GPSナノ粒子プラットフォームががん細胞に治療ペイロードを正確に送達(GPS nanoparticle platform precisely delivers therapeutic payload to cancer cells)


2024-03-11 ペンシルベニア州立大学(PennState)

ペンシルバニア州立大学の研究者らが開発した新しい「GPSナノ粒子」は、静脈内投与され、がん細胞にホーミングし、腫瘍の成長と拡がりに関与するタンパク質に遺伝子的なパンチを届けることができると報告されています。彼らはこのアプローチを、人間の細胞株とマウスでテストし、難治性の基底様乳がんに対するより正確で効果的な治療法を提供する可能性があると報告しました。この研究成果は、「ACS Nano」誌に掲載され、同研究で使用された技術に関する特許の申請も行われました。


合成双性イオン性リン脂質から誘導された文脈応答性ナノ粒子が基底様乳がんの標的CRISPR/Cas9療法に応用される Context-Responsive Nanoparticle Derived from Synthetic Zwitterionic Ionizable Phospholipids in Targeted CRISPR/Cas9 Therapy for Basal-like Breast Cancer

Parikshit Moitra, David Skrodzki, Matthew Molinaro, Nivetha Gunaseelan, Dinabandhu Sar, Teresa Aditya, Dipendra Dahal, Priyanka Ray, and Dipanjan Pan
ACS Nano  Published:March 11, 2024


Abstract Image

The majority of triple negative breast cancers (TNBCs) are basal-like breast cancers (BLBCs), which tend to be more aggressive, proliferate rapidly, and have poor clinical outcomes. A key prognostic biomarker and regulator of BLBC is the Forkhead box C1 (FOXC1) transcription factor. However, because of its functional placement inside the cell nucleus and its structural similarity with other related proteins, targeting FOXC1 for therapeutic benefit, particularly for BLBC, continues to be difficult. We envision targeted nonviral delivery of CRISPR/Cas9 plasmid toward the efficacious knockdown of FOXC1. Keeping in mind the challenges associated with the use of CRISPR/Cas9 in vivo, including off-targeting modifications, and effective release of the cargo, a nanoparticle with context responsive properties can be designed for efficient targeted delivery of CRISPR/Cas9 plasmid. Consequently, we have designed, synthesized, and characterized a zwitterionic amino phospholipid-derived transfecting nanoparticle for delivery of CRISPR/Cas9. The construct becomes positively charged only at low pH, which encourages membrane instability and makes it easier for nanoparticles to exit endosomes. This has enabled effective in vitro and in vivo downregulation of protein expression and genome editing. Following this, we have used EpCAM aptamer to make the system targeted toward BLBC cell lines and to reduce its off-target toxicity. The in vivo efficacy, biodistribution, preliminary pharmacokinetics, and biosafety of the optimized targeted CRISPR nanoplatform is then validated in a rodent xenograft model. Overall, we have attempted to knockout the proto-oncogenic FOXC1 expression in BLBC cases by efficient delivery of CRISPR effectors via a context-responsive nanoparticle delivery system derived from a designer lipid derivative. We believe that the nonviral approach for in vitro and in vivo delivery of CRISPR/Cas9 targeted toward FOXC1, studied herein, will greatly emphasize the therapeutic regimen for BLBC.