Dual-Surface Modified Virus Capsids for Targeted Delivery of Photodynamic Agents to Cancer Cells

Abstract

Bacteriophage MS2 was used to construct a targeted, multivalent photodynamic therapy vehicle for the treatment of Jurkat leukemia T cells. The self-assembling spherical virus capsid was modified on the interior surface with up to 180 porphyrins capable of generating cytotoxic singlet oxygen upon illumination. The exterior of the capsid was modified with ∼20 copies of a Jurkat-specific aptamer using an oxidative coupling reaction targeting an unnatural amino acid. The capsids were able to target and selectively kill more than 76% of the Jurkat cells after only 20 min of illumination. Capsids modified with a control DNA strand did not target Jurkat cells, and capsids modified with the aptamer were found to be specific for Jurkat cells over U266 cells (a control B cell line). The doubly modified capsids were also able to kill Jurkat cells selectively even when mixed with erythrocytes, suggesting the possibility of using our system to target blood-borne cancers or other pathogens in the blood supply.

Selective chemical protein modification

“…Indeed, iodoacetamide is used routinely for capping before digestion for protein sequencing 17 . Notably, some derivatives react with N-nucleophiles 18 . However, commercial availability and ease of use and synthesis of maleimide derivatives 13,19 have led to widespread use (for example, vaccine candidates 20 or modified enzymes 21 ) 13 .…”

Virus-like nanoparticles: Emerging Tools for Targeted Cancer Diagnostics and Therapeutics

“…However, rational modification to the exterior of VLNPs aims to use the strength of polyvalent interactions to engineer novel specificity for cell surface receptors. To this end, VLNPs have been functionalized with diverse ligands to tumor-associated targets such as peptides [7], antibodies [8], other proteins such as EGF [9], as well as glycans [10], aptamers [11] and small molecules such as folic acid [12]. These studies and others have shown remarkably efficient and specific in vitro targeting.…”

“…A range of MRI and positron emission tomography agents have also been delivered by VLNPs [17]. Finally, VLNPs have been used to encapsidate high payloads of small molecule therapeutics such as doxorubicin [14], as well as photodynamic agents for light-triggered reactive oxygen generation [10,11].…”

X-ray spatial frequency heterodyne imaging of protein-based nanobubble contrast agents

“…For example, VLPs have been targeted to specific cells including melanoma cells and lymphocytes by attaching antibodies and peptides to their outer surface [20]. They have also been used for the delivery of chemotherapeutic agents such as the anticancer drug doxorubicin [15] and photodynamic agents like singlet oxygen [21], both of which were encapsulated inside the protein cage.…”

“…Protein cage structures such as those mentioned above have been studied for their potential in materials synthesis [7,12], catalysis [13,14], drug and gene delivery [15,16], bio-imaging [17][18][19], cell targeting [20,21], and vaccine development [11]. VLPs in particular are promising, as they exist in a large range of sizes (tens to hundreds of nanometers), have well-defined, monodisperse structures, can be purified in large quantities, and can be easily modified both genetically and chemically [22][23][24][25][26][27].…”