導語：醫學思維中的中藥研究方法(fa)探討一文(wen)來源于網友上傳(chuan)，不代表本站觀點，若(ruo)需要原創文(wen)章(zhang)可(ke)咨詢客服老(lao)師，歡迎參考(kao)。

摘要:物(wu)質在不(bu)同尺度(du)的(de)(de)(de)(de)聚(ju)集狀態是決定其性質的(de)(de)(de)(de)關(guan)鍵因素。結(jie)構中(zhong)(zhong)(zhong)藥(yao)學(xue)(xue)是以(yi)中(zhong)(zhong)(zhong)藥(yao)中(zhong)(zhong)(zhong)天然存在的(de)(de)(de)(de)或經加工形成(cheng)的(de)(de)(de)(de)聚(ju)集態為(wei)對象，研(yan)究(jiu)其組成(cheng)結(jie)構特(te)征、形成(cheng)機制、體內命運及其功(gong)能(neng)關(guan)聯(lian)性的(de)(de)(de)(de)中(zhong)(zhong)(zhong)藥(yao)學(xue)(xue)新興交叉領域(yu)。相較于(yu)中(zhong)(zhong)(zhong)藥(yao)傳統(tong)的(de)(de)(de)(de)分(fen)子層次研(yan)究(jiu)，結(jie)構中(zhong)(zhong)(zhong)藥(yao)學(xue)(xue)的(de)(de)(de)(de)研(yan)究(jiu)對象具有跨(kua)尺度(du)、異(yi)質性、多效應的(de)(de)(de)(de)特(te)點，是從介(jie)觀視角和空間(jian)維(wei)度(du)對中(zhong)(zhong)(zhong)藥(yao)藥(yao)效物(wu)質和起效機制的(de)(de)(de)(de)再認(ren)識(shi)和再研(yan)究(jiu)。中(zhong)(zhong)(zhong)藥(yao)外(wai)用是中(zhong)(zhong)(zhong)醫傳承千年的(de)(de)(de)(de)用藥(yao)特(te)色，但其科學(xue)(xue)內涵缺乏深(shen)入的(de)(de)(de)(de)闡釋(shi)。筆者以(yi)外(wai)用中(zhong)(zhong)(zhong)藥(yao)為(wei)例分(fen)析了目前(qian)中(zhong)(zhong)(zhong)藥(yao)研(yan)究(jiu)中(zhong)(zhong)(zhong)存在的(de)(de)(de)(de)共性和個性問題，并(bing)提出基于(yu)結(jie)構中(zhong)(zhong)(zhong)藥(yao)學(xue)(xue)思維(wei)的(de)(de)(de)(de)研(yan)究(jiu)路(lu)徑，以(yi)期為(wei)相關(guan)領域(yu)提供參考。

關鍵詞:結構中(zhong)藥(yao)學(xue);中(zhong)藥(yao)外用(yong);藥(yao)效物質;團(tuan)簇;聚集(ji)體;相(xiang)分離;囊泡;炭藥(yao);作用(yong)機(ji)制

