本研究主要探討以快溶型高分子微針經皮傳輸藥物微粒之可行性，及其應用於皮膚疾病治療之潛力。內容分為polyvinyl alcohol /polyvinyl pyrrolidone (PVA/PVP)微針經皮傳輸poly(D,L-lactide-co-glycolide) (PLGA)奈米粒子之傳遞效率的探討(第一部份)，與玻尿酸微針傳輸結合化療、光熱及光動力治療之polycapro-lactone(PCL)微米粒子，應用於鱗狀細胞癌之治療效果(第二部份)。
在第一部份的研究中，以離心灌模的方式，製備出攜帶Coumarin 6-loaded PLGA奈米粒子之PVA/PVP微針，將粒子集中包覆於微針之前端的金字塔部位，由於PVA與PVP之高度親水性，微針能於穿刺皮膚後的3分鐘內完全溶解。由於支撐軸結構的設計，所開發之微針能克服穿刺時皮膚的凹陷變形，讓微針刺入較深的部位，因此能讓包覆於金字塔部位的PLGA奈米粒子進入大鼠皮膚中。相較於以市售的3MTM 微針，以poke and cream的方式被動傳輸PLGA奈米粒子，僅能讓粒子進入角質層中；以具支撐軸結構的PVA/PVP微針進行傳輸，可將90%的PLGA奈米粒子成功傳遞至表皮與真皮層中。從大鼠的活體穿刺實驗也可觀察到，進入皮膚的PLGA奈米粒子能滯留於穿刺處達5天以上，有機會達到持續釋放藥物於皮膚中的效果，將可應用於深層皮膚疾病之治療。
第二部份的研究則是以具有支撐軸結構的玻尿酸微針，攜帶包覆具光熱與光動力治療特性的光敏物質(IR 780)和化療藥阿黴素(doxoru-bicin;DOX)之PCL微米粒子，應用於鱗狀皮膚癌之治療。利用玻尿酸微針，將含藥微粒傳入皮膚腫瘤處，待微針溶解後，照射近紅外光以驅動治療。IR 780能吸收光能，產生光熱轉換效應，導致粒子升溫，當粒子溫度超過48˚C時，PCL熔化造成分子流動，即可釋出DOX，產生光熱、光動力及化療多重治療的效果。經由體外藥物釋放實驗證實，近紅外光照射可明顯且重覆地驅動DOX由PCL微粒中釋放。與人類鱗狀細胞癌細胞株A431共培養後發現，未照射近紅光的含藥PCL微粒不具有明顯的細胞毒性(細胞存活率達90%)，但若照射近紅外光後，細胞存活率降至約10%，顯示照光後所觸發之光熱、光動力效應及DOX之釋放，確實能引起癌細胞死亡。將含有PCL微粒之玻尿酸微針應用於背部帶有鱗狀皮膚癌之ICR SCID小鼠，於第一天及第十四天分別照射近紅外光三分鐘，結果顯示，同時包覆IR 780及DOX的微粒能明顯地使腫瘤萎縮，並造成傷口結痂，持續觀察至24天，並無腫瘤復發的跡象。然而，僅包覆IR 780的微粒組，於治療初期雖可造成腫瘤萎縮，但後期仍有腫瘤仍有逐漸長大的趨勢。以上結果證實，藉由近紅外光之照射，包覆IR 780及DOX的PCL微粒能同時提供光熱、光動力及化療之效果，有效治療鱗狀皮膚癌。利用玻尿酸微針進行經皮傳輸，能讓微粒有效且均勻地分散於腫瘤各部位，有潛力應用於其他表淺性癌症之治療。

This study focuses on the feasibility of transdermal delivery of drug particles using dissolvable polymer microneedles and its potential for the treatment of skin diseases. Investigating the efficiency of transdermal delivery of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles using polyvinyl alcohol/polyvinyl pyrrolidone (PVA/PVP) microneedles is the first section. Transdermal delivery of doxorubicin (DOX) and IR 780-loaded polycaprolactone (PCL) microparticles using hyaluronic acid microneedles for treating A431 tumor by combination of chemotherapy, photodynamic and photothermal therapy is the second section.
The topic is efficient delivery of nanoparticles to deep skin layers using dissolvable microneedles with an extended-length design in the first section. Skin pretreatment with microneedles (MNs) increases drug permeation through the skin by creating microchannels in the skin. However, because of skin’s inherent elasticity and self-healing ability, these microchannels shrink or reseal rapidly, thus limiting the nanoparticle (NP) delivery efficiency. This study evaluated dissolvable PVA/PVP MNs with an extended-length design for the efficient transdermal delivery of NPs. In this system, PLGA NPs are encapsulated within the pyramidal structure of the MNs. The extended length of the PVA/PVP MN allows it to counteract skin indentation during insertion, thus enabling complete insertion of the pyramidal structure into the skin to deliver the NPs. In contrast to MN pretreatments that require passive diffusion of NPs through the skin, the extended PVA/PVP MNs can directly bring the NPs into the deeper skin layers, and then rapidly dissolve in 3 min to release the payload. An in vivo transdermal delivery study showed that approximately 90% of the loaded NPs were delivered to the viable epidermis and dermis, whereas only 2% of topically applied NPs were detected in the skin after being treated with a commercial MN product (3MTM Microchannel Skin System). The NPs delivered by the extended MN remained at the insertion site for 5 days, thus providing sustained drug release. The proposed MN system could be a promising tool for the transdermal delivery of NPs for treating deep skin diseases such as bacterial infection and malignant tumor.
The topic is delivery of IR 780 and DOX-loaded microparticles into skin cancer using hyaluronic acid microneedles with an extended-length design for treating squamous cell carcinoma in the second section. IR 780 is a near infrared (NIR) heptamethine indocyanine dye, it can exhibite remarkable photothermal effect and photodynamic therapy with NIR light. The NIR light-triggered release experiments demonstrated that PCL microparticles can quickly melt at 48˚C due to the heating of the encapsulated IR 780 when NIR irradiation and then release DOX into the medium. In vitro cell viability assays showed that IR 780 and DOX-loaded PCL microparticles significantly enhanced the cytotoxicity of combination therapy in A-431 cells. Dramatic size decreases in squamous cell carcinoma xenografts were observed for delivery of IR 780 and DOX-loaded PCL microparticles into skin tumor using dissolvable hyaluronic acid microneedles in ICR SCID mice. Compared with IR 780-loaded PCL microparticles, the combined treatment with chemotherapy, photodynamic and photothermal therapy possessed a better therapeutic efficacy, resulting from a DOX effect. In conclusion, we believe that delivery of DOX and IR 780-loaded microparticles into tumor using dissolvable microneedles are promising and may serve as a useful system for superficial cancer treatment.

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