent anticancer activity and its encapsulation into a stealth liposome formulation reduced the binding of ZOL to bone and increased its bioavailability in extraskeletal tumor sites through the enhanced permeability retention (EPR) effect[22]. To improve the in vivo efficacy of DOX, we modified the DOX-bearing liposomes with cationic polymethacrylate Eudragit RL100, which contains positively charged quaternary ammonium groups, because cationic polymers should provide better affinity to certain drugs, cell membrane and mucousa through electrostatic interactions. The new formulation showed a slow DOX release from the liposomes and a high DOX uptake by the cells, and resulted in significantly improved antitumor activities in various cancer cells and in an animal model for cancer
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