Docetaxel-trastuzumab stealth immunoliposome: development and in vitro proof of concept studies in breast cancer
Authors Rodallec A, Brunel JM, Giacometti S, Maccario H, Correard F, Mas E, Orneto C, Savina A, Bouquet F, Lacarelle B, Ciccolini J, Fanciullino R
Received 13 January 2018
Accepted for publication 24 February 2018
Published 18 June 2018 Volume 2018:13 Pages 3451—3465
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Cristina Weinberg
Peer reviewer comments 3
Editor who approved publication: Dr Thomas J Webster
Anne Rodallec,1 Jean-Michel Brunel,2 Sarah Giacometti,1 Helene Maccario,3 Florian Correard,3 Eric Mas,3 Caroline Orneto,4 Ariel Savina,5 Fanny Bouquet,5 Bruno Lacarelle,1 Joseph Ciccolini,1 Raphaelle Fanciullino1
1SMARTc Unit, Pharmacokinetics Laboratory, CRCM UMR U1068 CNRS UMR 7258 Aix Marseille Université, Marseille, France; 2CRCM CNRS UMR 7258 Aix Marseille Université, Marseille, France; 3CRO2 UMR S_911 Aix Marseille Université, Marseille, France; 4Biopharmacy Laboratory, Aix Marseille Université, Marseille, France; 5Institut Roche, Boulogne Billancourt Cedex, France
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%±6% vs 53%±4%) and longer stability (up to 1 week) as compared with ANC-2. Both ANC presented particle size ≤150 nm and showed similar or higher in vitro antiproliferative activities than standard treatment, ANC-1 performing better than ANC-2. The IC50s for docetaxel combined to free trastuzumab were 8.7±4, 2±0.7 and 6±2 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. The IC50s for ANC-1 were 2.5±1, 1.8±0.6 and 3.4±0.8 nM and for ANC-2 were 1.8±0.3 nM, 2.8±0.8 nM and 6.8±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
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