Engineered peptides for the development of actively tumor targeted liposomal carriers of doxorubicin.
Chemotherapy is still the treatment of choice for many types of cancer; but its effectiveness is hampered by dose limiting toxicity. Properly designed delivery systems can overcome this shortcoming by reducing the non-specific distribution and toxicity of chemotherapeutics in healthy organs and at the same time increasing drug concentrations at tumor tissue. In this study, we developed stealth liposomal formulations of doxorubicin (DOX) having a novel stable engineered peptide ligand, namely p18-4, that binds specifically to breast cancer cell line MDA-MB-435 on its surface. The coupling of p18-4 to liposomes was carried out through conventional, post insertion and post conjugation techniques and prepared liposomes were characterized for their size and level of peptide modification. The p18-4 decorated liposomal DOX formulations were then evaluated for their cellular uptake as well as cytotoxicity against the human breast cancer MDA-MB-435 cells. In this context, the effect of coupling technique on the uptake and cytotoxicity of p18-4 liposomal DOX in MDA-MB-435 cells was evaluated. The conventional and post conjugation methods of peptide incorporation were found to be more reliable for the preparation of p18-4 decorated liposomes for active DOX targeting to MDA-MB-435 cells. p18-4 decoration of liposomes by these methods did not have a notable effect on the size of prepared liposomes and DOX release, but increased the uptake and cytotoxicity of encapsulated DOX in MDA-MB-435 cells. The results show a potential for p18-4 decorated liposomes prepared by conventional and post conjugation method for tumor targeted delivery of DOX in breast tumor models.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
Mostafa
M
Shahin
Rania
R
Soudy
Haitham
H
El-Sikhry
John M
JM
Seubert
Kamaljit
K
Kaur
Afsaneh
A
Lavasanifar
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002627:Chemistry, Physical; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005818:Genetic Engineering / Q000379:methods; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry
D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D010455:Peptides; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin