Development of Multifunctional Hyaluronan-Coated Nanoparticles for Imaging and Drug Delivery to Cancer Cells

Abstract

Currently, there is high interest in developing multifunctional theranostic platforms for cancer monitoring and chemotherapy. Herein, we report hyaluronan (HA)-coated superparamagnetic iron oxide nanoparticles (HA-SPION) as a promising system for targeted imaging and drug delivery. When incubated with cancer cells, HA-SPIONs were rapidly taken up and the internalization of HA-SPION by cancer cells was much higher than the NPs without HA coating. The high magnetic relaxivity of HA-SPION coupled with enhanced uptake enabled magnetic resonance imaging of cancer cells. Furthermore, doxorubicin (DOX) was attached onto the nanoparticles through an acid responsive linker. While HA-SPION was not toxic to cells, DOX-HA-SPION was much more potent than free DOX to kill not only drug-sensitive but also multi-drug-resistant cancer cells. This was attributed to differential uptake mechanisms and cellular distributions of free DOX and DOX-HA-SPION in cancer cells.

Magnetic Nanocarriers Enhance Drug Delivery Selectively to Human Leukemic Cells

“…Interestingly, incubating the same cell lines with free Dox at equivalent concentrations, the red fluorescence was found to be directly localized in the nucleus of all cells with minimal detectable presence in the cytoplasm even after only 6 h of incubation. This phenomena is similar to earlier observations by us and others [13,38,43]. It is, thus, repeatedly evident that while free Dox is internalized by passive diffusion through the cell membrane, the uptake of Dox@PMNPs is rather directed by one type of endocytic trafficking mechanisms, specifically micropinocytosis [44,45].…”

“…MNPs have been extensively studied not only as imaging vehicles, but also as drug nanocarriers [13][14][15][16]. The main advantages of using MNPs for such purposes are: 1) easy preparation; 2) small sizes and large surface areas; 3) facile chemical functionalization; 3) excellent biocompatibility and stability; 4) efficient drug conjugation; and 5) superior magnetic responsiveness.…”

Superparamagnetic Iron Oxide Nanoparticles in Biomedicine: Applications and Developments in Diagnostics and Therapy

“…The second strategy was able to be successfully shown by binding magnetoliposome-antibody complexes to MN antigens of renal cell carcinoma cells [206], magnetoliposomeanti-Her2-AB to breast cancer cells [203], or anti-folate receptor-SPIO to different tumor cell lines [207]. The third strategy was able to be successfully proven on the basis of rhenium188-loaded immuno(hepama-1)magnetic nanoparticles (Re-SPIO-AB) against liver carcinoma cells [208], methotrexate-conjugated SPIO against breast (MCF7) and cervical (HeLa) carcinoma cells [209], doxorubicin-loaded nanomicelles [210], doxorubicin-carrying hyaluronan-SPIO (DOX-HA-SPIO) [211], docetaxel-carboxymethylcellulose-SPIO [212], layer-by-layer (LbL) polyelectrolyte capsules that can be loaded with SPIO and/or therapeutic agents [213], SPIO-and doxorubicin-loaded cetuximab-anti-EGFR immunomicelles or with doxorubicin(liposomal)-loaded macrophages (macrophage-LP-Dox) that accumulate in tumors [214]. Although major advances in tumor labeling and tumor therapy via therapeutic imaging SPIO constructs (theranostics) have been made in recent years, the development of potent in vivo theranostics with high specificity and sensitivity has remained a significant challenge due to the heterogeneity of the expression level of the target structure on the tumor cells and problems with overcoming physiological barriers (e. g. extravasation or blood-tissue barriers) preventing access to the target cell (pharmacological accessibility).…”

Hyaluronan Endocytosis: Mechanisms of Uptake and Biological Functions

“…Recently, HA has been coated onto superparamagnetic iron oxide nanoparticles [72]. These HA-coated nanoparticles were endocytosed by cancer cells allowing their magnetic resonance imaging in vitro.…”