Tumor-targeted Nanobullets: Anti-EGFR nanobody-liposomes loaded with anti-IGF-1R kinase inhibitor for cancer treatment

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• 作者：Roy van der Meel^a ; Sabrina Oliveira^b ; ^c ; Isil Altintas^a ; Rob Haselberg^d ; Joris van der Veeken^a ; Rob C. Roovers^b ; Paul M.P. van Bergen en Henegouwen^b ; Gert Storm^a ; Wim E. Hennink^a ; Raymond M. Schiffelers^a ; ^e ; Robbert J. Kok^a ; ^{R.J.Kok@uu.nl}
• 关键词：EGFR ; IGF-1R ; Nanobody ; Immunoliposomes ; Combination therapy
• 刊名：Journal of Controlled Release
• 出版年：2012
• 期刊代码：25_01683659
• 类别：pha
• 出版时间：30 April, 2012
• 卷：159
• 期：2
• 页码：281-289
• 文件大小：820 K

摘要

The epidermal growth factor receptor (EGFR) is a validated target for anti-cancer therapy and several EGFR inhibitors are used in the clinic. Over the years, an increasing number of studies have reported on the crosstalk between EGFR and other receptors that can contribute to accelerated cancer development or even acquisition of resistance to anti-EGFR therapies. Combined targeting of EGFR and insulin-like growth factor 1 receptor (IGF-1R) is a rational strategy to potentiate anti-cancer treatment and possibly retard resistance development. In the present study, we have pursued this by encapsulating the kinase inhibitor AG538 in anti-EGFR nanobody-liposomes. The thus developed dual-active nanobody-liposomes associated with EGFR-(over)expressing cells in an EGFR-specific manner and blocked both EGFR and IGF-1R activation, due to the presence of the EGFR-blocking nanobody EGa1 and the anti-IGF-1R kinase inhibitor AG538 respectively. AG538-loaded nanobody-liposomes induced a strong inhibition of tumor cell proliferation even upon short-term exposure followed by a drug-free wash-out period. Therefore, AG538-loaded nanobody-liposomes are a promising anti-cancer formulation due to efficient intracellular delivery of AG538 in combination with antagonistic and downregulating properties of the EGa1 nanobody-liposomes.