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US-12622983-B2 - Tumor-targeting, clearable human protein-based MRI nanoprobes, and compositions and methods thereof

US12622983B2US 12622983 B2US12622983 B2US 12622983B2US-12622983-B2

Abstract

The invention provides a novel class of clearable, tumor-targeting and human protein-based MRI nanoprobes and contrast agents and their compositions, and methods of preparation and use thereof.

Inventors

  • Gang Han
  • Yang Zhao

Assignees

  • UNIVERSITY OF MASSACHUSETTS

Dates

Publication Date
20260512
Application Date
20220502

Claims (8)

  1. 1 . A contrast agent for magnetic resonance imaging (MRI) comprising nanoparticles having a median size from about 5 nm to about 20 nm, wherein the nanoparticles consist of a human transferrin (Tf) protein having a tertiary structure and a gadolinium mineral deposited within said tertiary structure, wherein the gadolinium mineral is one or more selected from Gd 2 O 3 , GdOOH, GdN, GdPO 4 , Gd(C 2 O 4 ), GdF 3 and Gd 2 (CO 3 ) 3 .
  2. 2 . The contrast agent of claim 1 , wherein the human transferrin (Tf) protein is biocompatible.
  3. 3 . The contrast agent of claim 2 , wherein the human transferrin (Tf) protein is tumor-targeting.
  4. 4 . The contrast agent of claim 3 , wherein the human transferrin (Tf) protein is body-clearable.
  5. 5 . The contrast agent of claim 1 , wherein the nanoparticles have a median size about 9 nm.
  6. 6 . A composition comprising the contrast agent of claim 1 .
  7. 7 . The contrast agent of claim 1 , wherein the gadolinium mineral is Gd 2 O 3 .
  8. 8 . The composition of claim 6 , wherein the gadolinium mineral is Gd 2 O 3 .

Description

PRIORITY CLAIMS AND RELATED APPLICATIONS This application is a divisional of U.S. Ser. No. 16/608,837, filed Oct. 27, 2019, which is the U.S. national phase of and claims priority to PCT/US18/33071, filed May 17, 2018, which claims the benefit of priority from U.S. Provisional Application Ser. No. 62/508,417, filed on May 19, 2017, the entire content of each of which is incorporated herein by reference. TECHNICAL FIELDS OF THE INVENTION The invention generally relates to diagnostics and MRI contrast agents. More particularly, the invention relates to a novel class of clearable, tumor-targeting and human protein-based MRI nanoprobes and contrast agents and their compositions, and methods of preparation and use thereof. BACKGROUND OF THE INVENTION Magnetic resonance imaging (MRI), a medical imaging technique used in radiology, is one of the most used non-invasive and versatile imaging modalities for clinical detection, staging, and monitoring treatment of tumors. MRI affords unique advantages, for example, high spatial resolution, outstanding soft tissue contrast, and no radiation damage. MRI, however, often encounters an inherent shortage of low sensitivity since there is little difference between normal and abnormal soft tissues in relaxation time and the resulting contrast. To overcome this drawback, materials that possess magnetic properties, namely MRI contrast agents (MRI-CAs), have been used to enhance imaging quality and signal contrast of MRI. As reported, more than 40% of all MRI examinations utilize a contrast agent. Development of magnetic contrast agents (CAs) has improved the inherent sensitivity of MRI, enabling this technique to visualize specific biological processes at both cellular and molecular levels. (Sun, et al. 2008 Adv. Drug Delivery Rev. 60, (11), 1252-65; Zhang, et al. 2016 Nanoscale 8, (20), 10491-510.) Currently, the most frequently used magnetic CAs in clinical settings are Gd-based chelates due to their signal-enhancing positive contrast ability and negligible immunogenicity. Such Gd-based compounds, however, often suffer from short life spans, relatively low relaxivity, and the consequent need for high doses of intravenous administration, as well as the problematic gadolinium retention within vital organs. (Caravan, et al. 1999 Chem Rev. 99, (9), 2293-352; Na, et al. 2009 J. Mater. Chem. 19, (35), 6267; McDonald, et al. 2015 J. Radiology 275, (3), 772-82; Tu, et al. 2012 Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 4, (4), 448-57.) To overcome these drawbacks, inorganic based Gd-containing nanoparticles, for examples, gadolinium oxide, gadolinium fluoride, and gadolinium phosphate, have been explored in attempts to enhance MR imaging quality. While such nanoparticles enjoy large longitudinal relaxation, enhanced sensitivity, prolonged circulating time and facile chemical modifications, their long-term stability, biocompatibility and clearance remain largely unclear, hindering their further biomedical applications. (Zhang, et al. 2016 Nanoscale 8, (20), 10491-510; McDonald, et al. 2015 J. Radiology 275, (3), 772-82; Longmire, et al. 2008 Nanomedicine (Lond). 3, (5), 703-717; Chen, et al. 2014 Small 10, (18):3603-11.) Therefore, the development of nontoxic, biocompatible and effective MRI-CAs plays an important role in expanding and improving MRI clinical applications. It remains challenging and highly desirable to develop a biocompatible tumor-targeting, as well as systemically clearable and more efficient Gd-based nanoparticle MRI CAs. SUMMARY OF THE INVENTION The invention provides a novel class of MRI CAs that, not only possess superior paramagnetic properties compared to conventional Gd-based contrast agents, but also exhibit excellent biocompatibility, negligible immunogenicity, and outstanding tumor-targeting and body-clearable abilities. The invention offers a new approach to biocompatible multifunctional MRI contrast agents useful for a wide range of clinical imaging and treatment applications. Biocompatibility, targeting, and clearance are key challenges in the design of new MRI contrast agents. The invention provides a tumor-targeting, gadolinium biomineralized human transferrin (Tf) protein-based nanoparticle (Gd@Tf NP) for MRI use. As compared to the conventionally used gadolinium chelates, the Gd@Tf NPs disclosed herein possess outstanding chemical stability and exhibited superior longitudinal relaxation. As demonstrated herein, Gd@Tf retains the natural tumor targeting ability and the subsequent tumor retrieval biofunctions of Tf. Thus, the Tf protein-based MR NPs integrate T1 signal amplification, precise tumor targeting, and systematic clearance capabilities. In one aspect, the invention generally relates to a nanoparticle comprising a human transferrin protein and a gadolinium mineral. In another aspect, the invention generally relates to a composition including the nanoparticles disclosed herein. In yet another aspect, the invention generally relates to a