A combination of LightOn gene expression system and tumor microenvironment-responsive nanoparticle delivery system for targeted breast cancer therapy

Abstract

A light-switchable transgene system called LightOn gene expression system could regulate gene expression with a high on/off ratio under blue light, and have great potential for spatiotemporally controllable gene expression. We developed a nanoparticle drug delivery system (NDDS) to achieve tumor microenvironment-responsive and targeted delivery of diphtheria toxin A (DTA) fragment-encoded plasmids to tumor sites. The expression of DTA was induced by exposure to blue light. Nanoparticles composed of polyethylenimine and vitamin E succinate linked by a disulfide bond, and PEGylated hyaluronic acid modified with RGD peptide, accumulated in tumor tissues and were actively internalized into 4T1 cells via dual targeting to CD44 and α v β 3 receptors. The LightOn gene expression system was able to control target protein expression through regulation of the intensity or duration of blue light exposure. In vitro studies showed that light-induced DTA expression reduced 4T1 cell viability and induced apoptosis. Furthermore, the LightOn gene expression system enabled spatiotemporal control of the expression of DTA in a mouse 4T1 tumor xenograft model, which resulted in excellent antitumor effects, reduced tumor angiogenesis, and no systemic toxicity. The combination of the LightOn gene expression system and NDDS may be an effective strategy for treatment of breast cancer.

Optogenetic Approaches for the Spatiotemporal Control of Signal Transduction Pathways

“…Recently, biodegradable polyethylene glycol diacrylate (PEGDA) linked with DL-dithiothreitol (DTT) could be used to photo induce cell migration and drug release, while being able to have its lifetime adjusted to the desired time frame of the application [ 104 ]. To take advantage of the unique abilities of optogenetics there have been different ideas for a possible application like the control of the blood homeostasis in mice [ 105 ], targeting cancer cells via light for T-cells [ 106 ], gene therapy approaches to tackle breast cancer [ 107 ], adenoviral based therapy to selectively target cancer cells with light and reduce off-target effects [ 108 , 109 ]. Combining therapeutic approaches with optogenetic may result in an improvement of the safety and anti-cancer selectivity, making it a promising addition to existing therapeutic approaches to enhance their effectiveness.…”

The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors

“…This combinatorial therapy has gained popularity in pre-clinical research due to the synergy of specific drugs despite the potential for dosage issues when applied clinically. Alternatively, RGD, PEG and hyaluronic acid tagged polymersomes termed LightOn therapeutics, were successfully loaded with plasma DNA targeted to CD44 receptors [58,59]. Manipulation of LightOn transgene expression was used to modulate gene expression within the breast cancer TME, resulting in highly specific tumor inhibition and negligible off-target toxicity [58].…”

Chemodynamic Therapy Combined with Multifunctional Nanomaterials and Their Applications in Tumor Treatment

“…However, the long-term use of cisplatin [11] can also lead to drug resistance, [12] thereby severely impeding its therapeutic effectiveness and clinical transformation, showing a phenomenon of "drug-resistance". Due to the complexities of the biological barrier in vivo, [13] the present nano-drug delivery system [14] for cancer treatment still has obvious disadvantages such as poor tumor aggregation [15] and low efficacy. [16] Admittedly, chemotherapy is still effective against tumor cells.…”