Nanotechnology in bladder cancer: current state of development and clinical practice

Abstract

Nanotechnology is being developed for the diagnosis and treatment of both nonmyoinvasive bladder cancer (NMIBC) and invasive bladder cancer. The diagnostic applications of nanotechnology in NMIBC mainly focus on tumor identification during endoscopy to increase complete resection of bladder cancer while nanotechnology to capture malignant cells or their components continues to be developed. The therapeutic applications of nanotechnology in NMIBC are to reformulate biological and cytotoxic agents for intravesical instillation, combine both diagnostic and therapeutic application in one nanoformulation. In invasive and advanced bladder cancer, magnetic resonance imaging with supraparamagnetic iron oxide nanoparticles can improve the sensitivity and specificity in detecting small metastasis to lymph nodes. Nanoformulation of cytotoxic agents can potentially decrease the toxicity while increasing efficacy.

Keywords: bladder cancer; nanoparticle; photodynamic diagnosis; photodynamic therapy.

Figure 1. Photodynamic diagnosis and therapy of PLZ4-coated micelles

(A) Structure of PLZ4-micelles and their building polymer telodendrimer. A telodendrimer is synthesized through conjugation of cholic acid at one terminus of PEG and PLZ4 at the other terminus. To synthesize nanoporphyrin, porphyrin analogs can either be conjugated to PEG or loaded in micelles. To synthesize micelles, hydrophobic agents (therapeutic or diagnostic) and telodendrimers are mixed and dissolved in aqueous solution. The hydrophobic agents and the biphasic cholic acid units will form the core while exposing more hydrophilic PEG and PLZ4 on the surface for cancer-specific targeting. (B) Illustration of photodynamic diagnosis and therapy. PLZ4 can not only attach the nanoporphyrin on the surface of bladder cancer cells, but more important, induce uptake of the whole micelles into cells. Upon activation with blue light, porphyrin can yield red fluorescence for photodynamic diagnosis and produce reactive oxygen species to damage macromolecules and kill cells for photodynamic therapy. (C) PLZ4-guided specific drug delivery. A bladder cancer cell line 5637 cells transfected with GFP were incubated with PLZ4-coated micelles or nontargeting micelles, both loaded with fluorescent DiD dye. After incubation for 15 min, cells were fixed and incubated with 4′,6-diamidino-2-phenylindole for nuclear staining. Scarce scattered red fluorescence from DiD was observed when cells were incubated with nontargeting micelles. By contrast, cells incubated with PLZ4 targeting micelles showed strong multifocal aggregated fluorescence not only on cell membrane, but also in the cytoplasm with a peri-nucleus pattern. DiD: 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicar bocyanine.

Figure 2. In vivobioimaging of targeting micelles on patient-derived xenograft bearing mice

Mice carrying patient-derived xenografts were intravenously injected DiD loaded PLZ4 micelles (50 mg/kg of DiD) for 3 days. In vivo whole mouse and ex vivo imaging showed high retention of PLZ4-micelles-DiD at the PDX (yellow arrow) but only minimal signals were noted in other major organs. NIRF: Near infrared fluorescence; PDX:Patient-derived xenograft; WL: White light.

Figure 3. Comparison of antitumor activity in mice carrying patient-derived xenografts

Mice carrying patient-derived xenografts were treated with phosphate-buffered solution, free PTX at 10 mg/kg (therapeutic dose), PTX formulated in PLZ4 micelles (PLZ4-NM-PTX) at 10 or 30 mg/kg for six times with a 3-day interval. PTX formulated in the PLZ4 micelles showed a dose-dependent anticancer efficacy and G2/M phase cell cycle arrest rate on histopathologic examination. At the same dose of 10 mg/kg, PTX in PLZ4 micelles was associated with significantly reduced toxicity than free PTX evaluated at the 3 days after six doses [22]. PTX in PLZ4 micelles at 30 mg/kg had comparable toxicity as free PTX at 10 mg/kg, but significantly prolonged the progression-free survival (p < 0.0001) (A), and overall survival from 27 to 76 days (p < 0.0001) (B). PBS: Phosphate-buffered saline; PTX: Paclitaxel.