中藥的整個生命周期都伴隨有不同物種構成的多尺度聚集形式，大量證據顯示物質在不同尺度的聚集狀態是決定其性質的關鍵因素。例如，砷原子與氧原子的鍵合形式決定砷劑的活性［1］;小檗堿與黃酮苷的締合優勢構象是其抗菌的關鍵要素［2］;芍藥甘草共煎形成的納米粒影響芍藥主要成分的釋放和吸收［3］。目前已發現的與中藥藥效相關的尺寸區域包括原子分子、亞納米尺度和微納米尺度等，但對相關區域物種的聚集態研究還比較缺乏，也導致中藥藥效物質形式長期未能全面闡釋。結構中藥學是以中藥中天然存在的或經加工形成的聚集態為對象，研究其組成結構特征、形成機制、體內命運及其功能關聯性的中藥學新興交叉方向［4］。與中藥傳統的分子層次研究不同，結構中藥學的研究對象具有跨尺度、異質性、多效應的特點，是從介觀視角和空間維度對中藥藥效物質和起效機制的再認識和再研究。其中跨尺度體現在結構中藥學研究的物種既包括原子分子、也包括微納米粒子，其均被視為中藥起效的不同物質形式且存在特定環境下的轉化關系;異質性表現為化學物種在空間排布上的非均勻性及由此產生的聚集態結構域，這是由物種間互作關系決定的;多效應則是在跨尺度和異質化物質基礎上的宏觀效應表現，聚集態的拓撲結構演化產生的若干尺寸效應和起效模式將拓展現有的中藥功能評價體系。中藥外用是除口服外最常用的給藥途徑之一。目前發現的有關中藥外用的最早文字記載始于商代《殷墟卜辭》，距今已有三千多年歷史。《黃帝內經》提出“內者內治，外者外治”，為中藥外治法的形成奠定了理論基礎［5］。《傷寒雜病論》豐富和發展了中藥外治的理法原則和施治方法［6］。清代名醫吳尚先著第一部外治專著《理瀹駢文》，認為內服與外治只是給藥途徑和方法不同，而治病原理并無二致［7］。內服藥經口入體內，串行臟腑而遍布周身;外治用藥“雖在外，無殊治在內也”，可通過調諧經絡而透達體內，即所謂“外治之理即內治之理，外治之藥即內治之藥”。吳尚先的辨證思想將中藥的內服與外治統一起來，并提出外治法可“統治百病”，奠定了中藥外治的中醫學地(di)位。至(zhi)于現代，2020版《中(zhong)國(guo)藥(yao)典》共收載130余種中(zhong)藥(yao)外(wai)(wai)用制劑(ji)［8］。2018年，丁(ding)桂兒臍(qi)貼在加拿大(da)以天然健(jian)康產(chan)品(pin)形式成功上市，標志著(zhu)中(zhong)藥(yao)外(wai)(wai)用制劑(ji)在國(guo)際化進(jin)(jin)程中(zhong)更進(jin)(jin)一步［9］。然而(er)，受限于中(zhong)藥(yao)外(wai)(wai)用領域研(yan)究的不(bu)足，其科學內(nei)涵尚缺乏清晰的揭示，特別是(shi)在數十(shi)年未(wei)能破局(ju)的中(zhong)藥(yao)藥(yao)效物質不(bu)明、機制欠(qian)清等共性難題方面，亟需研(yan)究思路和方法的創新。

1中藥外用研究中存在的共性和個性問題

縱觀中(zhong)藥(yao)外(wai)(wai)用(yong)的(de)歷史，無外(wai)(wai)乎局(ju)部治療和(he)(he)全身調(diao)(diao)理，這與現代經皮(pi)用(yong)藥(yao)的(de)目標宗(zong)旨頗為相似。例(li)如在(zai)外(wai)(wai)治瘡瘍(yang)方(fang)面(mian)(mian)，中(zhong)醫治法(fa)可歸納為清(qing)(qing)熱解毒(du)、活(huo)血化瘀(yu)、煨膿(nong)長(chang)肉和(he)(he)祛(qu)腐生肌(ji)［10］。因此(ci)(ci)，清(qing)(qing)熱類(lei)中(zhong)藥(yao)黃(huang)芩、黃(huang)連、黃(huang)柏、紫花地丁(ding)、金銀(yin)花以及活(huo)血類(lei)中(zhong)藥(yao)當歸、川芎、血竭、紅花等在(zai)治療方(fang)劑中(zhong)多有使用(yong)。現代醫學對(dui)中(zhong)藥(yao)及其(qi)有效(xiao)(xiao)成(cheng)分(fen)(fen)促瘡瘍(yang)愈合機(ji)理也(ye)有一(yi)些(xie)(xie)(xie)報道，主要包括對(dui)創(chuang)面(mian)(mian)免(mian)疫(yi)細胞(bao)(bao)、成(cheng)纖(xian)維(wei)細胞(bao)(bao)及其(qi)分(fen)(fen)泌因子的(de)調(diao)(diao)節，改(gai)善創(chuang)面(mian)(mian)微循(xun)環，提(ti)高創(chuang)面(mian)(mian)Ⅲ型膠原(yuan)與Ⅰ型膠原(yuan)的(de)比例(li)，影響創(chuang)面(mian)(mian)微量元素(su)等［11］。但總(zong)體(ti)上，相比于(yu)結構清(qing)(qing)晰、機(ji)制較(jiao)明確的(de)西藥(yao)單成(cheng)分(fen)(fen)，中(zhong)藥(yao)藥(yao)效(xiao)(xiao)物質的(de)研究仍較(jiao)為模糊且缺乏標準，影響了中(zhong)藥(yao)外(wai)(wai)治的(de)發展和(he)(he)應用(yong)［4］;中(zhong)藥(yao)外(wai)(wai)用(yong)時(shi)存(cun)(cun)在(zai)特殊的(de)皮(pi)膚屏(ping)障，對(dui)透(tou)皮(pi)入(ru)血成(cheng)分(fen)(fen)來說是(shi)需(xu)要攻克的(de)難(nan)題;此(ci)(ci)外(wai)(wai)，中(zhong)藥(yao)外(wai)(wai)用(yong)研究中(zhong)的(de)一(yi)些(xie)(xie)(xie)做法(fa)是(shi)否科學、是(shi)否能直(zhi)接(jie)套(tao)用(yong)一(yi)般性(xing)思路(lu)和(he)(he)方(fang)法(fa)，也(ye)有待(dai)探討(tao)和(he)(he)論證(zheng)。現就該領域研究存(cun)(cun)在(zai)的(de)一(yi)些(xie)(xie)(xie)共性(xing)和(he)(he)個性(xing)問題探討(tao)如下。

