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Tumor-targeting upconversion–nanoparticle-based unimolecular micelles for simultaneous chemotherapy, photodynamic therapy, and fluorescence imaging for neuroendocrine cancer therapy

Guojun Chen1, 2*, Renata Jaskula-Sztul3, 4*, April Harrison3*, Corinne Vokoun5*, Liwei Wang6*, Kevin W. Eliceiri5*, Herbert Chen3, 4* and Shaoqin Gong1, 2, 6*
  • 1 University of Wisconsin-Madison, Materials Science and Engineering, United States
  • 2 University of Wisconsin-Madison, Wisconsin Institutes for Discovery, United States
  • 3 University of Wisconsin-Madison, Department of Surgery, United States
  • 4 University of Alabama-Birmingham, Department of Surgery, United States
  • 5 University of Wisconsin-Madison, Laboratory for Optical and Computational Instrumentation, United States
  • 6 University of Wisconsin-Madison, Department of Biomedical Engneering, United States

Introduction: Although neuroendocrine tumors (NETs) are slow growing, they are frequently metastatic at the time of discovery and no longer amenable to curative surgery. Hence, there is a great need to dev­elop new therapeutic strategies to reduce tumor burden and control the release of higher-than-normal amounts of hormones in patients with NETs. To address this need, we developed a novel multi­functional upconversion nanoparticle (UCNP)-based theranostic unimolecular micelle capable of deliver­ing a newly reported anticancer drug AB3 for NET-targeted combined chemotherapy, photodynamic therapy (PDT), and bioimaging. These micelles can efficiently target NET cells overexpressing somatostatin receptors (SSTRs) using somatostatin analog (KE108) as the active-tumor targeting ligand. In this study, we assessed the antitumor effects of the micelles both in vitro and in vivo.

Methods: The NaYF4:Yb/Tm/Er UCNP core was prepared via thermolysis. Both the amphiphilic PNBMA–PEG block copolymer arms and the photosensitizer Rose Bengal (RB) were conjugated onto the UCNP core. KE108 was conjugated on the surfaces of the micelles for active tumor-targeting. AB3 was loaded into the hydro­phobic core of the micelles. The effect of 980 nm NIR excitation on 1O2 generation and the in vitro drug release of the micelles were studied. Cell proliferation was assessed by MTT assay. The effect of KE108 on the cellular uptake of the micelles was measured by flow cytometry and multiphoton laser scanning microscopy. The in vivo biodistribution was studied based on the 650 nm luminescence of the UCNP upon 980 nm NIR excitation. The antitumor efficacy of the micelles was determined in NET xenografts at a dose of 20 mg/kg BW of AB3. The group treated with micelles containing RB was irradiated for 15 min with a 980 nm laser 4 hours post injection.

Results: The UCNPs emitted multiple luminescence bands (i.e., UV, 540 nm, and 650 nm) simul­tane­ously under 980 nm NIR illumination. The luminescence bands in the UV region overlapped with the absorption of photocleavable hydrophobic segments (PNBMA), thereby providing rapid drug release upon NIR illumination due to the NIR-induced hydrophobic-to-hydrophilic transition of the micelle core. The 540 nm luminescence effectively activated the RB molecules to generate 1O2 for PDT. The 650 nm luminescence was used for fluorescence imaging in vitro and in vivo. KE108 increased the cellular uptake of the micelle drastically due to its strong binding affinity for all five subtype SSTRs. Moreover, AB3-loaded micelles conjugated with RB and KE108—enabling targeted combined chemotherapy and PDT—induced the best antitumor efficacy (82% reduction in tumor volume) with no significant observable weight loss.

Conclusions: The novel KE108 targeting ligand drastically enhanced cell uptake in NETs. This novel multifunctional UCNP-based unimolecular micelle capable of NET-targeted combined chemotherapy, PDT, and bioimaging showed the best therapeutic effect among the various controls.

National Institutes of Health (1K25CA166178) to S.G.; University of Wisconsin Carbone Cancer Center Pilot Research Grant

Keywords: Micelle, theranostic, stimuli-response, targeting delivery

Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016.

Presentation Type: General Session Oral

Topic: Cell-targeting biomaterials in theranostic delivery

Citation: Chen G, Jaskula-Sztul R, Harrison A, Vokoun C, Wang L, Eliceiri KW, Chen H and Gong S (2016). Tumor-targeting upconversion–nanoparticle-based unimolecular micelles for simultaneous chemotherapy, photodynamic therapy, and fluorescence imaging for neuroendocrine cancer therapy. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02003

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Received: 27 Mar 2016; Published Online: 30 Mar 2016.

* Correspondence:
Dr. Guojun Chen, University of Wisconsin-Madison, Materials Science and Engineering, Madison, WI, United States, Email1
Dr. Renata Jaskula-Sztul, University of Wisconsin-Madison, Department of Surgery, Madison, WI, United States, SZTUL@surgery.wisc.edu
Dr. April Harrison, University of Wisconsin-Madison, Department of Surgery, Madison, WI, United States, harrison@surgery.wisc.edu
Dr. Corinne Vokoun, University of Wisconsin-Madison, Laboratory for Optical and Computational Instrumentation, Madison, WI, United States, corinnevokoun@gmail.com
Dr. Liwei Wang, University of Wisconsin-Madison, Department of Biomedical Engneering, Madison, WI, United States, lwang396@wisc.edu
Dr. Kevin W Eliceiri, University of Wisconsin-Madison, Laboratory for Optical and Computational Instrumentation, Madison, WI, United States, eliceiri@wisc.edu
Dr. Herbert Chen, University of Wisconsin-Madison, Department of Surgery, Madison, WI, United States, chen@surgery.wisc.edu
Dr. Shaoqin Gong, University of Wisconsin-Madison, Materials Science and Engineering, Madison, WI, United States, sgong@engr.wisc.edu