Development of Receptor Targeted Magnetic Iron Oxide Nanoparticles for Efficient Drug Delivery and Tumor Imaging

Abstract

The development of multifunctional nanoparticles that have dual capabilities of tumor imaging and delivering therapeutic agents into tumor cells holds great promises for novel approaches for tumor imaging and therapy. We have engineered urokinase plasminogen activator receptor (uPAR) targeted biodegradable nanoparticles using a size uniform and amphiphilic polymer-coated magnetic iron oxide (IO) nanoparticle conjugated with the amino-terminal fragment (ATF) of urokinase plasminogen activator (uPA), which is a high affinity natural ligand for uPAR. We further developed methods to encapsulate hydrophobic chemotherapeutic drugs into the polymer layer on the IO nanoparticles, making these targeted magnetic resonance imaging (MRI) sensitive nanoparticles drug delivery vehicles. Using a fluorescent drug doxorubicin (Dox) as a model system, we showed that this hydrophobic drug can be efficiently encapsulated into the uPAR-targeted IO nanoparticles. This class of Dox-loaded nanoparticles has a compact size and is stable in pH 7.4 buffer. However, encapsulated Doxcan be released from the nanoparticles at pH 4.0 to 5.0 within 2 hrs. In comparison with the effect of equivalent dosage of free drug or non-targeted IO-Dox nanoparticles, uPAR-targeted IO-Dox nanoparticles deliver higher levels of Dox into breast cancer cells and produce a stronger inhibitory effect on tumor cell growth. Importantly, Dox-loaded IO nanoparticles maintain their T2 MRI contrast effect after being internalized into the tumor cells due to their significant susceptibility effect in the cells, indicating that this drug delivery nanoparticle has the potential to be used as targeted therapeutic imaging probes for monitoring the drug delivery using MRI.

Double-receptor-targeting multifunctional iron oxide nanoparticles drug delivery system for the treatment and imaging of prostate cancer

“…42,49 Thus, we investigated the pH-dependent PTX release from LHRH-AE105-IONPs by placing the drug-loaded NPs in four buffers of different pHs. To simulate physiological conditions, we examined the amount of PTX that was released from the NPs at pH 7.…”

Temperature-Tunable Iron Oxide Nanoparticles for Remote-Controlled Drug Release

“…Recently, encapsulation of drugs into iron oxide nanoparticles has shown promise for overcoming multidrug resistance (29). In comparison to the covalent conjugation, physical loading of DOX in the polymer surface layer offers to preserve the therapeutic efficacy of the drug (30,31). Hence, our drug loading approach is based on the availability of a drug reservoir formed by copolymer chains on the developed IONPs surfaces.…”

“…The difference in release kinetics at 37°C and 39°C indicated that the developed drug delivery system shows temperature-dependent drug release behavior. Such behavior is important for the development of an effective and nontoxic drug delivery system because it ensures a very low drug release at the physiological pH 7.4 at 37°C during the transport of the drug in the blood stream (31,33,34). On the other hand, the IONPs-PNAP are capable of the temperature-triggered release above its LCST.…”

Chemotherapy of Prostate Cancer by Targeted Nanoparticles Trackable by Magnetic Resonance Imaging

“…The polymerization reaction is carried out at 7 • C for 24 h. The final product solution is cooled to room temperature and is stored at 4 • C until use. After the modification is completed, the IONPs concentration is determined by measuring absorbance at A 500 (Beckman DU 650 UV-VIS Spectrophotometer, CA) [9,33]. Generally, a 10 mg/mL solution of IONPs gives an absorbance of 32.5, so generally we make sure that the absorbance values fall between 0.2 and 0.8 by using appropriate dilution, and then we use the dilution factor to estimate the final IONPs concentration based on (1):…”