Modular Synthesis of Semiconducting Graft Copolymers to Achieve “Clickable” Fluorescent Nanoparticles with Long Circulation and Specific Cancer Targeting

Abstract

Semiconducting polymer nanoparticles (SPNs) are explored for applications in cancer theranostics because of their high absorption coefficients, photostability, and biocompatibility. However, SPNs are susceptible to aggregation and protein fouling in physiological conditions, which can be detrimental for in vivo applications. Here, a method for achieving colloidally stable and low‐fouling SPNs is described by grafting poly(ethylene glycol) (PEG) onto the backbone of the fluorescent semiconducting polymer, poly(9,9′‐dioctylfluorene‐5‐fluoro‐2,1,3‐benzothiadiazole), in a simple one‐step substitution reaction, postpolymerization. Further, by utilizing azide‐functionalized PEG, anti‐human epidermal growth factor receptor 2 (HER2) antibodies, antibody fragments, or affibodies are site‐specifically “clicked” onto the SPN surface, which allows the functionalized SPNs to specifically target HER2‐positive cancer cells. In vivo, the PEGylated SPNs are found to have excellent circulation efficiencies in zebrafish embryos for up to seven days postinjection. SPNs functionalized with affibodies are then shown to be able to target HER2 expressing cancer cells in a zebrafish xenograft model. The covalent PEGylated SPN system described herein shows great potential for cancer theranostics.

Impact of Macrophages on the Interaction of Cetuximab-Functionalized Polyelectrolyte Capsules with EGFR-Expressing Cancer Cells

“…23 Colorectal cancer is also characterized by the expression of the human A33 antigen, which serves as a molecular target for the variable fragments of Abs and recently designed single-chain Abs. 24,25 Specific interaction of the capsules functionalized with a full-size monoclonal anti-HER2 Ab (trastuzumab, Herceptin), 20,26 an anti-HER2 Fab fragment, an anti-HER2 affibody, 17 a bispecific anti-EGFR Ab, 18 or an anti-A33 monoclonal Ab 27 with model cancer cells has been demonstrated. Reducing the size and adjusting the shape of the capsules effectively enhance the interaction of the carriers with their targets and their internalization by cancer cells.…”

“…Designing approaches to cancer cell targeting and targeted delivery of anticancer drugs is a major challenge in modern personalized oncology. , Multilayered polymer capsules have been demonstrated to be a promising system that can be adapted for this purpose. − Traceable delivery and accumulation of polymer capsules in cancer cells can be ensured by their magnetic retention, for which purpose magnetic nanoparticles are embedded into the capsule shell. − However, this approach lacks specificity, and capsule interactions with nontarget cells diminish the efficiency of delivery. To increase the specificity of capsule interaction with target cells, the surface of the capsule can be functionalized with various recognition molecules, including folic acid; − synthetic agents, such as N6L binding nucleolin on the surface of human pancreatic carcinoma cells; short linear peptides, such as the mUNO (CSPGAK) peptide binding mouse CD206 expressed by M2 macrophages and the IPLVVPL peptide binding hepsin expressed by human breast carcinoma cells and human ovarian carcinoma cells; and antibodies (Abs) or their Fab fragments. , …”

“…Conventional full-size Abs or their active fragments are widely used for surface functionalization and engineering of cancer-cell-targeting carriers. − Clinically approved therapeutics based on monoclonal Abs, such as cetuximab and trastuzumab, are used for treating metastatic human lung, colorectal, and breast tumors expressing proteins of the human epidermal growth factor receptor family, in particular, EGFR , and HER2 . Colorectal cancer is also characterized by the expression of the human A33 antigen, which serves as a molecular target for the variable fragments of Abs and recently designed single-chain Abs. , Specific interaction of the capsules functionalized with a full-size monoclonal anti-HER2 Ab (trastuzumab, Herceptin), , an anti-HER2 Fab fragment, an anti-HER2 affibody, a bispecific anti-EGFR Ab, or an anti-A33 monoclonal Ab with model cancer cells has been demonstrated. Reducing the size and adjusting the shape of the capsules effectively enhance the interaction of the carriers with their targets and their internalization by cancer cells. , …”

“…17,18 Conventional full-size Abs or their active fragments are widely used for surface functionalization and engineering of cancer-cell-targeting carriers. 17 epidermal growth factor receptor family, in particular, EGFR 21,22 and HER2. 23 Colorectal cancer is also characterized by the expression of the human A33 antigen, which serves as a molecular target for the variable fragments of Abs and recently designed single-chain Abs.…”

“…To increase the specificity of capsule interaction with target cells, the surface of the capsule can be functionalized with various recognition molecules, including folic acid; 11−13 synthetic agents, such as N6L binding nucleolin on the surface of human pancreatic carcinoma cells; 14 short linear peptides, such as the mUNO (CSPGAK) peptide binding mouse CD206 expressed by M2 macrophages 15 and the IPLVVPL peptide binding hepsin expressed by human breast carcinoma cells and human ovarian carcinoma cells; 16 and antibodies (Abs) or their Fab fragments. 17,18 Conventional full-size Abs or their active fragments are widely used for surface functionalization and engineering of cancer-cell-targeting carriers. 17 epidermal growth factor receptor family, in particular, EGFR 21,22 and HER2.…”