Cell-Penetrating Peptidic GRP78 Ligand-Conjugated Iron Oxide Magnetic Nanoparticles for Tumor-Targeted Doxorubicin Delivery and Imaging

Abstract

Although chemotherapy is regarded as an essential option in cancer treatment, it is still far from being perfect. Inadequate tumor drug concentration and systemic toxicity along with broad biodistribution have diminished the utility of chemotherapy. Tumor-targeting peptide-conjugated multifunctional nanoplatforms have emerged as an effective strategy for site-directed tumor tissues in cancer treatment and imaging. Herein, Pep42-targeted iron oxide magnetic nanoparticles (IONPs) functionalized with β-cyclodextrin (ßCD) containing doxorubicin (DOX) (Fe3O4-ßCD-Pep42-DOX) were successfully developed. The physical effects of the prepared NPs were characterized by employing various techniques. Transmission electron microscopy (TEM) images disclosed that the developed Fe3O4-ßCD-Pep42-DOX nanoplatforms had a spherical morphology and a core–shell structure with a size of nearly 17 nm. Fourier transform infrared (FT-IR) spectroscopy showed that β-cyclodextrin, DOX, and Pep42 molecules were successfully loaded on the IONPs. In vitro cytotoxicity analysis revealed that the fabricated multifunctional Fe3O4-ßCD-Pep42 nanoplatforms possessed excellent biosafety toward BT-474, MDA-MB468 (cancerous cells), and MCF10A normal cells, while Fe3O4-ßCD-Pep42-DOX exhibited great cancer cell killing ability. The high cellular uptake along with intracellular trafficking of Fe3O4-ßCD-Pep42-DOX highlights the usefulness of the Pep42-targeting peptide. In vivo results strongly supported the in vitro results, i.e., significant tumor size reduction was observed by single-dose injection of Fe3O4-ßCD-Pep42-DOX into tumor-bearing mice. Interestingly, in vivo MR imaging (MRI) of Fe3O4-ßCD-Pep42-DOX revealed T 2 contrast improvement in the tumor cells and therapeutic ability in cancer theranostics. Taken together, these findings provided strong evidence for the potential capability of Fe3O4-ßCD-Pep42-DOX as a multifunctional nanoplatform in cancer therapy and imaging and opens up a new avenue of research in this area.

Recent Progress and Challenges Regarding Magnetite-Based Nanoparticles for Targeted Drug Delivery

“…T 2 relaxation rates showed linearity with increasing Fe concentration (0.04-0.20 mM) and high transverse relaxivity (119 mM −1 s −1 ). Another approach assumed magnetite core func-tionalization with β-CD and further conjugation of cyclic 13mer oligopeptide Pep42 as a targeting agent to glucose-regulated protein 78 (GRP78) overexpressed in cancer cells [112]. The presence of loaded DOX and Pep42 resulted in a decrease in breast cancer cell viability and significant induction of apoptosis.…”

“…The core-shell structure demonstrated excellent photothermal conversion properties, which resulted in much higher tumor inhibition efficiency, but also was capable of simultaneous enhancement in ultrasound imaging (USI), photoacoustic tomography (PAT), and MR imaging. Carbon quantum dots MRI DOX/breast [110] Poly(glycidyl methacrylate-polyethylene glycol), salep dialdehyde MRI DOX/breast [111] β-cyclodextrin, Pep42 MRI DOX/breast [112] Poly (ε-caprolactone), chitosan MRI GEM/breast [113] Polyvinylpyrrolidone MRI, MHT DOX/osteosarcoma [114] Punica granatum fruit peel extract MRI, MHT 5-FU/colorectal [115] Gold nanoparticles MRI, PTT DOX/cervical [116] Polyethylene glycol, poly(lactic-co-glycolic acid), Prussian blue MRI, PAT, USI, PTT DOX/osteosarcoma [117] * Each drug delivery system demonstrates potential application in chemotherapy.…”

“…In the context of utilizing magnetic nanoparticles for diagnostics and therapy, the optimal approach for their studying in biological systems is to integrate imaging techniques that facilitate their visualization with those employed for the pathological examination of tissues. Various imaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), have been extensively utilized to track the targeting and biodistribution of nanoparticles throughout the entire body [13,112,113]. On the other hand, magnetic particle imaging (MPI) enables the direct detection of the quantity and location of superparamagnetic nanoparticles within biological tissue, surpassing the sensitivity of MRI [129].…”

Advances in Brain Tumor Therapy Based on the Magnetic Nanoparticles

“…In active targeting, MNPs are conjugated with ligands that can recognize highly expressed receptors on the membranes of cancer cells and tumor-associated cells. For instance, many ligands such as transferrin, [125][126][127][128][129][130] folate, [131][132][133] hyaluronic acid, 134,135 aptamers, 136,137 antibodies, 15,[138][139][140] and peptides [141][142][143][144] have been conjugated with MNPs for active targeted delivery into brain tumor sites. 145 MNPs present unique advantages for drug delivery into brain tumors, particularly due to their strong response to EMF.…”

Preparation of Hybrid Fe 3 O 4 @SiO 2 Biopolymer Core-Shell Anticancer Drug Carrier for Sustainable Release of Doxorubicin

“…For systems (A) and (B), the corresponding yields achieved using the single emulsion approach were determined. The introduction of the Fe3O4 nanoparticles in the core of the microcapsule was preconized to control the drug release under a strong external magnetic field applied at the tumor proximity [9]. All materials obtained were characterized by scanning electron microscopy (SEM), and infrared Fourier transform (ATR-FTIR) spectroscopy.…”