Antibodies are often used clinically to treat a variety of diseases, especially cancer. However, mutations in antigens lead to resistance to therapeutic antibodies. Human epidermal growth factor receptor 2 (HER2) plays an important role in the proliferation of cancer cells, especially breast cancer. At present, pertuzumab and trastuzumab are often used clinically to target HER2, inhibit heterodimer of HER2 and cause antibody-dependent cell-mediated cytotoxic (ADCC) effects to kill cancer cells. However, a large amount of truncated HER2 (P95HER2) that lacks extracellular binding regions accumulates on the surface of cancer cells, causing drug resistance in cancer cells. At the same time, the free tail of the extracellular region of P95HER2 is covalently linked by disulfide bonds, which mediates the strong proliferation signal downstream and the difficulty of generating corresponding therapeutic antibodies to block P95HER2 dimerization. Besides, in aggressive tumors, Fc receptors on the surface of natural killer cells are poorly expressd, which leads to a low-response ADCC effect. On the other hand, although the small molecule inhibitor lapatinib is clinically used to treat P95HER2+ cancer, lapatinib lacks specificity for P95HER2 and has more side effect than antibodies. Therefore, the development of new specific therapies for P95HER2+ cancer is an urgent medical need.
Figure 1. Illustration of specific targeting and PDT for P95HER2+ cancers via MINT.
In view of this, based on their previous progresses on reverse microemulsion-confined epitope-oriented surface imprinting and cladding (Adv. Sci.2021, 8, 2101713) and molecularly imprinted nanomedicines for cancer treatment (Angew. Chem. Int. Ed. 2019, 58, 10621; Angew. Chem. Int. Ed. 2021, 60, 2663; ACS Nano, 2021, 15, 18214; Small 2022, 18, 2201671; Chem. Sci. 2022, 13, 10897; Angew. Chem. Int. Ed. 2023, 62, e202301202) and via combining with upconversion nanoparticles (UCNP) and photodynamic therapy (PDT), Professor Zhen Liu’s team at our school has developed a new strategy called molecularly imprinted nanoconverters (MINT) for the treatment of drug-resistant breast cancer. As shown in Figure 1, MINT has a core-shell structure with a UCNP as the core while an MIP imprinting layer as the shell. MINT can not only specifically target P95HER2, but also effectively convert near-infrared light to visible light for converting ground state oxygen to reactive oxygen species to kill cancer cells. As a proof of the concept, in this study, P95HER2 was selected as a mutated target and the N-terminal epitope with 9 amino acids at the N-terminus of P95HER2 was selected as a template to prepare MINT. The resulting MINT can specifically target P95HER2 in tumor tissue. After MINT binds to the surface of cancer cells, MINT can be taken up by cancer cells. Under the irradiation of 980 nm near-infrared light, MINT can produce reactive oxygen species (ROS) to kill tumor cells through PDT. In this paper, the structure and properties of MINT are systematically characterized and verified. In vivo and in vitro experiments show that MINT can not only specifically target P95HER2+ breast cancer cells, but also effectively transform NIR and generate ROS. Therefore, MINT offers a new strategy for the treatment of therapeutic antibody-resistant breast cancer. Because mutations in cancer targets occur widely in various cancer cells, this strategy provides a new insight into the treatment of drug-resistant cancers caused by target mutations.
This study was recently on-line published in ACS Nano under the title Hierarchically Structured Molecularly Imprinted Nanotransducers for Truncated HER2-Targeted Photodynamic Therapy of Therapeutic Antibody-Resistant Breast Cancer (ACS Nano, 2023, 10.1021/acsnano.3c00148). Professor Zhen Liu is the corresponding author, while Gu Zikuan, a Ph. D candidate, is the first author of the paper. This research was supported by the National Natural Science Foundation of China (Grant No. 21834003), Nanjing University Research Excellence Program (Grant No. ZYJH004), and the Program B for Outstanding Ph.D. candidates of Nanjing University.