Virus Like Particles: A Self-Assembled Toolbox for Cancer Therapy

Nanoparticle-based therapeutics have been applied in a broad range of clinical and pre-clinical applications from diagnosis to treatment for cancer. A wide range of synthetic and naturally occurring materials such as polymers, metal oxides, silicate, liposomes, and carbon nanotubes have been developed to overcome key barriers in small molecule therapeutics including intracellular trafficking, cell/tissue targeting, poor biodistribution, and low efficiency. Virus like particles (VLPs)—engineered and non-infectious self-assembling systems based on viral nanostructures—are new approach toward overcoming these limitations, as they are a protein-based nanomaterial that closely mimics the highly symmetrical and polyvalent conformation of viruses while lacking the viral genomes. Their innate biocompatibility, biodegradability, monodispersity, mild immunogenicity, and safety combined with the capacity to chemically modify the interior and exterior surfaces of these systems offer scientists a highly customizable tool to design and engineer multi-component therapeutic agents. In this review, we discuss how these systems have been used in a wide array of cancer treatments including phototherapy, immunotherapy, gene therapy, and chemotherapy

Supramolecular and Biomacromolecular Enhancement of Metal-Free Magnetic Resonance Imaging Contrast Agents

Many contrast agents for magnetic resonance imaging are based on gadolinium, however side effects limit their use in some patients. Organic radical contrast agents (ORCAs) are potential alternatives, but are reduced rapidly in physiological conditions and have low relaxivities as single molecule contrast agents. Herein, we use a supramolecular strategy where cucurbit[8]uril binds with nanomolar affinities to ORCAs and protects them against biological reductants to create a stable radical in vivo. We further over came the weak contrast by conjugating this complex on the surface of a self-assembled biomacromolecule derived from the tobacco mosaic virus.</div

Zeolitic Imidazolate Framework Nanoencapsulation of CpG for Stabilization and Enhancement of Immunoadjuvancy

Metal-organic frameworks (MOFs) have been used to improve vaccine formulations by stabilizing proteins and protecting them against thermal degradation. This has led to increased 2 immunogenicity of these proteinaceous therapeutics. In this work we show that MOFs can also be used to protect the ssDNA oligomer, CpG, to increase its immunoadjuvancy. By encapsulating phosphodiester CpG in the zinc-based MOF, ZIF-8, the DNA oligomer is protected from nuclease degradation and exhibits improved cellular uptake. As a result, we have been able to achieve drastically enhanced B-cell activation in splenocyte cultures comparable to the current state-of-the-art, phosphorothioate CpG. Furthermore, we have made a direct comparison of micro- and nano-sized MOF for the optimization of particulate delivery of immunoadjuvants to maximize immune activation

PhotothermalPhage: A Virus-Based Photothermal Therapeutic Agent

ABSTRACT: Virus-like particles (VLPs) are multifunctional nanocarriers that mimic the architecture of viruses. They can serve as a safe platform for specific functionalization and immunization, which provides benefits in a wide range of biomedical applications. In this work, a new generation immunophotothermal agent is developed that adjuvants photothermal ablation using a chemically modified VLP called bacteriophage Qβ. The design is based on the conjugation of near-infrared absorbing croconium dyes to lysine residues located on the surface of Qβ, which turns it to a powerful NIR-absorber called Photothermal Phage. This system can generate more heat upon 808 nm NIR laser radiation than free dye and possesses a photothermal efficiency comparable to gold nanostructures, yet it is biodegradable and acts as an immunoadjuvant combined with the heat it produces. The synergistic combination of thermal ablation with the mild immunogenicity of the VLP leads to effective suppression of primary tumors, reduced lung metastasis, and increased survival time

A Scalable Synthesis of Adjuvanting Antigen Depots Based on Met-al-Organic Frameworks

Vaccines have saved countless lives by preventing and even irradicating infectious diseases. Commonly used subunit vaccines comprising one or multiple recombinant proteins isolated from a pathogen demonstrate a better safety profile than live or attenuated vaccines. However, the immunogenicity of these vaccines is weak, and therefore, subunit vaccines require a series of doses to achieve sufficient immunity against the pathogen. Here, we show that the biomimetic mineralization of the inert model antigen, ovalbumin (OVA), in zeolitic imidazolate framework-8 (ZIF-8) significantly improves the humoral immune response over three bolus doses of OVA (OVA 3×). Encapsulation of OVA in ZIF-8 (OVA@ZIF) demonstrated higher serum antibody titers against OVA than OVA 3×. OVA@ZIF vaccinated mice displayed higher populations of germinal center (GC) B cells and IgG1+ GC B cells as opposed to OVA 3×, indicative of class-switching recombination. We show that the mechanism of this phenomenon is at least partly owed to the metalloimmunological effects of the zinc metal as well as the sustained release of OVA from the ZIF-8 composite. The system acts as an antigen reservoir for antigen-presenting cells to traffic into the draining lymph node, enhancing the humoral response. Lastly, our model system OVA@ZIF is produced quickly at the gram scale in a laboratory setting, sufficient for up to 20,000 vaccine doses

Carrier Gas Triggered Controlled Biolistic Delivery of DNA and Protein Therapeutics from Metal-Organic Frameworks

Abstract: The efficacy and specificity of protein, DNA, and RNA-based drugs have made them popular in the clinic; however, their susceptibility to environmental stressors adds significant challenges to formulating biomacromolecules into delivery systems where the kinetics of release can be tuned. Further, these drugs are often delivered via injection, which requires skilled medical personnel and produces biohazardous waste. Here, we report an approach that allows for the controlled delivery of DNA and protein therapeutics to allow for either burst or slow-release kinetics without altering the formulation; further, we show we can deliver these materials into the tissues of very different organisms without the use of needles. We show that biomaterials encapsulated within the highly porous metal-organic Framework ZIF-8 are stable as a powder formulation that can be shot into tissue with a low-cost gas-powered “MOF-Jet” for direct delivery into living tissues of plants and animals and the release of the biomaterials can be controlled by judiciously choosing the compressed gas used in the gun. Many MOFs, including ZIF-8, are acid labile and readily dissolve at low pH. When CO2 is used as the carrier gas to shoot MOFs into moist tissue, we show that we can create a transient and weakly acidic local environment that causes the near-instantaneous release of the biomolecules. Conversely, when air is used, the MOF is delivered into tissue and degrades slowly over a week, releasing biomolecules. This innovation represents the first example of biolistic-mediated controlled delivery of biomolecules with ZIF-8 and provides a powerful tool for fundamental and applied plant and animal sciences research