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Published on: June 13, 2014
Structurally Dynamic Polyplexes Enhance Sentinel Lymph Node Delivery of Antisense Oligonucleotides to Inhibit Breast
Chun Yin Jerry Lau1, Hiroaki Kinoh2, Xueying Liu2
1Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Abstract:
Sentinel lymph nodes (SLNs), the first tumor-draining lymph nodes, play a prominent role in tumor progression. Cytotoxic CD8+ T cells in the SLN are typically suppressed in advanced cancer but, when rejuvenated, can slow cancer progression. Here, we demonstrated a molecular approach to engineering a dynamic polyplex, predominantly comprising two poly(ethylene glycol)-(glycine-lysine)10 [PEG-(GK)10] per antisense oligonucleotide (ASO) based on charge neutralization at a minimum molecular ratio, that can enhance SLN functional delivery of ASOs for replenishing immunity against breast cancer recurrence and metastasis. Using a murine breast cancer model, we successfully enriched the ASO distribution in the SLN while limiting off-target organ distribution by tuning the size of the PEG (3-80 kDa). Moreover, we obtained a less compact polyplex using conserved glycine-lysine repeats as cationic segments instead of conventional lysine repeats, resulting in improved structural dynamics and better target gene silencing efficiency in SLN. Polyplex with the optimized PEG size and dynamics was subsequently utilized to develop a regimen to deplete the transforming growth factor-β1 (TGF-β1) level in the SLN. Consequently, we successfully rejuvenated the depleted CD8+ T cells in the SLNs, corresponding to reduced postoperative tumor relapse and lung metastasis. Our findings provide a molecular rationale to enable a simple but robust TGF-β1 ASO therapeutic regimen for managing advanced breast cancer.
Insights
This study engineered a dynamic polyplex for targeted delivery of antisense oligonucleotides (ASOs) to sentinel lymph nodes, rejuvenating CD8+ T cells and reducing breast cancer recurrence and metastasis.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
- Drug Delivery
Background:
- Sentinel lymph nodes (SLNs) are critical in tumor progression, and CD8+ T cells within them are often suppressed in advanced cancer.
- Rejuvenating these T cells can potentially slow cancer progression, offering a therapeutic target for breast cancer recurrence and metastasis.
Purpose of the Study:
- To develop a molecular approach for enhancing the functional delivery of antisense oligonucleotides (ASOs) to SLNs.
- To engineer a dynamic polyplex system for targeted delivery and improved gene silencing in SLNs.
- To investigate the potential of this system in rejuvenating CD8+ T cells and reducing breast cancer relapse and metastasis.
Main Methods:
- Engineered a dynamic polyplex using poly(ethylene glycol)-(glycine-lysine)10 [PEG-(GK)10] and antisense oligonucleotides (ASOs).
- Tuned polyplex size by varying PEG size (3-80 kDa) to optimize SLN distribution and limit off-target organ distribution in a murine breast cancer model.
- Utilized conserved glycine-lysine repeats for improved polyplex dynamics and target gene silencing efficiency.
Main Results:
- Achieved enriched ASO distribution in SLNs with minimal off-target organ distribution.
- Demonstrated improved structural dynamics and enhanced target gene silencing efficiency in SLNs using the engineered polyplex.
- Successfully depleted transforming growth factor-β1 (TGF-β1) levels in SLNs, leading to rejuvenated CD8+ T cells, reduced tumor relapse, and decreased lung metastasis.
Conclusions:
- Developed a novel dynamic polyplex for effective ASO delivery to SLNs, enhancing anti-tumor immunity.
- This approach successfully rejuvenated CD8+ T cells by targeting TGF-β1 in SLNs, offering a promising strategy for managing advanced breast cancer.
- The findings provide a molecular rationale for a robust TGF-β1 ASO therapeutic regimen to combat breast cancer recurrence and metastasis.
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