| 摘要: | 癌症仍是全球主要死因，2022 年新增病例近二千萬、死亡近千萬，傳統手術、放射及小分子化療雖延長患者壽命，卻受全身毒性、耐藥與選擇性不足等侷限。奈米藥物應運而生：藉1–200 nm 載體利用腫瘤「高通透與滯留效應」（EPR）與表面主動標靶，得以提高腫瘤累積、降低脫靶副作用，並結合影像診斷與控釋機制，開啟精準治療新篇章。
在眾多奈米載體中，共軛高分子奈米粒子（polymer dots, Pdots）尤具潛力。其 π-共軛骨架賦予超大光吸收截面與高量子效率，不含重金屬且可經化學修飾接枝配體，兼具高亮度、生物相容與多色成像能力；核心可同時封裝光敏劑或抗癌藥，可望一次滿足追蹤、診斷與治療三合一需求。
然而，傳統批量式奈米沈澱或乳化法製備 Pdots，其粒徑易受注射速率、攪拌剪切強度及溶劑揮發等外在條件干擾，因而呈現寬分佈且批次間重現性差。雖然 PDMS 微流體晶片可提升流體混合效率，卻因有機溶劑易引發膨脹而限制其耐用性；相對地，玻璃／矽基晶片雖具優異化學穩定性，卻因成本高昂且製程週期冗長，難以支援快速迭代與大規模生產。鑑此，本研究擬開發一款兼具耐溶劑性、可量產性與高再現性的微流體平台，以突破現有製備方法之瓶頸。
本研究採用全氟聚醚（Perfluoropolyether）材料-MD700，透過 3D 列印翻模製備出具耐溶劑性且可重複使用之三維流體聚焦微流體平台。藉由調控流速比與通道幾何結構，本平台得以進行高效率奈米沈澱，穩定合成粒徑介於 30–100 nm 之高分子奈米點（Pdots），其顆粒尺寸可透過系統化參數調整進行控製，提升Pdots用於生物領域之專一性與靶向性。為驗證平台的通用性，進一步分別以 PSMA、Triton-X100界面活性劑與殼聚醣進行表面修飾，觀察細胞攝取效能。在 PC-9 肺腺癌細胞試驗中，PSMA 修飾之 Pdots於水中迅速水解為雙羧酸基團，殼聚醣修飾之 Pdots表面帶有正電荷，均能顯著提升 Pdots 之細胞攝取率，而Triton則會破壞細胞膜，對細胞具有顯著毒性。
本平台所建立的系統化製程與表面工程策略，有效克服了長期以來粒徑控制不佳與批次間一致性不足的技術瓶頸，不僅為 Pdots 與光動力治療、影像導航及多模態診療奠定了穩固的製造基礎，也為後續臨床轉譯提供了一條可重複、具成本效益的路徑。
;Cancer remains a leading cause of death, with ~20 million new cases and ~10 million deaths in 2022. Traditional therapies—surgery, radiotherapy and chemotherapy—are limited by systemic toxicity, resistance and poor targeting. Nanomedicines using 1–200 nm carriers exploit the enhanced permeability and retention (EPR) effect and surface ligands to boost tumor accumulation, reduce off-target effects and enable imaging-guided release.
Conjugated polymer dots (Pdots) combine a π-conjugated backbone (for large absorption cross-section and high quantum yield), heavy-metal-free composition and facile ligand grafting, yielding bright, biocompatible probes whose hydrophobic core can co-encapsulate photosensitizers or drugs. However, batch nanoprecipitation/emulsification produces broad size distributions and poor reproducibility due to flow-rate, shear and evaporation variabilities. PDMS chips swell in organic solvents, while glass/silicon devices are costly and slow to iterate.
We developed a reusable, solvent-resistant 3D-printed microfluidic device (MD700 resin) that, by tuning aqueous:organic flow ratios and channel geometry, achieves millisecond-scale nanoprecipitation of uniform 30–100 nm Pdots. Surface functionalization with PSMA or chitosan markedly increased uptake in PC-9 lung cancer cells, whereas Triton X-100 proved cytotoxic. PSMA coatings hydrolyze to dicarboxylates, and chitosan coatings carry positive charge, both enhancing internalization.
This platform overcomes size-control and batch-consistency challenges, offering a scalable, cost-effective route for clinical translation of multifunctional Pdots. |
