奈米碳管結合低電壓電穿孔之藥物釋放平台於癌症治療應用

Abstract

本研究將奈米碳管視為奈米電極，分散於細胞外液中，在施予電壓的情況下，透過奈米碳管良好的導電性以及場致發射能力，可於碳管尖端處放大電場效應，降低電穿孔(electroporation)所需之電壓，有效刺激細胞膜改變其通透性 (electro-permeability)，令小分子與奈米粒子皆能達到高效能傳輸，大量累積於癌細胞與腫瘤。在細胞實驗中，我們證明了奈米碳管結合低電壓能在細胞膜上產生可恢復性(reversible)之孔洞，克服了傳統電穿孔所需之高電壓對細胞所造成不可恢復性(irreversible)孔洞的導致細胞死亡之障礙，增加細胞存活率並使小分子能有效的傳遞。在動物實驗中，我們給予老鼠尾靜脈注射奈米碳管電極液後，於腫瘤位置進行低電壓刺激，有效的增加了血管的通透性，使奈米粒子從血管穿透到癌細胞組織中，增強高滲透長滯留效應 (enhanced permeability and retention effect)。於癌症治療中，我們分別使用了光熱治療與化療兩種癌症療法，其結果顯示皆能有效的達到癌細胞毒殺以及腫瘤抑制之效果。綜合上述，我們證明此藥物傳輸平台不僅可用於傳統電脈衝化療(electro-chemotherapy)，結合奈米碳管的光學性質與熱傳導性，可適用於多樣化的癌症治療中。

Effective delivery of biomolecules or functional nanoparticles into target sites has always been the primary objective for cancer therapy. We demonstrated that by combining single-walled carbon nanotubes (SWNTs) with low-voltage (LV) electrical stimulation, biomolecule delivery can be effectively enhanced through reversible electroporation (EP). Clear pore formation in the cell membrane is observed due to LV (50 V) pulse electrical stimulation amplified by SWNTs. The cell morphology remains intact and high cell viability is retained. This modality of SWNT + LV pulses can effectively transfer both small molecules and macromolecules into cells through reversible EP. This drug delivery system we established could combine with various cancer treatments, such as phototherapy and chemotherapy. The results of animal studies also suggest that treatment with LV pulses alone cannot increase vascular permeability in tumors unless after the injection of SWNTs. The nanoparticles can cross the permeable vasculature, which enhances their accumulation in the tumor tissue. Therefore, in cancer treatment, both SWNT + LV pulse treatment followed by the injection of LIPO-DOX® and SWNT/DOX + LV pulse treatment can increase tumor inhibition and delay tumor growth. This novel treatment modality applied in a human cancer xenograft model can provide a safe and effective therapy using various nanomedicines in cancer treatment.