1．1偏離(li)了鮮藥外用的優勢場景和用法

作為(wei)(wei)傳統(tong)中(zhong)(zhong)醫(yi)藥(yao)(yao)(yao)(yao)實(shi)踐的(de)起點(dian)，鮮(xian)(xian)藥(yao)(yao)(yao)(yao)一直為(wei)(wei)歷代(dai)醫(yi)家所(suo)重視(shi)。早在(zai)兩千多年前(qian)的(de)《神農本草(cao)經(jing)》中(zhong)(zhong)就有(you)“生者尤良”的(de)記載;葛(ge)洪收(shou)(shou)錄在(zai)《肘后備急(ji)方》中(zhong)(zhong)的(de)鮮(xian)(xian)藥(yao)(yao)(yao)(yao)占比(bi)近半，其(qi)(qi)中(zhong)(zhong)“青蒿一握，以水二(er)升漬(zi)，絞取汁(zhi)(zhi)，盡(jin)服之”更(geng)是成為(wei)(wei)屠呦(you)呦(you)獲得諾貝爾獎的(de)思想源泉;迨及(ji)清代(dai)，伴隨溫病學(xue)大興，鮮(xian)(xian)藥(yao)(yao)(yao)(yao)使用(yong)(yong)日盛。葉天士著(zhu)《臨(lin)證指(zhi)南醫(yi)案(an)》收(shou)(shou)錄的(de)89類(lei)醫(yi)案(an)中(zhong)(zhong)涉(she)及(ji)鮮(xian)(xian)藥(yao)(yao)(yao)(yao)的(de)多達79類(lei)，可謂(wei)推崇備至(zhi)［12］。在(zai)《中(zhong)(zhong)華本草(cao)》收(shou)(shou)載的(de)4000余種(zhong)(zhong)鮮(xian)(xian)藥(yao)(yao)(yao)(yao)中(zhong)(zhong)，以“搗汁(zhi)(zhi)”“絞汁(zhi)(zhi)”作為(wei)(wei)入(ru)藥(yao)(yao)(yao)(yao)前(qian)處理工(gong)序(xu)的(de)約(yue)占85%，且主要為(wei)(wei)外(wai)(wai)(wai)用(yong)(yong)，這(zhe)是區別于(yu)干藥(yao)(yao)(yao)(yao)的(de)特色加(jia)工(gong)和使用(yong)(yong)方法［13］;臨(lin)床(chuang)上，鮮(xian)(xian)藥(yao)(yao)(yao)(yao)善治急(ji)表熱證，在(zai)內外(wai)(wai)(wai)科(ke)、皮膚科(ke)、婦科(ke)等涉(she)及(ji)的(de)癰疽(ju)、諸毒、潰瘍等各(ge)類(lei)感(gan)染(ran)(ran)創面的(de)局部(bu)治療(liao)方面應(ying)(ying)用(yong)(yong)廣泛，約(yue)占60%［14］。由此可見，鮮(xian)(xian)藥(yao)(yao)(yao)(yao)取汁(zhi)(zhi)外(wai)(wai)(wai)用(yong)(yong)于(yu)治療(liao)創面感(gan)染(ran)(ran)是其(qi)(qi)優(you)勢使用(yong)(yong)場(chang)景(jing)之一。然而，目前(qian)中(zhong)(zhong)藥(yao)(yao)(yao)(yao)研究多以干燥飲片(pian)為(wei)(wei)對(dui)(dui)象(xiang)，鮮(xian)(xian)藥(yao)(yao)(yao)(yao)研究較(jiao)少，忽(hu)略了中(zhong)(zhong)藥(yao)(yao)(yao)(yao)不同取材的(de)差異(yi);研究過程(cheng)中(zhong)(zhong)，僅關注中(zhong)(zhong)藥(yao)(yao)(yao)(yao)的(de)成分與藥(yao)(yao)(yao)(yao)理機制，未對(dui)(dui)應(ying)(ying)其(qi)(qi)臨(lin)床(chuang)優(you)勢病種(zhong)(zhong)，致(zhi)使鮮(xian)(xian)藥(yao)(yao)(yao)(yao)外(wai)(wai)(wai)用(yong)(yong)研究不足;而忽(hu)視(shi)鮮(xian)(xian)藥(yao)(yao)(yao)(yao)傳統(tong)用(yong)(yong)法，采(cai)用(yong)(yong)有(you)機溶劑等提取方法分離(li)有(you)效部(bu)位，則破壞(huai)了鮮(xian)(xian)藥(yao)(yao)(yao)(yao)的(de)應(ying)(ying)用(yong)(yong)基(ji)礎。上述(shu)種(zhong)(zhong)種(zhong)(zhong)，反映出目前(qian)中(zhong)(zhong)藥(yao)(yao)(yao)(yao)研究重品種(zhong)(zhong)而輕場(chang)景(jing)和用(yong)(yong)法的(de)普遍現象(xiang)，導致(zhi)中(zhong)(zhong)藥(yao)(yao)(yao)(yao)外(wai)(wai)(wai)用(yong)(yong)的(de)對(dui)(dui)象(xiang)和用(yong)(yong)法場(chang)景(jing)錯配，很難正確詮(quan)釋鮮(xian)(xian)藥(yao)(yao)(yao)(yao)外(wai)(wai)(wai)用(yong)(yong)的(de)優(you)勢。

1．2忽(hu)視(shi)了中藥外用中成分間的互(hu)作關(guan)系(xi)

