Next-Generation Imaging and Drug-Delivery System with a Mucosal Capsid Platform

Naresh N Dhanasekar and R Holland Cheng^*
*Correspondence: R Holland Cheng, Department of Molecular and Cellular Biology, University of California, Davis, USA, Email:

About the Study

The development of smart carriers for drug delivery has significantly benefited from recent developments in nanotechnology. In particular, Virus-Like Particles (VLP) have gained tremendous attention for offering a variable framework for drug encapsulation [1]. Besides drug delivery, VLPs contribute to many applications, including gene therapy, vaccine development, theranostic agents, cancer treatment, and Positron Emission Tomography (PET) imaging [2-6]. VLPs are simple protein capsids whose structure is engineered to void the typical viral genome for viral replication. Similarly, the design of Hepatitis E Nanoparticles (HEVNP) conjugated with the positron-emitting radionuclide ⁶⁸Ga (Gallium) could enable targeted delivery of drugs and enhanced diagnostic capabilities through PET imaging. By utilizing the unique properties of ⁶⁸Ga-conjugated HEVNP, this research aims to develop a various platform for targeted drug delivery and improved diagnostics, potentially significantly impacting the management of various diseases.

As reported in molecular pharmaceutics, Lambidis and colleagues have taken a critical step in utilizing HEVNP as liver-specific vehicles [6]. The cush feature makes them harmless and biocompatible under physiological conditions, where HEVNP contributed significantly to the field of theranostics and drug delivery [7]. Additionally, the epitome destruction of the engineered viral particles was less identified by the floating antibodies against viral capsids and the pharmaceutical industry utilized the phenomenal behavior of HEVNP in the production of vaccines [8]. Replacing traditional diagnostic radionuclides with alternative isotopes that emit different types of radiation can convert imaging tracers into potent and targeted molecular therapies. In this context, developing a ⁶⁸ Ga-conjugated HEVNP holds promise for targeted drug delivery and diagnostic applications using PET. The authors used the chemical stability of the HEVNP to be visualized ex vivo through PET. To be used as a liver carrier, the authors initially modified the surface of HEVNP with (⁶⁸Ga)-Dodecane Tetra Acetic Acid (DOTA) through covalent bond formation between the primary amine of the amino acid lysine and the NHS ester of the DOTA molecule. The structural properties of the HEVNP were not altered, as the authors confirmed them through cryo-electron microscopy assessment. To further throw light on the radioactivity of the modified HEVNP, the authors purified complex particle, (⁶⁸Ga)-DOTA–HEVNP, exhibited a higher radiolabeled yield of ~98% as compared to native HEVNP with only 0.2%. 

Understanding the challenge underlying in vivo conditions, the authors performed ex vivo protocol to demonstrate the uptake of gallium-modified HEVNP through intravenous administration in healthy mice [9]. Ex vivo experiments revealed HEVNPs are superior to other VLPs in their absorption by the liver (~97% ID/g) followed by spleen (~18% ID/g) than the pancreas, kidney, lung, heart, stomach, and intestinal regions. Furthermore, in vitro experiments with cell lines specific for macrophages (RAW 264.7) and Hepatocytes (Hep G2) revealed higher uptake of HEVNP, which was strongly associated with clathrin-mediated endocytosis. Clathirin-mediated endocytosis is a significant biological process adopted by cancer cells for internalization. Further, to prove this effect of HEVNP in cancer cells, the authors used colorectal cancer cell lines, HCT116 for their internalization experiments [10-12]. HCT116 cells adopted a step-wise gradient absorption of HEVNP from <1% to >6% within a short period, thus confirming the internalization property of HEVNP.

Molecular imaging has emerged as a powerful tool for the noninvasive visualization and quantification of biological processes at the cellular and molecular levels [13]. Radionuclide imaging techniques like PET have become increasingly valuable in drug development [14]. Improvements in surface modification with different chemical/physical strategies are of great value to investigate. Such modifications could lead to the delivery of several drugs attached to a single HEVNP. The creation of such stable drug delivery vehicles could orchestrate drug delivery or be expensive and tedious to perform in vivo. While organic and inorganic-based nanoparticles have potential toxicological concerns, HEVNP, being biocompatible, overcomes such limitations to exhibit little or no physiological concern with noninvasive mucosa-homing attributes [12]. Further, implementing a water-borne viral capsid demonstrates how HEVNP could lead to noninvasive means of diagnosis and therapeutics. These methods enable quantifying radiolabeled pharmaceutical formulations' in vivo distribution and kinetics, allowing for a direct correlation between pharmacological effects and the precise drug delivery site. Further advances in nuclear medicine have expanded the range of molecular radiotherapies, enabling the application of targeted treatments across a broad spectrum of diseases with the recently added HEVNP platforms, as demonstrated by Lambidis and colleagues [6,9,11,15].

Acknowledgement

Juselius Foundation, National Institute of Health (TR002866, CA198880, CA225266, and EB021230), National Institute Food Agricul-ture (nos. CADMCB-7399-H), FiDiPro, and University of California (UC) Science Translation and Innovative Research (STAIR) programs.

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