RSC Advances Blog

Frontline therapies for treating colorectal cancer have shortcomings. These include their inability to impede local tumor recurrence and metastatic spread to distant sites such as the abdomen.  

Researchers have now utilized a gene therapy approach that simultaneously compromises cancer cell survival while activating immune system cells with cancer-killing abilities.

Gene therapy – an advanced technique developed to insert or inject therapeutic genes into human cells – has shown some success in treating the disease. In a previous study, Xiao and co-investigators at State Key Laboratory of Biotherapy, and the Department of Thoracic Oncology Cancer Center, West China Hospital, Sichuan University, had used a gene therapy approach to induce cancer cell death. Their study found that Vesicular Stomatitis Virus Matrix Protein (VSVMP), when inserted into a cancer cell,  compromises the cellular skeletal framework, which is made up of structural proteins. Cell death ensued as a consequence.

In the current study, the research team further armed with VSVMP gene delivery vessel with Interleukin-12 (IL-12) – a protein known to recruit and switch on the cancer-killing functions of immune cells.

The novel drug particles are based on Heparin-polyethyleneimine (HPEI) nanoparticles. To overcome the high toxicity and non-biocompatible nature of PEI, the team used a method to covalently conjugate this substance with heparin.

Their results, based on lab-grown cancer cells and animal studies, suggest that this novel complexed drug molecule (particle size: 53nm) increases tumor cell death, reduces division frequency, and stimulates the recruitment and activation of two types of cancer-killing cells: T cells and NK cells.

Specifically, the drug inhibited the growth of C-26 colon cancer cells. Animal studies showed that the drug reduced tumor weight. Metastatic spread of tumor cells to the abdomen was also reduced. The team proposes that the drug-derived IL-12 induces a secondary cascade of chemical mediators, which in turn recruit and activate cancer-killing immune cells. Their data supports this proposal. Interestingly, their study also found that the complexed drug molecule did not show adverse side effects within the major organs.

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Nanoparticles co-delivering pVSVMP and pIL12 for synergistic gene therapy of colon cancer

Yuanyuan Xiao, Yuping Yang, Yujiao Wu, Chunmei Wang, Hao Cheng, Wei Zhao, Yang Li, Beibei Liu, Jianlin Long, Wenhao Guo, Guangping Gaoa and Maling Gou

Monoclonal antibodies (mAbs) are antibodies made by clones of immune cells derived from a common parent cell. These synthesized molecules have achieved widespread clinical utility in the treatment of cancer owing to their high degree of specificity to proteins present on the surface of cancer cells, lower toxicity compared to other classes of targeted therapies, and improved treatment outcomes among patients with advanced stage cancer.

Non-Hodgkin Lymphoma (NHL) is a type of cancer where a subtype of immune cells called B-cells exhibit unrestrained cell division. The abnormal B-cell, now called a malignant B-cell, produces more abnormal cells like it. CD20 is a protein present on the surface of malignant B-cells. Rituximab (RTX) is used to treat patients with NHL because it can bind CD20 and consequently trigger cell death.

To address the growing need for CD20 targeted therapeutics, Cong and colleagues at the Department of Laboratory Diagnosis/Thoracic Surgery, Changhai Hospital Affiliated to The Second Military Medical University, Shanghai, China, developed molecules called aptamers that can bind to CD20 with greater specificity and strength compared to RTX.

Graphical Abstract

Aptamers are molecules made up of  single stranded DNA that form complex 3D structures and can bind to target proteins, analogous to mAbs. The team used a method called cell-SELEX to retrieve an enriched pool of highly specific CD20-binding aptamers starting with their initial aptamer library. The aptamers used in the study were obtained after 15 rounds of selective refinement.

The study finds that Anti-CD20 DNA Aptamer (ACDA) can bind surface CD20 in NHL cells with greater strength compared to RTX. In the past, experiments have shown that cross-linking surface CD20 with mAbs (i.e. extracellular cross-linking) is a potent method of inducing cell death. A major limitation is that extracellular cross-linking cannot be realized in vivo. Cong et al. develop a method to link two ACDA molecules with polyethyleneimine (PEI) linker’, forming a molecular bridge  – the P-ACDA – capable of spanning the distance between and cross-linking two CD20 molecules. The study finds that P-ACDA led to substantially more cell death compared to ACDA.

Aptamers as a novel class of targeted therapies are expected to outperform mAbs because they do not evoke the body’s endogenous immune response (i.e. less immunogenic) and therefore in good compliance with current FDA recommendations. They are also easier to store since they are stable across a broad temperature range ,less expensive to manufacture, show consistency between production batches and can bind to both protein as well as non-protein targets. For these reasons, the clinical relevance of aptamers in treating HNL and potentially other cancers must be watched closely in the years to come.

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Cong Wu, Wei Wan, Ji Zhua, Hai Jina, Tiejun Zhao and Huafei Li