Targeted nanoassembly loaded with docetaxel improves intracellular drug delivery and efficacy in murine breast cancer model.
Docetaxel is one of the most promising chemotherapeutic agents for the treatment of metastatic breast cancer, but it shows fearful side effects. We hypothesized that a novel targeted nanoassembly (TNA) could provide efficient intracellular drug delivery in breast tumor cells overexpressing epidermal growth factor (EGF) receptor and thus improve the efficacy and reduce the side effects of docetaxel. We prepared the novel docetaxel loaded TNAs formed by polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) and modified with EGF. Compared with nontargeted nanoassemblies (NNAs), TNAs showed obvious improvement of cell-specific uptake and internalization, and revealed more cytotoxicity against MDA-MB-468 cells by inducing more late apoptosis and subG1 cells at low drug concentration, or more G2/M arrest at high drug concentration than NNAs or Taxotere. In BALB/c mice bearing breast tumor xenografts, TNAs showed stronger inhibition of tumor growth compared with NNAs (relative tumor volume in mice treated with 5 mg/kg TNAs = 0.99 and 10 mg/kg NNAs = 1.71, p < 0.05) or Taxotere (relative tumor volume in mice treated with 5 mg/kg TNAs = 0.99 and 10 mg/kg Taxotere = 4.20, p < 0.01). In particular, tumor disappeared completely in the TNA group at a dose of 10 mg/kg. The maximum tolerated dose (MTD) of TNAs was about four times higher than that of Taxotere. TNAs also demonstrated a much longer circulation time in vivo and more drug accumulation in tumor in a murine breast cancer model than Taxotere. TNA treatment also prolonged survival of mice. These results suggested that TNAs could have more potential as a delivery system for breast cancer chemotherapy.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Yu
Y
Gao
Lingli
L
Chen
Wangwen
W
Gu
Yong
Y
Xi
Liping
L
Lin
Yaping
Y
Li
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D000077143:Docetaxel; D004337:Drug Carriers / Q000378:metabolism*; D016503:Drug Delivery Systems; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004337:Drug Carriers; D010714:Phosphatidylethanolamines; D043823:Taxoids; C107570:polyethylene glycol-distearoylphosphatidylethanolamine; D000077143:Docetaxel; D011092:Polyethylene Glycols; D004815:Epidermal Growth Factor