Tumor Targeting Chitosan Nanoparticles for Dual-Modality Optical/MR Cancer Imaging

Abstract

We report tumor targeting nanoparticles for optical/MR dual imaging based on self-assembled glycol chitosan to be a potential multimodal imaging probe. To develop an optical/MR dual imaging probe, biocompatible and water-soluble glycol chitosan (M(w) = 50 kDa) were chemically modified with 5beta-cholanic acid (CA), resulting in amphiphilic glycol chitosan-5beta-cholanic acid conjugates (GC-CA). For optical imaging near-infrared fluorescence (NIRF) dye, Cy5.5, was conjugated to GC-CA resulting in Cy5-labeled GC-CA conjugates (Cy5.5-GC-CA). Moreover, in order to chelate gadolinium (Gd(III)) in the Cy5.5-GC-CA conjugates, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was directly conjugated in Cy5.5-GC-CA. Finally, the excess GdCl(3) was added to DOTA modified Cy5.5-GC-CA conjugates in distilled water (pH 5.5). The freshly prepared Gd(III) encapsulated Cy5.5-GC-CA conjugates were spontaneously self-assembled into stable Cy5.5 labeled and Gd(III) encapsulated chitosan nanoparticles (Cy5.5-CNP-Gd(III)). The Cy5.5-CNP-Gd(III) was spherical in shape and approximately 350 nm in size. From the cellular experiment, it was demonstrated that Cy5.5-CNP-Gd(III) were efficiently taken up and distributed in cytoplasm (NIRF filter; red). When the Cy5.5-GC-Gd(III) were systemically administrated into the tail vein of tumor-bearing mice, large amounts of nanoparticles were successfully localized within the tumor, which was confirmed by noninvasive near-infrared fluorescence and MR imaging system simultaneously. These results revealed that the dual-modal imaging probe of Cy5.5-CNP-Gd(III) has the potential to be used as an optical/MR dual imaging agent for cancer treatment.

Tailoring nanoparticle designs to target cancer based on tumor pathophysiology

“…Vascular density was calculated by counting the number of vessels per tumor cross-section. We observed that the concentration of blood vessels increased with tumor volume but plateaued at 44 ± 3 blood vessels/mm 2 for tumor volumes exceeding 1.0 cm 3 (Fig. 1A).…”

“…Beyond tumor vascularization, the fraction of the tumor composed of proteoglycans and mucopolysaccharides increased at a rate of 4.2 arbitrary units/cm 3 (Fig. 1B), whereas tumor cell density increased at a rate of 1.70 cells/cm 3 (Fig.…”

“…3C) was largely insensitive to changes in tumor volume (two-way ANOVA, P = 0.05); 15-, 60-, and 100-nm AuNPs maintained tumor entry rates of 4.2 ± 0.6%, 3.2 ± 0.9%, and 2.9 ± 0.8% ID·h −1 as tumors grew to 1.0 cm 3 . Particles with 30-and 45-nm diameters were the exception as their rate of uptake steadily rose from 2.3 ± 0.3% to 5.7 ± 0.9% ID·h −1 and 2.8 ± 0.9 to 7.0 ± 1.0% ID·h −1 , respectively, as tumors grew beyond 0.5 cm 3 . Although the rate of delivery did not statistically vary with growth, AuNP entry into the tumor compartment trended higher as tumors increased in size.…”

“…AuNP accumulation was evaluated via tail vein injection of formulations into CD1 nude athymic mice bearing orthotopic MDA-MB-435 human breast melanoma tumors. Tumors volumes evaluated in this study ranged from 0.05-3.00 cm 3 . AuNP delivery to the different sized tumors was fluorescently profiled in mice to assess tumor accumulation kinetics and to measure total AuNP exposure.…”

“…Nanomaterials can be engineered with different sizes, shapes, and surface chemistries, as well as assembled into hierarchical nanosystems (1). Nanomaterials can also be engineered with unique properties such as emission of light for fluorescence detection (2), magnetism for magnetic resonance imaging (3,4), and thermal emission for ablation of tumor cells (5). Despite the potential of nanomaterials, typically less than 5% of an administered dose reaches the tumor compartment (6) because of poor retention within the tumor space and uptake by the skin (7), spleen, and liver (8)(9)(10).…”