Multifunctional targeting micelle nanocarriers with both imaging and therapeutic potential for bladder cancer

Tzu-yin Lin,¹ Hongyong Zhang,¹ Juntao Luo,^2,5 Yuanpei Li,² Tingjuan Gao,³ Primo N Lara Jr,^1,4,6 Ralph de Vere White,⁴ Kit S Lam,^1,2 Chong-Xian Pan,^1,3,6
1Division of Hematology and Oncology, Department of Internal Medicine, ²Department of Biochemistry and Molecular Medicine, ³NSF Center for Biophotonics Science and Technology, School of Medicine, ⁴Department of Urology, University of California-Davis, Sacramento, CA, ⁵Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, ⁶VA Northern California Health Care System, Mather, CA, USA

Background: We previously developed a bladder cancer-specific ligand (PLZ4) that can specifically bind to both human and dog bladder cancer cells in vitro and in vivo. We have also developed a micelle nanocarrier drug-delivery system. Here, we assessed whether the targeting micelles decorated with PLZ4 on the surface could specifically target dog bladder cancer cells.
Materials and methods: Micelle-building monomers (ie, telodendrimers) were synthesized through conjugation of polyethylene glycol with a cholic acid cluster at one end and PLZ4 at the other, which then self-assembled in an aqueous solution to form micelles. Dog bladder cancer cell lines were used for in vitro and in vivo drug delivery studies.
Results: Compared to nontargeting micelles, targeting PLZ4 micelles (23.2 ± 8.1 nm in diameter) loaded with the imaging agent DiD and the chemotherapeutic drug paclitaxel or daunorubicin were more efficient in targeted drug delivery and more effective in cell killing in vitro. PLZ4 facilitated the uptake of micelles together with the cargo load into the target cells. We also developed an orthotopic invasive dog bladder cancer xenograft model in mice. In vivo studies with this model showed the targeting micelles were more efficient in targeted drug delivery than the free dye (14.3×; P < 0.01) and nontargeting micelles (1.5×; P < 0.05).
Conclusion: Targeting micelles decorated with PLZ4 can selectively target dog bladder cancer cells and potentially be developed as imaging and therapeutic agents in a clinical setting. Preclinical studies of targeting micelles can be performed in dogs with spontaneous bladder cancer before proceeding with studies using human patients.

Keywords: bladder urothelial carcinoma, nanoparticle, bladder cancer-specific peptide, targeted therapy, diagnostic imaging