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IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer
Hongyu Zhou1, Weiping Qian1, Fatih M Uckun2
1Department of Surgery and Radiology, Emory University School of Medicine, Atlanta, Georgia.
Abstract:
Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.
Insights
Targeted nanoparticles deliver multiple drugs to overcome cancer drug resistance and penetrate tumor barriers. Image-guided therapy using IGF-1R targeted iron oxide nanoparticles shows promise for treating resistant cancers like pancreatic cancer.
Area of Science:
- Oncology
- Nanomedicine
- Biotechnology
Background:
- Cancer drug delivery faces challenges due to heterogeneous cells and tumor microenvironment, leading to low efficiency and resistance.
- Insulin-like growth factor 1 receptor (IGF-1R) is overexpressed in tumor cells and stromal cells, and its expression increases in drug-resistant cancers.
Purpose of the Study:
- To develop and evaluate an IGF-1R targeted theranostic nanoparticle system for enhanced drug delivery and image-guided therapy in drug-resistant cancers.
Main Methods:
- Development of magnetic iron oxide nanoparticles (IONPs) coated with amphiphilic polymers for biocompatibility, drug loading (Doxorubicin), and conjugation of IGF-1 targeting molecules.
- Encapsulation and/or surface conjugation of Doxorubicin (Dox) to the IONPs.
- In vitro and in vivo evaluation using human pancreatic cancer patient-derived xenograft (PDX) models to assess tumor penetration, therapeutic efficacy, and monitoring via MR and NIR imaging.
Main Results:
- IGF-1R targeted theranostic nanoparticles successfully penetrated the tumor stromal barrier in PDX models.
- Repeated systemic administration of Dox-loaded IONPs broke down the tumor stromal barrier, leading to improved therapeutic effects.
- Non-invasive MR and near-infrared (NIR) optical imaging allowed for effective monitoring of nanoparticle delivery and therapeutic responses.
Conclusions:
- IGF-1R targeted nanoparticles loaded with multiple drugs represent a promising strategy for combination therapy in image-guided treatment of stroma-rich, drug-resistant cancers.
- This theranostic approach holds potential for improving treatment outcomes in challenging cancers like pancreatic cancer.
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