학술논문
Docetaxel--trastuzumab stealth immunoliposome: development and in vitro proof of concept studies in breast cancer
ORIGINAL RESEARCH
ORIGINAL RESEARCH
Document Type
Academic Journal
Author
Source
International Journal of Nanomedicine. Annual 2018, Vol. 13, p3451, 15 p.
Subject
Language
English
ISSN
1178-2013
Abstract
Introduction Taxanes are a mainstay in the treatment of several solid tumors including breast cancer. (1) By interfering with spindle dynamics, they stabilize microtubules and cause cell cycle arrest at [...]
Background: Trastuzumab plus docetaxel is a mainstay to treat HER2-positive breast cancers. However, developing nanoparticles could help to improve the efficacy/toxicity balance of this doublet by improving drug trafficking and delivery to tumors. This project aimed to develop an immunoliposome in breast cancer, combining docetaxel encapsulated in a stealth liposome engrafted with trastuzumab, and comparing its performances on human breast cancer cell lines with standard combination of docetaxel plus trastuzumab. Methods: Several strategies to engraft trastuzumab to pegylated liposomes were tested. Immunoliposomes made of natural (antibody nanoconjugate-1 [ANC-1]) and synthetic lipids (ANC-2) were synthesized using standard thin film method and compared in size, morphology, docetaxel encapsulation, trastuzumab engraftment rates and stability. Antiproliferative activity was tested on human breast cancer models ranging from almost negative (MDA-MB-231), positive (MDA-MB-453) to overexpressing (SKBR3) HER2. Finally, cell uptake of ANC-1 was studied by electronic microscopy. Results: ANC-1 showed a greater docetaxel encapsulation rate (73%[+ or -]6% vs 53%[+ or -]4%) and longer stability (up to 1 week) as compared with ANC-2. Both ANC presented particle size [less than or equal to]150 nm and showed similar or higher in vitro antiproliferative activities than standard treatment, ANC-1 performing better than ANC-2. The I[C.sub.50s] for docetaxel combined to free trastuzumab were 8.7[+ or -]4, 2[+ or -]0.7 and 6[+ or -]2 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. The I[C.sub.50s] for ANC-1 were 2.5[+ or -]1, 1.8[+ or -]0.6 and 3.4[+ or -]0.8 nM and for ANC-2 were 1.8[+ or -]0.3 nM, 2.8[+ or -]0.8 nM and 6.8[+ or -]1.8 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. Cellular uptake appeared to depend on HER2 expression, the higher the expression, the higher the uptake. Conclusion: In vitro results suggest that higher antiproliferative efficacy and efficient drug delivery can be achieved in breast cancer models using nanoparticles. Keywords: immunoliposomes, biopharmaceutical development, breast cancer, docetaxel, trastuzumab, HER2
Background: Trastuzumab plus docetaxel is a mainstay to treat HER2-positive breast cancers. However, developing nanoparticles could help to improve the efficacy/toxicity balance of this doublet by improving drug trafficking and delivery to tumors. This project aimed to develop an immunoliposome in breast cancer, combining docetaxel encapsulated in a stealth liposome engrafted with trastuzumab, and comparing its performances on human breast cancer cell lines with standard combination of docetaxel plus trastuzumab. Methods: Several strategies to engraft trastuzumab to pegylated liposomes were tested. Immunoliposomes made of natural (antibody nanoconjugate-1 [ANC-1]) and synthetic lipids (ANC-2) were synthesized using standard thin film method and compared in size, morphology, docetaxel encapsulation, trastuzumab engraftment rates and stability. Antiproliferative activity was tested on human breast cancer models ranging from almost negative (MDA-MB-231), positive (MDA-MB-453) to overexpressing (SKBR3) HER2. Finally, cell uptake of ANC-1 was studied by electronic microscopy. Results: ANC-1 showed a greater docetaxel encapsulation rate (73%[+ or -]6% vs 53%[+ or -]4%) and longer stability (up to 1 week) as compared with ANC-2. Both ANC presented particle size [less than or equal to]150 nm and showed similar or higher in vitro antiproliferative activities than standard treatment, ANC-1 performing better than ANC-2. The I[C.sub.50s] for docetaxel combined to free trastuzumab were 8.7[+ or -]4, 2[+ or -]0.7 and 6[+ or -]2 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. The I[C.sub.50s] for ANC-1 were 2.5[+ or -]1, 1.8[+ or -]0.6 and 3.4[+ or -]0.8 nM and for ANC-2 were 1.8[+ or -]0.3 nM, 2.8[+ or -]0.8 nM and 6.8[+ or -]1.8 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. Cellular uptake appeared to depend on HER2 expression, the higher the expression, the higher the uptake. Conclusion: In vitro results suggest that higher antiproliferative efficacy and efficient drug delivery can be achieved in breast cancer models using nanoparticles. Keywords: immunoliposomes, biopharmaceutical development, breast cancer, docetaxel, trastuzumab, HER2