目前的(de)(de)(de)(de)中(zhong)(zhong)藥(yao)外治研(yan)(yan)究(jiu)(jiu)(jiu)主要(yao)關(guan)注的(de)(de)(de)(de)是(shi)提取物(wu)或(huo)單成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)施用(yong)(yong)后的(de)(de)(de)(de)轉(zhuan)化或(huo)效(xiao)(xiao)用(yong)(yong)，但很少關(guan)注成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)間的(de)(de)(de)(de)互(hu)(hu)作(zuo)(zuo)關(guan)系，導(dao)致(zhi)對(dui)中(zhong)(zhong)藥(yao)多成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)復雜體(ti)系的(de)(de)(de)(de)解析能(neng)(neng)力和(he)內(nei)涵揭示比較(jiao)薄(bo)弱。大(da)量實驗證據顯示，中(zhong)(zhong)藥(yao)活性(xing)化合物(wu)的(de)(de)(de)(de)集合構(gou)(gou)成(cheng)(cheng)(cheng)(cheng)(cheng)了(le)中(zhong)(zhong)藥(yao)起效(xiao)(xiao)的(de)(de)(de)(de)化學(xue)(xue)基礎(chu)，而多成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)互(hu)(hu)作(zuo)(zuo)形(xing)(xing)成(cheng)(cheng)(cheng)(cheng)(cheng)的(de)(de)(de)(de)適宜存在(zai)形(xing)(xing)式和(he)物(wu)相(xiang)狀(zhuang)態是(shi)中(zhong)(zhong)藥(yao)起效(xiao)(xiao)的(de)(de)(de)(de)物(wu)理基礎(chu)［15］。化學(xue)(xue)成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)是(shi)中(zhong)(zhong)藥(yao)效(xiao)(xiao)用(yong)(yong)的(de)(de)(de)(de)來源(yuan)和(he)基礎(chu)，多成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)物(wu)理結(jie)構(gou)(gou)是(shi)中(zhong)(zhong)藥(yao)起效(xiao)(xiao)的(de)(de)(de)(de)形(xing)(xing)式和(he)途徑，拋開成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)談結(jie)構(gou)(gou)會變(bian)成(cheng)(cheng)(cheng)(cheng)(cheng)無(wu)(wu)本之(zhi)木、無(wu)(wu)源(yuan)之(zhi)水，而摒棄結(jie)構(gou)(gou)談成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)則很可能(neng)(neng)喪失(shi)舟楫而難以行(xing)船［4］。外用(yong)(yong)中(zhong)(zhong)藥(yao)成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)間的(de)(de)(de)(de)相(xiang)互(hu)(hu)作(zuo)(zuo)用(yong)(yong)不(bu)(bu)(bu)僅能(neng)(neng)形(xing)(xing)成(cheng)(cheng)(cheng)(cheng)(cheng)獨特的(de)(de)(de)(de)聚集結(jie)構(gou)(gou)，還能(neng)(neng)發(fa)揮(hui)(hui)諸如透皮促滲、穴位刺激、經絡傳感(gan)等(deng)(deng)協同效(xiao)(xiao)應［16］。中(zhong)(zhong)醫歷(li)來強調(diao)“整體(ti)觀”，但這并(bing)不(bu)(bu)(bu)意味著可以將(jiang)中(zhong)(zhong)藥(yao)視為無(wu)(wu)關(guan)聯成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)組成(cheng)(cheng)(cheng)(cheng)(cheng)的(de)(de)(de)(de)物(wu)理學(xue)(xue)質點。