Functionalized milk-protein-coated magnetic nanoparticles for MRI-monitored targeted therapy of pancreatic cancer

Abstract

Engineered nanocarriers have emerged as a promising platform for cancer therapy. However, the therapeutic efficacy is limited by low drug loading efficiency, poor passive targeting to tumors, and severe systemic side effects. Herein, we report a new class of nanoconstructs based on milk protein (casein)-coated magnetic iron oxide (CNIO) nanoparticles for targeted and image-guided pancreatic cancer treatment. The tumor-targeting amino-terminal fragment (ATF) of urokinase plasminogen activator and the antitumor drug cisplatin (CDDP) were engineered on this nanoplatform. High drug loading (~25 wt%) and sustained release at physiological conditions were achieved through the exchange and encapsulation strategy. These ATF-CNIO-CDDP nanoparticles demonstrated actively targeted delivery of CDDP to orthotopic pancreatic tumors in mice. The effective accumulation and distribution of ATF-CNIO-CDDP was evidenced by magnetic resonance imaging, based on the T 2 -weighted contrast resulting from the specific accumulation of ATF-CNIO-CDDP in the tumor. Actively targeted delivery of ATF-CNIO-CDDP led to improved therapeutic efficacy in comparison with free CDDP and nontargeted CNIO-CDDP treatment. Meanwhile, less systemic side effects were observed in the nanocarrier-treated groups than that in the group treated with free CDDP. Hematoxylin and Eosin and Sirius Red staining of tumor sections revealed the possible disruption of stroma during the treatment with ATF-CNIO-CDDP. Overall, our results suggest that ATF-CNIO-CDDP can be an effective theranostic platform for active targeting-enhanced and image-guided cancer treatment while simultaneously reducing the systemic toxicity.

<p>Doxorubicin/Cisplatin-Loaded Superparamagnetic Nanoparticles As A Stimuli-Responsive Co-Delivery System For Chemo-Photothermal Therapy</p>

“…In this regard nanotechnology has been the most sought after science to which the major share of research in this field is dedicated. The unique properties that some materials represent at the nanoscale enable them to be used for innovative applications; due to their very small size and surface properties, some types of nanoparticles can accumulate in specific tissues or cells and demonstrate a great potential for application in cancer diagnosis and therapy 4,6,10. The application of nanostructures as drug carriers11 and bioimaging12 and thermal treatment agents13 has been studied for more than a decade.…”

“…1,2 The current clinical cancer therapies including chemotherapy, radiotherapy, and surgery lack the desirable effectiveness and are associated with severe side effects. [3][4][5] For these reasons, finding an improved cancer therapy method has been the subject of extensive research efforts worldwide.…”

Human cytotoxic T-lymphocyte membrane-camouflaged nanoparticles combined with low-dose irradiation: a new approach to enhance drug targeting in gastric cancer

“…51 External stimuli, including variations in temperature, magnetic fields, 52,53 and NIR light, 54,55 have been well employed in drug delivery systems in previous studies. However, compared with the LDI in this study, externally placed magnets have no antitumor efficacy themselves, while NIR light or thermotherapy are not widely applied.…”

Protease-triggered bioresponsive drug delivery for the targeted theranostics of malignancy

“…Besides, uPA-stimulated theranostic nanocompositions have also played an important role in cancer management such as luteinizing hormone releasing hormone receptor/uPAR dual-targeting IONPs for the diagnosis and treatment of prostate cancer 174 , uPAR-targeted PEGylated IONPs for MRI-guided drug delivery into peritoneal tumors 175 , milk protein-protected uPA-targeted IONPs loading cisplatin for MRI-monitored effective therapy of pancreatic cancer with minimal side effects 176 , pH responsive, uPAR-targeted MSNs for the identification of pancreatic cancer using multispectral optoacoustic tomography 177 , iridium (Ir) complex-loaded Au nanostars functionalized with uPAR targeting module for photothermal/X-ray CT/PA three type diagnosis-synergized PTT/chemotherapy combination treatment for triple negative breast cancer (TNBC) 178 . Typical uPA-mediated cancer diagnosis and treatment events are briefly summarized in Table 4 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 .…”

“… Nanocarrier Substrate Drug Diagnosis Therapy Tumor Ref. DGL-U11 U11 Gd 3+ -DTPA, Cy5.5 MRI, NIR FI – PANC1 human pancreatic cancer cells 168 Four-arm PEGylated 64 Cu-bombesin analog tetramer CGSGRSAG 64 Cu PET – PC-3 human prostate cancer cells 169 Ultra-small magnetic IONPs DKK1, ATF 24 DOX NIR FI Chemotherapy MDA-MB-231 human breast cancer cells 170 ATF-HSA ATF DOX FI Chemotherapy H1299 human non-small cell lung cancer cells H22 mouse hepatoma cells 171 U11-DOX/curcumin NPs U11 DOX, curcumin – Chemotherapy A549 human non-small cell lung cancer cells 172 ALA fusion protein ATF AGAP – Gene therapy MDA-MB-231 human breast cancer cells 173 LHRH-AE105-IONPs Modified LHRH peptide, AE105 peptide PTX MRI Chemotherapy PC-3 human prostate cancer cells 174 PEGylated IONPs ATF Cisplatin, DOX NIR FI, MRI Chemotherapy PANC02 mouse pancreatic cancer cells 175 Milk protein-coated IONPs ATF Cisplatin MRI Chemotherapy MIA PaCa-2 human pancreatic cancer cells 176 …”