以胜肽為基礎發展之生醫材料具備多樣性的功能及專一性的配體-受體結合能力，已廣泛使用於腫瘤診斷及治療之生醫應用開發。在結締組織增生性(desmoplastic)癌組織細胞間質(stroma)中，癌症微環境是由間質細胞、內皮細胞、細胞因子及胞外基質(extracellular matrix、ECM)等交互作用形成。在非小細胞肺癌及胰腺癌中，與癌細胞互動密切的纖維母細胞(cancer associated fibroblasts)會大量分泌堆積胞外基質於腫瘤組織，並形成膠狀結構屏蔽癌細胞不受外來物質接近。此膠狀結構主要由蛋白及醣胺多醣(glycosaminoglycans、GAGs)組成，大幅限制外來生物材料的腫瘤穿透能力，導致藥物無法堆積於腫瘤組織亦無法穿透至深層癌組織。本研究探討細胞表面及胞外基質的硫酸肝素聚糖(heparan sulfate、HS)及其蛋白聚糖(proteoglycan)作為癌標靶分子標誌之可行性，以一段含有色氨酸的醣胺多醣結合胜肽(GAG binding peptide、GBP)發展標的HS之生醫材料運輸系統。GBP共接合之物質包括同位素、重組蛋白及奈米粒子等，與HS特異性結合後可有效穿透細胞。本研究以GBP修飾阿黴素之微脂體抗癌藥物(liposomal doxorubicin、LipoDox)形成新劑型之GBP鑲嵌之微脂體藥物(GBP-modified LipoDox、LipoDox-GBP)。以人類肺腺癌來源細胞株A549為基礎的試管內(in vitro)研究顯示，LipoDox-GBP能有效增強HS引導之細胞吞噬作用，產生高效率的細胞致死功能；此外，GBP修飾亦優化LipoDox於活體內(in vivo)的藥物分佈及抗癌藥物於腫瘤組織內的穿透能力，大幅提升活體腫瘤模式小鼠的治療效率。總而言之，在高度表現HS的結締組織增生性癌組織中，GBP能有效引導奈米粒子聚積於腫瘤組織並提升組織穿透效率，明顯強化抗癌藥物功能。本研究具體貢獻為成功開發新劑型之GBP鑲嵌型微脂體藥物，透過促進奈米粒子特異性標的硫酸肝素聚糖異常表現癌組織。此新穎策略可應用於奈米粒子標的及穿透腫瘤組織已解決尚未滿足之醫療需求。

Peptide-based biomaterials have been extensively developed for biomedical applications against neoplasma due to their functional versatility and specific ligand-receptor binding activity. Desmoplastic stroma of a malignant tumor constitutes a tumor microenvironment that consists of closely interacting elements including stroma cells, endothelial cells, cytokines, and extracellular matrix (ECM). In the case of non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma, cancer associated fibroblasts elicit aggregation of gel-like ECM to form physical barrier in desmoplastic stroma of the tumor. These stroma composes of protein network and glycosaminoglycans (GAGs) that greatly compromise tumor-penetrating performance, leading to insufficient extravasation and tissue penetration of biomaterials. Interestingly, the presence of heparan sulfate (HS) and related proteoglycans on the cell surface and tumor ECM may serve as molecular targets for HS-mediated drug delivery. In this study a tryptophan-containing GAG binding peptide (GBP) with high affinity to HS and high cell penetrating activity was used to develop a HS-targeting delivery to shuttle isotope, protein, as well as nanoparticles. Specifically, liposomal doxorubicin (LipoDox) is modified by post-insertion with GBP. Interestingly, in vitro uptake of LipoDox in lung adenocarcinoma cells A549 is increased by GBP modification. Cellular uptake of GBP-modified LipoDox (LipoDox-GBP) is diminished in the presence of extracellular HS, but not chondroitin sulfate or hyaluronic acid, indicating that the interaction with HS is critical for the cell surface binding of LipoDox-GBP. Cytotoxicity of doxorubicin positively correlates with the molecular composition of GBP. Moreover, GBP modification improves in vivo distribution and anti-cancer efficiency of LipoDox, with enhanced desmoplastic targeting and interstitial transport activities. Taken together, we have discovered that GBP modification may largely improve tissue penetration and delivery of NP against HS-abundant desmoplastic stroma associated neoplasm, which in turn many contribute to novel drug design and formulation to fulfill unmet medical need.

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