目前外用(yong)(yong)中(zhong)(zhong)藥(yao)的(de)(de)(de)(de)研(yan)(yan)究(jiu)(jiu)(jiu)主要(yao)聚焦于(yu)(yu)小分(fen)(fen)子成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)，對(dui)大(da)分(fen)(fen)子的(de)(de)(de)(de)研(yan)(yan)究(jiu)(jiu)(jiu)較(jiao)少，且個別活性(xing)成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)經皮吸收不(bu)(bu)(bu)佳導(dao)致(zhi)藥(yao)效(xiao)(xiao)不(bu)(bu)(bu)理想，與(yu)傳統用(yong)(yong)法(fa)療效(xiao)(xiao)相(xiang)悖，這與(yu)忽視多成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)的(de)(de)(de)(de)相(xiang)互(hu)(hu)作(zuo)(zuo)用(yong)(yong)不(bu)(bu)(bu)無(wu)(wu)關(guan)系。因此將(jiang)成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)間相(xiang)互(hu)(hu)作(zuo)(zuo)用(yong)(yong)的(de)(de)(de)(de)規(gui)律及其與(yu)功能(neng)(neng)的(de)(de)(de)(de)關(guan)聯性(xing)研(yan)(yan)究(jiu)(jiu)(jiu)清楚，對(dui)闡明方(fang)劑(ji)配(pei)伍規(gui)律和(he)指導(dao)制劑(ji)設計(ji)等(deng)(deng)都有現(xian)實意義。陳軍課(ke)題組［17］從中(zhong)(zhong)藥(yao)揮(hui)(hui)發(fa)油(you)促滲角度研(yan)(yan)究(jiu)(jiu)(jiu)成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)間的(de)(de)(de)(de)作(zuo)(zuo)用(yong)(yong)規(gui)律，發(fa)現(xian)高良(liang)姜、干姜等(deng)(deng)5味辛熱中(zhong)(zhong)藥(yao)的(de)(de)(de)(de)揮(hui)(hui)發(fa)油(you)中(zhong)(zhong)倍半萜(tie)類成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)(β－石竹(zhu)(zhu)烯、α－衣(yi)蘭油(you)烯、吉馬(ma)烯等(deng)(deng))的(de)(de)(de)(de)質量分(fen)(fen)數(shu)高于(yu)(yu)防風等(deng)(deng)10味辛溫中(zhong)(zhong)藥(yao)，且外用(yong)(yong)給(gei)藥(yao)時更(geng)傾向于(yu)(yu)滯留(liu)在(zai)皮內(nei)，可能(neng)(neng)是(shi)決(jue)定(ding)揮(hui)(hui)發(fa)油(you)透皮促滲能(neng)(neng)力的(de)(de)(de)(de)關(guan)鍵(jian)成(cheng)(cheng)(cheng)(cheng)(cheng)分(fen)(fen)。Wei等(deng)(deng)［18］曾研(yan)(yan)究(jiu)(jiu)(jiu)發(fa)現(xian)β－石竹(zhu)(zhu)烯和(he)氧(yang)化石竹(zhu)(zhu)烯可以與(yu)多種(zhong)動物(wu)的(de)(de)(de)(de)冷(leng)敏(min)感(gan)通道蛋(dan)白TRPM8結(jie)合，從而抑(yi)制機體(ti)對(dui)低溫的(de)(de)(de)(de)敏(min)感(gan)性(xing)，這為揭示中(zhong)(zhong)藥(yao)藥(yao)性(xing)的(de)(de)(de)(de)科(ke)學(xue)(xue)內(nei)涵提供(gong)了(le)思(si)路。

