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Next-generation viral nanoparticles for targeted delivery of therapeutics: Fundamentals, methods, biomedical applications, and challenges

Tan JS, Jaffar Ali MNB, Gan BK, Tan WS

Expert Opin Drug Deliv, 2023;20(7):955-978.
PMID: 37339432 DOI: 10.1080/17425247.2023.2228202

INTRODUCTION: Viral nanoparticles (VNPs) are virus-based nanocarriers that have been studied extensively and intensively for biomedical applications. However, their clinical translation is relatively low compared to the predominating lipid-based nanoparticles. Therefore, this article describes the fundamentals, challenges, and solutions of the VNP-based platform, which will leverage the development of next-generation VNPs.
AREAS COVERED: Different types of VNPs and their biomedical applications are reviewed comprehensively. Strategies and approaches for cargo loading and targeted delivery of VNPs are examined thoroughly. The latest developments in controlled release of cargoes from VNPs and their mechanisms are highlighted too. The challenges faced by VNPs in biomedical applications are identified, and solutions are provided to overcome them.
EXPERT OPINION: In the development of next-generation VNPs for gene therapy, bioimaging and therapeutic deliveries, focus must be given to reduce their immunogenicity, and increase their stability in the circulatory system. Modular virus-like particles (VLPs) which are produced separately from their cargoes or ligands before all the components are coupled can speed up clinical trials and commercialization. In addition, removal of contaminants from VNPs, cargo delivery across the blood brain barrier (BBB), and targeting of VNPs to organelles intracellularly are challenges that will preoccupy researchers in this decade.
Fulltext Targeted Delivery of Cell Penetrating Peptide Virus-like Nanoparticles to Skin Cancer Cells

Gan BK, Yong CY, Ho KL, Omar AR, Alitheen NB, Tan WS

Sci Rep, 2018 05 31;8(1):8499.
PMID: 29855618 DOI: 10.1038/s41598-018-26749-y

Skin cancer or cutaneous carcinoma, is a pre-eminent global public health problem with no signs of plateauing in its incidence. As the most common treatments for skin cancer, surgical resection inevitably damages a patient's appearance, and chemotherapy has many side effects. Thus, the main aim of this study was to screen for a cell penetrating peptide (CPP) for the development of a targeting vector for skin cancer. In this study, we identified a CPP with the sequence NRPDSAQFWLHH from a phage displayed peptide library. This CPP targeted the human squamous carcinoma A431 cells through an interaction with the epidermal growth factor receptor (EGFr). Methyl-β-cyclodextrin (MβCD) and chlorpromazine hydrochloride (CPZ) inhibited the internalisation of the CPP into the A431 cells, suggesting the peptide entered the cells via clathrin-dependent endocytosis. The CPP displayed on hepatitis B virus-like nanoparticles (VLNPs) via the nanoglue successfully delivered the nanoparticles into A431 cells. The present study demonstrated that the novel CPP can serve as a ligand to target and deliver VLNPs into skin cancer cells.
Fulltext Targeted delivery of 5-fluorouracil-1-acetic acid (5-FA) to cancer cells overexpressing epithelial growth factor receptor (EGFR) using virus-like nanoparticles

Gan BK, Rullah K, Yong CY, Ho KL, Omar AR, Alitheen NB, et al.

Sci Rep, 2020 Oct 08;10(1):16867.
PMID: 33033330 DOI: 10.1038/s41598-020-73967-4

Chemotherapy is widely used in cancer treatments. However, non-specific distribution of chemotherapeutic agents to healthy tissues and normal cells in the human body always leads to adverse side effects and disappointing therapeutic outcomes. Therefore, the main aim of this study was to develop a targeted drug delivery system based on the hepatitis B virus-like nanoparticle (VLNP) for specific delivery of 5-fluorouracil-1-acetic acid (5-FA) to cancer cells expressing epithelial growth factor receptor (EGFR). 5-FA was synthesized from 5-fluorouracil (5-FU), and it was found to be less toxic than the latter in cancer cells expressing different levels of EGFR. The cytotoxicity of 5-FA increased significantly after being conjugated on the VLNP. A cell penetrating peptide (CPP) of EGFR was displayed on the VLNP via the nanoglue concept, for targeted delivery of 5-FA to A431, HT29 and HeLa cells. The results showed that the VLNP displaying the CPP and harboring 5-FA internalized the cancer cells and killed them in an EGFR-dependent manner. This study demonstrated that the VLNP can be used to deliver chemically modified 5-FU derivatives to cancer cells overexpressing EGFR, expanding the applications of the VLNP in targeted delivery of chemotherapeutic agents to cancer cells overexpressing this transmembrane receptor.
Size-selective purification of hepatitis B virus-like particle in flow-through chromatography: Types of ion exchange adsorbent and grafted polymer architecture

Ng HW, Lee MFX, Chua GK, Gan BK, Tan WS, Ooi CW, et al.

J Sep Sci, 2018 May;41(10):2119-2129.
PMID: 29427396 DOI: 10.1002/jssc.201700823

Hepatitis B virus-like particles expressed in Escherichia coli were purified using anion exchange adsorbents grafted with polymer poly(oligo(ethylene glycol) methacrylate) in flow-through chromatography mode. The virus-like particles were selectively excluded, while the relatively smaller sized host cell proteins were absorbed. The exclusion of virus-like particles was governed by the accessibility of binding sites (the size of adsorbents and the charge of grafted dextran chains) as well as the architecture (branch-chain length) of the grafted polymer. The branch-chain length of grafted polymer was altered by changing the type of monomers used. The larger adsorbent (90 μm) had an approximately twofold increase in the flow-through recovery, as compared to the smaller adsorbent (30 μm). Generally, polymer-grafted adsorbents improved the exclusion of the virus-like particles. Overall, the middle branch-chain length polymer grafted on larger adsorbent showed optimal performance at 92% flow-through recovery with a purification factor of 1.53. A comparative study between the adsorbent with dextran grafts and the polymer-grafted adsorbent showed that a better exclusion of virus-like particles was achieved with the absorbent grafted with inert polymer. The grafted polymer was also shown to reduce strong interaction between binding sites and virus-like particles, which preserved the particles' structure.