A new polymer-lipid hybrid nanoparticle system increases cytotoxicity of doxorubicin against multidrug-resistant human breast cancer cells.
OBJECTIVE
This work is intended to develop and evaluate a new polymer-lipid hybrid nanoparticle system that can efficiently load and release water-soluble anticancer drug doxorubicin hydrochloride (Dox) and enhance Dox toxicity against multidrug-resistant (MDR) cancer cells.


METHODS
Cationic Dox was complexed with a new soybean-oil-based anionic polymer and dispersed together with a lipid in water to form Dox-loaded solid lipid nanoparticles (Dox-SLNs). Drug loading and release properties were measured spectrophotometrically. The in vitro cytotoxicity of Dox-SLN and the excipients in an MDR human breast cancer cell line (MDA435/LCC6/MDR1) and its wild-type line were evaluated by trypan blue exclusion and clonogenic assays. Cellular uptake and retention of Dox were determined with a microplate fluorometer.


RESULTS
Dox-SLNs were prepared with a drug encapsulation efficiency of 60-80% and a particle size range of 80-350 nm. About 50% of the loaded drug was released in the first few hours and an additional 10-20% in 2 weeks. Treatment of the MDR cells with Dox-SLN resulted in over 8-fold increase in cell kill when compared to Dox solution treatment at equivalent doses. The blank SLN and the excipients exhibited little cytotoxicity. The biological activity of the released Dox remained unchanged from fresh, free Dox. Cellular Dox uptake and retention by the MDR cells were both significantly enhanced (p < 0.05) when Dox was delivered in Dox-SLN form.


CONCLUSIONS
The new polymer-lipid hybrid nanoparticle system is effective for delivery of Dox and enhances its efficacy against MDR breast cancer cells.
Wong
Ho Lun
HL
Leslie Dan Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada, M5S 2S2.
Rauth
Andrew M
AM
Bendayan
Reina
R
Manias
Janet L
JL
Ramaswamy
Manisha
M
Liu
Zengshe
Z
Erhan
Sevim Z
SZ
Wu
Xiao Yu
XY
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000473:Alkanes / Q000138:chemical synthesis*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004317:Doxorubicin / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004852:Epoxy Compounds / Q000138:chemical synthesis*; D006801:Humans; D049329:Nanostructures; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D012995:Solubility; D013024:Soybean Oil / Q000737:chemistry; D013499:Surface Properties; D013997:Time Factors; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000473:Alkanes; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D004852:Epoxy Compounds; C513544:HPESO compound; D011108:Polymers; D013024:Soybean Oil; D004317:Doxorubicin