TY - JOUR

T1 - HER2-targeted, enzyme-activated liposomes show superior in vivo efficacy in an ovarian cancer model

AU - Juul, Christian Ammitzbøll

AU - Engel, Trine Bjørnbo

AU - Fliedner, Frederikke Petrine

AU - Ringgaard, Lars

AU - Eliasen, Rasmus

AU - Melander, Fredrik

AU - Bak, Martin

AU - Kjær, Andreas

AU - Henriksen, Jonas Rosager

AU - Elema, Dennis Ringkjøbing

AU - Hansen, Anders Elias

AU - Andresen, Thomas Lars

N1 - Publisher Copyright: © 2023

PY - 2024

Y1 - 2024

N2 - Liposomes carrying chemotherapeutic drugs can accumulate passively in solid tumors at high levels. However, additional targeting of the liposomes towards e.g. receptors expressed on cancer cells may improve their interaction and therapeutic properties. In this study, we designed a liposomal delivery system, which utilizes the intrinsic characteristics of HER2-positive tumors to ensure efficient delivery of oxaliplatin to the cancer cells. On the liposome surface, trastuzumab, an antibody specific to the HER2 receptor, was shown to facilitate internalization by the cancer cells. A polyethylene glycol (PEG) layer on the liposome surface provides protection from mononuclear phagocyte system uptake. To optimize the interaction between liposomes and cancer cells, a protease-sensitive cleavable peptide linker was inserted at the base of each PEG. The PEG layer is then cleaved off by intra- and extracellular matrix metalloproteinases (MMPs) upon accumulation in the tumor. Our data demonstrate that the removal of PEG significantly destabilizes the liposomes and leads to substantial oxaliplatin release. The proposed beneficial effect of combining antibody-mediated internalization with MMP sensitivity was confirmed in a series of in vivo studies using ovarian cancer xenograft models. The results demonstrated that HER2-targeted MMP-sensitive liposomes have superior anticancer activity compared to non-targeted and non-cleavable liposomes.

AB - Liposomes carrying chemotherapeutic drugs can accumulate passively in solid tumors at high levels. However, additional targeting of the liposomes towards e.g. receptors expressed on cancer cells may improve their interaction and therapeutic properties. In this study, we designed a liposomal delivery system, which utilizes the intrinsic characteristics of HER2-positive tumors to ensure efficient delivery of oxaliplatin to the cancer cells. On the liposome surface, trastuzumab, an antibody specific to the HER2 receptor, was shown to facilitate internalization by the cancer cells. A polyethylene glycol (PEG) layer on the liposome surface provides protection from mononuclear phagocyte system uptake. To optimize the interaction between liposomes and cancer cells, a protease-sensitive cleavable peptide linker was inserted at the base of each PEG. The PEG layer is then cleaved off by intra- and extracellular matrix metalloproteinases (MMPs) upon accumulation in the tumor. Our data demonstrate that the removal of PEG significantly destabilizes the liposomes and leads to substantial oxaliplatin release. The proposed beneficial effect of combining antibody-mediated internalization with MMP sensitivity was confirmed in a series of in vivo studies using ovarian cancer xenograft models. The results demonstrated that HER2-targeted MMP-sensitive liposomes have superior anticancer activity compared to non-targeted and non-cleavable liposomes.

KW - cancer

KW - HER2

KW - Liposomes

KW - Matrix metalloproteinase

KW - Targeting

U2 - 10.1016/j.jconrel.2024.05.005

DO - 10.1016/j.jconrel.2024.05.005

M3 - Journal article

C2 - 38705519

AN - SCOPUS:85194745669

VL - 371

SP - 288

EP - 297

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -