Docetaxel-trastuzumab stealth immunoliposome: development and in vitro proof of concept studies in breast cancer

• Published in: International journal of nanomedicine Vol. 13; pp. 3451 - 3465
• Main Authors: Rodallec, Anne, Brunel, Jean-Michel, Giacometti, Sarah, Maccario, Helene, Correard, Florian, Mas, Eric, Orneto, Caroline, Savina, Ariel, Bouquet, Fanny, Lacarelle, Bruno, Ciccolini, Joseph, Fanciullino, Raphaelle
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01-01-2018; Taylor & Francis Ltd; Dove Medical Press
• Subjects: Antibodies; Antibodies, Monoclonal - immunology; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Breast Neoplasms - ultrastructure; Cancer research; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cetuximab; Clinical trials; Comparative analysis; Design of experiments; Development and progression; Docetaxel; Drug Delivery Systems; Drug traffic; EDTA; Endocytosis - drug effects; Epidermal growth factor; Female; Hematology; Humans; immunoliposomes – biopharmaceutical development –breast cancer – docetaxel - trastuzumab - HER2; Immunotherapy; Laboratories; Life Sciences; Lipids; Liposomes - therapeutic use; Medical tests; Microscopy; Monoclonal antibodies; Nanoparticles; Original Research; Particle Size; Polyethylene glycol; Proof of Concept Study; Receptor, ErbB-2 - metabolism; Targeted cancer therapy; Taxoids - pharmacology; Taxoids - therapeutic use; Thin films; Trastuzumab; Trastuzumab - pharmacology; Trastuzumab - therapeutic use; Tumors; France; United States > US; trastuzumab; biopharmaceutical development; breast cancer; HER2; docetaxel; immunoliposomes
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S162454

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.
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.
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 IC
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 IC
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.
In vitro results suggest that higher antiproliferative efficacy and efficient drug delivery can be achieved in breast cancer models using nanoparticles.