Doxorubicin loaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma.
BACKGROUND
Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated the efficacy.


METHODS
Doxorubicin was loaded onto a lipid-modified dextran based polymeric nano-system. The effect of various concentrations of doxorubicin alone or nanoparticle loaded doxorubicin on KHOS, KHOSR2, U-2OS, and U-2OSR2 cells was analyzed. Effects on drug retention, immunofluorescence, Pgp expression, and induction of apoptosis were also analyzed.


RESULTS
Dextran nanoparticles loaded with doxorubicin had a curative effect on multidrug resistant osteosarcoma cell lines by increasing the amount of drug accumulation in the nucleus via Pgp independent pathway. Nanoparticles loaded with doxorubicin also showed increased apoptosis in osteosarcoma cells as compared with doxorubicin alone.


CONCLUSIONS
Lipid-modified dextran nanoparticles loaded with doxorubicin showed pronounced anti-proliferative effects against osteosarcoma cell lines. These findings may lead to new treatment options for MDR osteosarcoma.
Susa
Michiro
M
Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. msusa@partners.org
Iyer
Arun K
AK
Ryu
Keinosuke
K
Hornicek
Francis J
FJ
Mankin
Henry
H
Amiji
Mansoor M
MM
Duan
Zhenfeng
Z
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003911:Dextrans / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage*; D004337:Drug Carriers / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000627:therapeutic use; D012516:Osteosarcoma / Q000188:drug therapy*; D011108:Polymers / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D003911:Dextrans; D004337:Drug Carriers; D011108:Polymers; D004317:Doxorubicin