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Development and Evaluation of Tri-Functional Immunoliposomes for the Treatment of HER2 Positive Breast Cancer

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Abstract

Purpose

Trastuzumab combined with Doxorubicin (DOX) demonstrates significant clinical activity in human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC). However, emergence of treatment resistance and trastuzumab associated cardiotoxicity remain clinical challenges. In an effort to improve patient outcome, we have developed and evaluated novel tri-functional immunoliposomes (TFIL) that target HER2-receptors on BC cells and CD3-receptors on T-lymphocytes, and deliver DOX.

Methods

Trastuzumab (anti-HER2) and OKT-3 (anti-CD3) antibodies were conjugated to liposomes using a micelle-transfer method. Cytotoxicity of targeted immunoliposomes loaded with DOX was examined in vitro on HER2-positive BC cells (BT474), with peripheral blood monocytic cells (PBMC) as immune effector cells.

Results

TFIL demonstrated high antibody-liposome conjugation ratios (100–130 μg protein/μmol phospholipid) and cargo capacity (0.21 mol:mol drug:lipid), highly efficient DOX loading (>90%), a particle size favorable for extended circulation (~150 nm), and good stability (up to 3 months at 4°C). In the presence of PBMCs, TFIL showed complete killing of BT474 cells, and were superior to mono-targeted trastuzumab-bearing liposomes, non-targeted liposomes, and free Trastuzumab and DOX.

Conclusions

Novel anti-HER2xCD3 + DOX TFIL show promise as a means to both engage immune cells against HER2 positive breast cancer cells and deliver chemotherapy, and have the potential to improve clinical outcomes.

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Abbreviations

BC:

Breast Cancer

CD3:

Cluster of Differentiation Receptor Type 3

CTLs:

Cytotoxic T Lymphocytes

DOX:

Doxorubicin

HER2:

Human Epidermal Growth Factor Receptor Type 2

PBMCs:

Peripheral Blood Mononuclear Cells

TFIL:

Tri-Functional Immunoliposomes

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Author information

Authors and Affiliations

  1. Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, 6550 Sanger Road Room 469, Orlando, FL, 32827, USA

    Tanaya Vaidya & Sihem Ait-Oudhia

  2. Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, 14214, USA

    Robert M. Straubinger

Authors
  1. Tanaya Vaidya
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Correspondence to Sihem Ait-Oudhia.

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Vaidya, T., Straubinger, R.M. & Ait-Oudhia, S. Development and Evaluation of Tri-Functional Immunoliposomes for the Treatment of HER2 Positive Breast Cancer. Pharm Res 35, 95 (2018). https://doi.org/10.1007/s11095-018-2365-x

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  • DOI: https://doi.org/10.1007/s11095-018-2365-x

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