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Enhanced in vitro cancer cell cytotoxicity of dual ligand‐targeted liposomes (842.10)
Author(s) -
Sriraman Shravan Kumar,
Torchilin Vladimir
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.842.10
Subject(s) - liposome , folate receptor , cytotoxicity , hela , transferrin receptor , chemistry , cytotoxic t cell , doxorubicin , cancer cell , internalization , transferrin , in vitro , drug delivery , flow cytometry , targeted drug delivery , pharmacology , microbiology and biotechnology , receptor , biochemistry , cancer , biology , medicine , chemotherapy , organic chemistry
A broad variety of cancer cells over‐express different types of cell surface receptors like transferrin (TfR) and folate (FR) receptors compared to normal cells. This receptor expression increases as the tumor progresses and grows aggressively. With this in mind, polyethylene glycol (PEG)‐coated long‐circulating liposomes targeted with varying densities of transferrin and folic acid were loaded with doxorubicin (Dox), a frequently used chemotherapeutic drug. Purpose: To enhance the uptake of drug‐loaded liposomes by cancer cells using the combination of these two tumor‐specific ligands resulting in increased cytotoxic effects even at low drug concentrations. Methods: Transferrin and folic acid were conjugated to the distal ends of the PEG chain and post‐inserted into liposomes made of eggphosphatidylcholine (ePC), cholesterol and dioleoylphosphatidylethanolamine (DOPE). For cell association studies, the liposomes were fluorescently labeled with rhodamine. The optimized formulations were loaded with Dox, and their in vitro cytotoxic potential was evaluated with human cervical cancer (HeLa) cells. Results: Flow cytometry demonstrated a 7‐fold increase in cell association of the dual ligand‐targeted liposomes (DL) compared to any single ligand‐targeted liposomes (SL). The association and subsequent internalization of the DL was further confirmed using the confocal microscopy. The DL also significantly increased cytotoxicity of Dox when compared to SL and non‐targeted Dox‐liposomes in vitro. The IC50 for DL was also decreased by almost 7‐fold compared to SL. Conclusions: Simultaneous targeting of TfR and FR has been shown to be an effective strategy to deliver drugs and enhance their cytotoxic effects on cancer cells in vitro. The decrease in IC50 of DL allows us to work with lower drug concentrations thereby reducing the off‐target drug toxicity. Grant Funding Source : 86R01CA128486