TTFields-TTONIC：将肿瘤电场治疗与靶向化疗协同用于肺癌

Tumor Treating Fields (TTFields) represent a clinically established, safe, and non-invasive cancer therapy. The USFDA has approved TTFields in combination with docetaxel or immune checkpoint inhibitors for patients with metastatic non-small cell lung cancer (NSCLC). TTFields deliver low to intermediate frequency (100-500 kHz) alternating electric fields that disrupt mitosis by interfering with highly polar or charged macromolecules, which are essential for cell division. Although TTFields are generally well tolerated, their clinical application in combination with systemic chemotherapy can result in non-site specific drug induced toxicities, limiting patient compliance, adherence, and therapeutic benefit.To address this limitation, we developed a novel strategy, ‘Treating Fields Triggered Targeting of Nanoparticles in Cancer (TTFields-TTONIC)'. The strategy integrates TTFields with specialized chemotherapeutic nanoparticles for tumor targeted drug delivery. Specifically, for this, we designed and engineered self-assembling cationic-anionic polymer nanoparticles (S-CAP NPs) encapsulating chemotherapeutic drugs. These NPs are expected to accumulate preferentially in tumors due to their leaky vasculature. Upon TTFields exposure, the high charge density of the cationic and anionic polymers destabilizes the nanoparticle structure, triggering controlled drug release at the tumor site and minimizing off target toxicity. Our earlier studies on gemcitabine and paclitaxel S-CAP NPs have shown synergistic and targeted treatment efficacy in the pancreatic cancer model. In this investigation, we developed docetaxel-loaded S-CAP NPs for targeted NSCLC treatment. Docetaxel loaded S-CAP NPs were formulated using cationic polyethylenimine (PEI) and anionic bovine serum albumin (BSA) polymer and were optimized in accordance with the QbD approach. The optimized formulation exhibited a mean particle size of 228.59 ± 19.34 nm, a polydispersity index of 0.122, an encapsulation efficiency of 61.38 ± 4.73%, and a positive zeta potential of 18.27 ± 3.78 mV. The in vitro drug release studies with the developed S-CAP NPs exhibited a sustained drug release over 72 hours. Furthermore, the formulation was observed to be stable for up to 12 months, as per ICH guidelines. In vitro cytotoxicity assays performed to compare the anticancer efficacy of docetaxel PEI-BSA S-CAP NPs in multiple NSCLC cell lines (A549 and PC9). The studies demonstrated a significant enhancement in anticancer efficacy with combination of docetaxel PEI-BSA S-CAP NPs with TFields compared to nanoparticle treatment alone (A549: P < 0.001; PC9: P < 0.0001). Further, the efficacy was corroborated with in vitro colony formation assay that showed significant inhibition of colony formation with docetaxel PEI-BSA S-CAP NPs in the presence of TTFields compared with treatment without TTFields (A549: P < 0.0001; PC9: P < 0.0001).Overall, TTFields-TTONIC represents a promising strategy to enhance the safety and therapeutic efficacy of TTFields and chemotherapy combination treatments for lung cancer, further establishing TTFields as a novel external stimulus for targeted nanoparticle drug delivery.The equipment used for this research was provided by the AACR-Novocure Tumor Treating Fields Research Fellowship (2019-2021). The Chat-GPT tool was used for English grammar correction.