1．3束縛了(le)外用中藥作(zuo)用途徑和(he)機制研究的思路

方(fang)法(fa)自20世紀初保羅?埃爾(er)利希(xi)(PaulEhrlich)提出“受體”概念和(he)“鎖鑰”學(xue)(xue)說以來(lai)(lai)，基于“分(fen)(fen)(fen)子(zi)(zi)－靶(ba)(ba)標(biao)”理(li)論(lun)的(de)(de)(de)(de)藥(yao)(yao)物作(zuo)(zuo)用(yong)和(he)研究(jiu)模(mo)式(shi)成(cheng)(cheng)為業(ye)界(jie)主(zhu)流(liu)共識(shi)。經過(guo)百余年的(de)(de)(de)(de)發(fa)(fa)(fa)展，大(da)量中藥(yao)(yao)成(cheng)(cheng)分(fen)(fen)(fen)的(de)(de)(de)(de)作(zuo)(zuo)用(yong)靶(ba)(ba)點(dian)被(bei)發(fa)(fa)(fa)現(xian)(xian)。然而，在(zai)實踐中也發(fa)(fa)(fa)現(xian)(xian)現(xian)(xian)有(you)的(de)(de)(de)(de)“分(fen)(fen)(fen)子(zi)(zi)－靶(ba)(ba)點(dian)”模(mo)式(shi)并(bing)不(bu)(bu)能解釋(shi)和(he)解決中藥(yao)(yao)的(de)(de)(de)(de)所有(you)問(wen)題。例如，很多(duo)中藥(yao)(yao)并(bing)未從(cong)(cong)分(fen)(fen)(fen)子(zi)(zi)層次發(fa)(fa)(fa)現(xian)(xian)與其活(huo)性(xing)(xing)相稱的(de)(de)(de)(de)藥(yao)(yao)效物質(zhi);很多(duo)成(cheng)(cheng)分(fen)(fen)(fen)與活(huo)性(xing)(xing)響(xiang)應之間不(bu)(bu)滿足(zu)經典的(de)(de)(de)(de)量效關(guan)系;基于疾病相關(guan)靶(ba)(ba)點(dian)篩(shai)選或網絡藥(yao)(yao)理(li)學(xue)(xue)方(fang)法(fa)并(bing)未發(fa)(fa)(fa)現(xian)(xian)太多(duo)高特(te)異(yi)性(xing)(xing)、強結合的(de)(de)(de)(de)中藥(yao)(yao)成(cheng)(cheng)分(fen)(fen)(fen)，這從(cong)(cong)新藥(yao)(yao)開發(fa)(fa)(fa)難(nan)度(du)上(shang)可(ke)見一(yi)斑。誠然，這些(xie)(xie)問(wen)題可(ke)以通過(guo)“成(cheng)(cheng)分(fen)(fen)(fen)疊加(jia)效應”學(xue)(xue)說予以一(yi)定程度(du)解釋(shi)［19］，不(bu)(bu)過(guo)在(zai)“分(fen)(fen)(fen)子(zi)(zi)－靶(ba)(ba)標(biao)”直接作(zuo)(zuo)用(yong)模(mo)式(shi)之外(wai)的(de)(de)(de)(de)思考和(he)探(tan)索是必要(yao)的(de)(de)(de)(de)。特(te)別(bie)是中藥(yao)(yao)外(wai)用(yong)如何發(fa)(fa)(fa)揮全(quan)身調控作(zuo)(zuo)用(yong)，是否都(dou)需要(yao)通過(guo)入血起效，仍(reng)有(you)待探(tan)明(ming)。近年來(lai)(lai)涌現(xian)(xian)出的(de)(de)(de)(de)一(yi)些(xie)(xie)實驗證(zheng)據(ju)提示，中藥(yao)(yao)研究(jiu)或許存在(zai)不(bu)(bu)同于現(xian)(xian)有(you)認(ren)識(shi)觀(guan)和(he)方(fang)法(fa)論(lun)架構(gou)下(xia)的(de)(de)(de)(de)新研究(jiu)維(wei)度(du)［20－21］。

