A Theranostic Heptamethine-Feraheme Nanoparticle for the Dual Fluorescent and MRI Detection of Tumors and Drug Delivery

The standard of care for solid tumor cancers is to have patients undergo surgery, followed by chemotherapy. This typically minimizes metastasis and increases patient survival. During surgery, surgeons utilize visual and tactile methods to distinguish between cancerous and non-cancerous tissue, but due to the proximity of some cancers to vital organs, surgeons are limited in how much additional tissue they can remove. Previous methods to address this involve pre-operatively visualizing cancer tissues using X ray computed tomography, positron emission tomography, magnetic resonance imaging (MRI), and ultrasound to visualize and identify the cancerous tissues. However, these techniques cannot be utilized while in surgery to precisely identify the tumor’s margins in real time. Therefore, there is an unmet need for the development of a real-time imaging modality that can identify cancer tissues during surgery to aid in the removal of cancerous tissue, thus reducing the need for subsequent systemic chemotherapy treatment.

The inventors, led by Dr. Perez, developed a novel theranostic fluorescent nanoparticle that can visualize prostate cancers and glioblastomas via MRI or real-time fluorescent visualization during surgery and can be utilized as a therapeutic through the conjugation of chemotherapy medications. These nanoparticles are a conjugation of a heptamethine dye, which is readily taken up by cancer cells, to ferumoxytol, an iron oxide nanoparticle that has been FDA authorized for the treatment of anemia. After administering the nanoparticle, surgeons can use fluorescence-guided surgery to outline the tumor’s location, increasing the likelihood that cancerous tissue is removed. The nanoparticles can also be loaded with chemotherapy therapeutics, such as docetaxel, Brefeldin A, and cabozantinib. These conjugated medications are better at reducing tumor size in mouse models compared to the drugs by themselves. Additionally, the nanoparticle has been demonstrated to be able to transport past the blood brain barrier in mouse models and treat glioblastomas. Due to the way heptamethine is attracted to cancer cells, the invention can be applied to other cancers, such as brain, liver, colon, breast, leukemia, pancreatic, ovarian, head and neck, skin, and lung.

Figure 1. (A) A representative xerograft mouse model shown under near infrared fluorescence showing the localization of the nanoparticle to cancer tissue. (B) Average tumor growth of mice containing subcutaneous 22Rv1 prostate tumors with three different treatments: Phosphate-buffered saline (PBS), docetaxel (DXT), and nanoparticles loaded with docetaxel (HMC-FMX(DXT)). (C) Mice bearing subcutaneous 22Rv1 and PC3 prostate cancer tumors 72 hours after injection with heptamethine-ferumoxytol nanoparticle (HMC-FMX). Images show near infrared fluorescence detection of tumors alongside other excised organs.

Figure 2. (A) Heptamethine-ferumoxytol (HMC-FMX) nanoparticle accumulates in human glioblastoma tumors in mice and remains in cancer tumors for over 168 hours. (B) Mock fluorescence image-guided surgery to remove GBM tumors after 24 hours.

Website

https://cedars.flintbox.com/technologies/AFE62404076B494DB1437B99F1FA3E80

Advantages

The nanoparticles can be:

  • Utilized as either a diagnostic and/or as a therapeutic
  • Administered pre-surgery to identify tumors via MRI and for surgical procedures for the direct visualization of cancer cells
  • Combined with chemotherapy drugs to help to eliminate any cancer tissues that are not able to be removed during the surgical procedure

Potential Applications

  • Treatment for prostate cancer and glioblastomas
  • Real-time imaging of cancers during surgery
  • Theranostic option for other cancers (e.g.; brain, liver, colon, breast, leukemia, pancreatic, ovarian, head and neck, skin, and lung.)

Contact Information

Name: Alexandra Mendoza

Email: Alexandra.Mendoza@cshs.org

Phone: 310.423.0326