Cancer Theranostic Applications of Albumin-Coated Tobacco Mosaic Virus Nanoparticles

Abstract

Nanotechnology holds great promise in cancer drug delivery, and of particular interest are theranostic approaches in which drug delivery and imaging are integrated. In this work, we studied and developed the plant virus tobacco mosaic virus (TMV) as a platform nanotechnology for drug delivery and imaging. Specifically, a serum albumin (SA)-coated TMV formulation was produced. The SA coating fulfils two functions: SA provides a stealth coating for enhanced biocompatibility; it also acts as a targeting ligand enabling efficient tumor accumulation of SA-TMV versus TMV in mouse models of breast and prostate cancer. We demonstrate drug delivery of the chemotherapy doxorubicin (DOX); TMV-delivered DOX outperformed free DOX, resulting in significant delayed tumor growth and increased survival. Furthermore, we demonstrated the ability of SA-coated TMV loaded with chelated Gd(DOTA) for magnetic resonance imaging detection of tumors. In the future, we envision the application of such probes as theranostic, where first imaging is performed to assess whether the nanoparticles are effective at targeting a particular patient tumor. If targeting is confirmed, the therapeutic would be added and treatment can begin. The combination of imaging and therapy would allow to monitor disease progression and therefore inform about the effectiveness of the drug delivery approach.

Plant molecular farming of virus‐like nanoparticles as vaccines and reagents

“…Plant virus particles or virions are possibly among the simplest VNPs available. They can often be propagated at very large scale, in easy‐to‐cultivate plants; yields can be very high—TMV, for example, can yield ~4 g/kg wet weight of tobacco—and purification is often very easy; they are often highly stable, and are excellent scaffolds for chemical modification (Aljabali, Shukla, Lomonossoff, Steinmetz, & Evans, ; Barnhill, Reuther, Ferguson, Dreher, & Wang, ; Bruckman & Steinmetz, ) and for conjugation to other payload molecules such as albumin (Pitek, Hu, Shukla, & Steinmetz, ) or epitopes derived from viruses or other pathogens (Rybicki, ) . These properties have been extensively used to repurpose virion‐derived VNPs as contrast agents (Bruckman et al, , ) and drug delivery vehicles (Bruckman, Czapar, VanMeter, Randolph, & Steinmetz, ; Kernan, Wen, Pitek, & Steinmetz, ; K. L. Lee, Carpenter, Wen, Ghiladi, & Steinmetz, ), topics which will be covered in more detail elsewhere in this issue.…”

Virus‐Like Particles as Theranostic Platforms

“…Therefore, a large number of multifunctional VLPs have been constructed in recent years. The viral capsids of viruses such as CCMV, [ 95,96 ] CPMV, [ 97–99 ] RCNMV, [ 65 ] bacteriophage MS2, [ 100–102 ] bacteriophage M13, [ 103,104 ] TMV, [ 105,106 ] Turnip yellow mosaic virus , [ 107,108 ] Brome mosaic virus (BMV), [ 109 ] Canine parvovirus , [ 110 ] and SV40 [ 26,72,111–113 ] have been used as nanocarriers to entrap contrast agents or drug molecules. These VLPs are particularly useful for targeting contrast agents in vivo for either imaging or drug and theranostic delivery.…”

“…It encapsulated DOX and was loaded with chelated Gd–DOTA for drug delivery to and MRI detection of tumors (Figure 5b). [ 105 ] Pang et al. reported the fabrication of gVLPs that were loaded with epirubicin (EPI), modified with cell‐penetrating peptide (CPP), and labeled with 68Ga–DOTA to form a virus‐like nanotherapeutic agent ( 68 Ga–DOTA‐labeled EPI@CPP‐gVLPs) that could be monitored with PET–fluorescence dual imaging to visualize and treat brain tumors.…”

“…The TMV‐delivered DOX outperformed free DOX in inhibiting tumor growth and increased the survival of mice with breast or prostate cancer. [ 105 ] We also constructed multifunctional SV40 VLPs encapsulating NIR QDs and bearing peptides that targeted atherosclerosis at different stages of the disease (peptides targeting VCAM‐1, macrophages, or fibrin) and the anticoagulant drug hirulog (Figure 5c). These multifunctional SV40 VLPs were used to specifically target the atherosclerosis markers VACM‐1, macrophages, and fibrin to image atherosclerosis at different stages in live apolipoprotein‐E‐deficient (Apoe −/− ) mice and increased the anticoagulant concentration in the plaques.…”

“…Reproduced with permission. [ 105 ] Copyright 2018, American Chemical Society. c) SV40 VLPs encapsulating NIR QDs and bearing atherosclerotic targeting peptides and the anticoagulant drug hirulog for targeted imaging and drug delivery.…”