Theranostic Nanoparticles with Controlled Release of Gemcitabine for Targeted Therapy and MRI of Pancreatic Cancer

Abstract

The tumor stroma in human cancers significantly limits the delivery of therapeutic agents into cancer cells. To develop an effective therapeutic approach overcoming the physical barrier of the stroma, we engineered urokinase plasminogen activator receptor (uPAR)-targeted magnetic iron oxide nanoparticles (IONPs) carrying gemcitabine (Gem) as a chemotherapy drug for targeted delivery into uPAR-expressing tumor and stromal cells. The uPAR-targeted nanoparticle construct, ATF-IONP-Gem, was prepared by conjugating IONPs with the amino-terminal fragment (ATF) peptide of the receptor-binding domain of uPA, a natural ligand of uPAR, and Gem via a lysosomally cleavable tetrapeptide linker. These theranostic nanoparticles enable intracellular release of Gem following receptor-mediated endocytosis of ATF-IONP-Gem into tumor cells, and also allow in vivo magnetic resonance imaging (MRI) of tumors. Our results demonstrated the pH- and lysosomal enzyme-dependent release of gemcitabine, preventing the drug from enzymatic degradation. Systemic administrations of ATF-IONP-Gem significantly inhibited the growth of orthotopic human pancreatic cancer xenografts in nude mice. With MRI contrast enhancement by IONPs, we detected the presence of IONPs in the residual tumor lesions following the treatment, suggesting the possibility of monitoring drug delivery and assessing drug resistant tumors by MRI. The theranostic ATF-IONP-Gem nanoparticle has great potential for the development of targeted therapeutic and imaging approaches that are capable of overcoming the tumor stromal barrier, thus enhancing the therapeutic effect of nanoparticle drugs on pancreatic cancers.

Magnetic Nanoparticles for Precision Oncology: Theranostic Magnetic Iron Oxide Nanoparticles for Image-Guided and Targeted Cancer Therapy

“…Targeted IONPs are produced by covalently or noncovalently modifications with molecular-targeting ligands that bind to specific cancer biomarkers or overexpressed surface moieties on cancer cells. For example, peptides, antibodies or antibody fragments that specifically bind to receptors overexpressed in tumor cells, such as MUC-1, αvβ3 integrin, EGFR, HER2/neu, uPAR and prostate-specific membrane antigen, were conjugated to the surface of IONPs, leading to the targeted accumulation and retention of the IONPs in tumor tissues, and resulting in T 2 contrast for the detection of tumors by MRI [90][91][92][93][94]. Furthermore, receptor-mediated endocytosis increased intratumoral delivery of nanoparticles and relatively long-term retention of the nanoparticles in tumors for sensitive imaging of drug delivery and tumor responses to the therapy [95].…”

Review: The Role of Hyperthermia in Treating Pancreatic Tumors

“…While doxorubicin was among the first drugs to be tested in this way, others like cisplatin and gemcitabine follow [27][28][29]. Lipidal strcutures can be designed in a thermosensitive manner that release only at predesigned thresholds (e.g.…”

Nanomaterials for biomedical applications

“…These trifunctional NPs could selectively target and induce apoptosis to folate-receptor overexpressing cancer cells with higher efficacy in comparison with the free drug. Iron oxide NPs can also be used for delivery of chemotherapeutics such as gemcitabine (Lee et al 2013).…”