ABSTRACT
By using radio-labeled multifunctional superparamagnetic iron oxide nanoparticles (SPIONs) and an alternating magnetic field (AMF), we carried out targeted hyperthermia, drug delivery, radio-immunotherapy (RIT), and controlled chemotherapy of cancer tumors. We synthesized and characterized Indium-111-labeled, Trastuzumab and Doxorubicin (DOX)-conjugated APTES-PEG-coated SPIONs in our previous work. Then, we evaluated their capability in SPECT/MRI (single photon emission computed tomography/magnetic resonance imaging) dual modal molecular imaging, targeting, and controlled release. In this research, AMF was introduced to evaluate therapeutic effects of magnetic hyperthermia on radionuclide-chemo therapy of HER2+ cells and tumor (HER2+)-bearing mice. In vitro and in vivo experiments using synthesized complex were repeated under an AMF (f: 100 KHz, H: 280 Gs). Instead of an intra-tumor injection in most hyperthermia experiments, SPIONs were injected to the tail vein, based on our delivery strategies. For magnetic delivery, we held a permanent Nd-B-Fe magnet near the tumor region. The results showed that simultaneous magnetic hyperthermia enhanced SKBR3 cancer cells, killing by 24%, 28%, 33%, and 80% at 48 hours post-treatment for treated cells with (1) bare SPIONs; (2) antibody-conjugated, DOX-free, surface-modified SPIONs; (3) 111In-labeled, antibody-conjugated surface-modified SPIONs; and (4) 111In-labeled, antibody- and DOX-conjugated surface-modified SPIONs, respectively. Moreover, tumor volume inhibitory rate was 85% after a 28 day period of treatment. By using this method, multimodal imaging-guided, targeted hyperthermia, RIT, and controlled chemotherapy could be achievable in the near future.
Subject(s)
Breast Neoplasms/enzymology , Breast Neoplasms/therapy , Ferric Compounds/administration & dosage , Fever/therapy , Magnetic Field Therapy/methods , Nanoparticles/administration & dosage , Receptor, ErbB-2/biosynthesis , Animals , Cell Line, Tumor , Combined Modality Therapy , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Female , Humans , Indium Radioisotopes/administration & dosage , Indium Radioisotopes/chemistry , Magnetics/methods , Mice , Mice, Inbred BALB C , Radioimmunotherapy/methods , Random Allocation , Trastuzumab/administration & dosage , Trastuzumab/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Indium-111 labeled, Trastuzumab-Doxorubicin Conjugated, and APTES-PEG coated magnetic nanoparticles were designed for tumor targeting, drug delivery, controlled drug release, and dual-modal tumor imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized by thermal decomposition method to obtain narrow size particles. To increase SPIONs circulation time in blood and decrease its cytotoxicity in healthy tissues, SPIONs surface was modified with 3-Aminopropyltriethoxy Silane (APTES) and then were functionalized with N-Hydroxysuccinimide (NHS) ester of Polyethylene Glycol Maleimide (NHS-PEG-Mal) to conjugate with thiolated 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA) bifunctional chelator (BFC) and Trastuzumab antibody. In order to tumor SPECT/MR imaging, SPIONs were labeled with Indium-111 (T1/2=2.80d). NHS ester of monoethyl malonate (MEM-NHS) was used for conjugation of Doxorubicin (DOX) chemotherapeutic agent onto SPIONs surface. Mono-Ethyl Malonate allows DOX molecules to be attached to SPIONs via pH-sensitive hydrazone bonds which lead to controlled drug release in tumor region. Active and passive tumor targeting were achieved through incorporated anti-HER2 (Trastuzumab) antibody and EPR effect of solid tumors for nanoparticles respectively. In addition to in vitro assessments of modified SPIONs in SKBR3 cell lines, their theranostic effects were evaluated in HER2 + breast tumor bearing BALB/c mice via biodistribution study, dual-modal molecular imaging and tumor diameter measurements.
