High molecular weight chitosan derivative polymeric micelles encapsulating superparamagnetic iron oxide for tumor-targeted magnetic resonance imaging

Abstract

Magnetic resonance imaging (MRI) contrast agents based on chitosan derivatives have great potential for diagnosing diseases. However, stable tumor-targeted MRI contrast agents using micelles prepared from high molecular weight chitosan derivatives are seldom reported. In this study, we developed a novel tumor-targeted MRI vehicle via superparamagnetic iron oxide nanoparticles (SPIONs) encapsulated in self-aggregating polymeric folate-conjugated N-palmitoyl chitosan (FAPLCS) micelles. The tumor-targeting ability of FAPLCS/SPIONs was demonstrated in vitro and in vivo. The results of dynamic light scattering experiments showed that the micelles had a relatively narrow size distribution (136.60±3.90 nm) and excellent stability. FAPLCS/SPIONs showed low cytotoxicity and excellent biocompatibility in cellular toxicity tests. Both in vitro and in vivo studies demonstrated that FAPLCS/SPIONs bound specifically to folate receptor-positive HeLa cells, and that FAPLCS/SPIONs accumulated predominantly in established HeLa-derived tumors in mice. The signal intensities of T 2 -weighted images in established HeLa-derived tumors were reduced dramatically after intravenous micelle administration. Our study indicates that FAPLCS/SPION micelles can potentially serve as safe and effective MRI contrast agents for detecting tumors that overexpress folate receptors.

Progress in the Development of Chitosan-Based Biomaterials for Tissue Engineering and Regenerative Medicine

“…Controlled anticancer drug release [142] Tumor targeted therapy [143] N-octyl-O-sulfate chitosan Self-assembled polymeric micelles Absorption enhancement of anticancer drug [144,145] Tumor targeted therapy [146][147][148] Increasing stability of drug loaded liposomes [149] 2-[phenylhydrazine (or hydrazine)-thiosemicarbazone]-chitosan Powder Pharmaceutical and food industries [150] (Ser-Ile-Lys-Val-Ala-Val) peptide-modified chitosan Hydrogel Skin substitutes for wound closure in mice [53,151] Galactosylated chitosan (GC) NPs Tumor targeted therapy [152][153][154][155] siRNA delivery [156,157] N-palmitoyl chitosan (NPCS) MPs and micelles Tumor targeted therapy [158,159] O-palmitoyl chitosan (OPC) Liposomes Intestinal drug delivery [160] Hydroxyapatite/CS NPs Drug delivery [161][162][163][164] CS loaded with antioxidant NPs Hydrogel Drug release [165] PEGylated CS NPs Tumor targeted therapy [166][167][168] Chitosan-based vaccine Polyelectrolyte, NPs Intranasal CS-DNA vaccine [169,170] 4. Conclusions CS, as a natural polymer, is actively used in tissue engineering and regenerative medicine as a biomaterial alone, as well as in combination with other polymers.…”

Evaluation of Chitosan Derivative Microparticles Encapsulating Superparamagnetic Iron Oxide and Doxorubicin as a pH-Sensitive Delivery Carrier in Hepatic Carcinoma Treatment: An in vitro Comparison Study

“…For example, the vascular pore cutoff size of solid tumors is between 380 and 780 nm (Hobbs et al, 1998 ); hence, our particles with sizes of 185 ± 87 nm in neutral pH fall within the suitable range to pass through the leaky junction of the angiogenesis vessel into the tumor tissue according to the enhanced permeation and retention effect (EPR effect). Another benefit of using these large particles is that they are sufficiently large to obstruct vascular pores and even capillaries because of their swelling effect and aggregation behavior in acidic environment (Szymanska and Winnicka, 2015 ; Xiao et al, 2015 ). Thus, these particles combine the beneficial effects of traversing and obstructing small and big angiogenesis vessels to improve antitumor efficacy, which the treatment response can be simultaneously monitored by MRI T2 image.…”

Challenges and opportunities in developing targeted molecular imaging to determine inner ear defects of sensorineural hearing loss

“…Although their clinical applications have been limited, SPION agents have shown greater promise in research fields where the ability to conjugate ligands to these particles has been utilized in numerous applications. The conjugation process is relatively straight forward using variations of NHS/EDC (N-Hydroxysuccinimide/ ethyl(dimethylaminopropyl) carbodiimide) methodology 42, 43 . Limited cytotoxicity has been detected with uncoated SPIONs 44 .…”

“…However, MTT (3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide) studies have indicated that coating untargeted SPIONs with polyvinyl alcohol can almost eliminate cytotoxicity 44 . One study with particles targeted to HeLa tumors showed significant decrease in tumor signal intensity indicative of nanoparticle accumulation, and also demonstrated minimal cytotoxicity 42 . A second construct, was able to pass through the blood brain barrier, doubling the number of Alzheimer's disease plaques detected by MR imaging 43 .…”