Targeted imaging and therapy of brain cancer using theranostic nanoparticles

Abstract

The past decade has seen momentous development in brain cancer research in terms of novel imaging-assisted surgeries, molecularly targeted drug-based treatment regimens or adjuvant therapies and in our understanding of molecular footprints of initiation and progression of malignancy. However, mortality due to brain cancer has essentially remained unchanged in the last three decades. Thus, paradigm-changing diagnostic and therapeutic reagents are urgently needed. Nanotheranostic platforms are powerful tools for imaging and treatment of cancer. Multifunctionality of these nanovehicles offers a number of advantages over conventional agents. These include targeting to a diseased site thereby minimizing systemic toxicity, the ability to solubilize hydrophobic or labile drugs leading to improved pharmacokinetics and their potential to image, treat and predict therapeutic response. In this article, we will discuss the application of newer theranostic nanoparticles in targeted brain cancer imaging and treatment.

Figure 1

Tumor targeting ability of F3 peptide. The ability of F3 peptide to carry a cargo to tumor cells was assessed in mouse xenografts of human glioblastoma cell line D54. The animal in the left panel received an 100 μg/ml amount of control peptide (AAVALLPAVLLALLAPESASGASADASVNFLC) conjugated to a near infrared fluorescent cargo while the animal in the right panel received an F3 peptide (KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK) coupled to fluorescent cargo.

Figure 2

Schematic diagram of a Theranostic nanoparticle. Multifunctional nanoparticles targeted to cancer cell membranes using a ligand to tumor cell specific surface receptor. The nanoparticles harbor an imaging (blue sphere within the core) and therapeutic agent (yellow structures with the core).

Figure 3

Imaging and monitoring of therapeutic efficacy using multifunctional nanoparticles in 9L brain tumors. Shown in A and B are representative images from two animals. A images were collected from a rat following iv administration of nontargeted nanoparticles. Images shown were acquired at 0, 10, 60, and 120 min following injection, revealing that significant tumor contrast enhancement was achieved at 10 min. Results following administration of targeted nanoparticles are shown in B, which reveal that the contrast enhancement was increased in both magnitude and duration for this preparation. The F3-targeted nanoparticles had ~3-fold prolonged tumor transit time (P < 0.001). Moreover, the presence of the F3-targeting moiety also resulted in a significantly improved contrast-to-noise ratio of ~2-fold at 1 h (P < 0.01) and 2 h (P <0.008) after contrast administration. Color diffusion maps overlaid on top of T2-weighted images represent the apparent diffusion coefficient (ADC) distribution in each tumor slice shown. MR images shown from day 8 post-treatment from (C) a representative control 9L tumor and tumors treated with (D) laser light only, (E) iv administration of Photofrin plus laser light, and (F) nontargeted nanoparticles containing Photofrin plus laser light. Treatment with F3-targeted Photofrin-encapsulated nanoparticles resulted in the most significant increase in mean tumor apparent diffusion coefficient values (G). (H) Tumor from the same tumor shown in (G), which was treated with the F3-targeted nanoparticle preparation but at day 40 after treatment revealed a high diffusion value indicative of a cystic cavity. (I) Mean peak percentage change in tumor apparent diffusion coefficient values for each of the experimental groups (bars ± SEM).