2基于結構中藥學思維的研究方法及其在中藥外用中的應用

結構中藥學是在辨析了中藥活性關聯物質存在化學成分和物理結構雙重屬性的基礎上，聚焦于中藥聚集態結構形成與藥效間關系的新興研究方向［4］。該方向不單以化學分子為對象，而是以特定施用場景下中藥的真實組成和聚集態為切入點，解析其化學物理特征和形成規律，闡明物質與功能的傳遞過程，旨在比較完整地揭示中藥“化學成分－物理結構－多維藥效”的內在關系。與經典的“分子－靶標”研究模式相比，結構中藥學關注的對象具有跨尺度、異質化和多效應特征。結構中藥學的認識觀和方法論可以拓展中藥分子層次研(yan)究的邊界，填(tian)補缺失的中藥物質結構基礎，有(you)利于(yu)解決因單純研(yan)究有(you)限化學(xue)成分所產(chan)生的物質基礎不(bu)明(ming)、機制欠清、體內外不(bu)相關(guan)等中藥學(xue)歷史(shi)積(ji)弊，對包括中藥外用在內的中藥學(xue)各領域研(yan)究都有(you)一定的參考意義。

2．1外用(yong)中(zhong)藥(yao)跨尺度藥(yao)效物質(zhi)的(de)發現(xian)

屠呦呦先生(sheng)(sheng)(sheng)從中(zhong)(zhong)(zhong)醫(yi)典籍“絞(jiao)取汁”用(yong)(yong)法(fa)(fa)(fa)中(zhong)(zhong)(zhong)汲取靈感，采用(yong)(yong)低(di)溫冷萃法(fa)(fa)(fa)提取到(dao)青蒿素，為(wei)全球(qiu)攻克瘧疾作(zuo)(zuo)出卓越貢獻。但(dan)另一(yi)方(fang)(fang)面(mian)，青蒿素水(shui)溶性(xing)差、生(sheng)(sheng)(sheng)物利用(yong)(yong)度低(di)的(de)(de)(de)(de)問題(ti)表(biao)明取汁用(yong)(yong)法(fa)(fa)(fa)的(de)(de)(de)(de)奧秘仍有(you)待(dai)進一(yi)步(bu)探究。在(zai)結(jie)(jie)構(gou)中(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)學思(si)維引導(dao)下，遵(zun)從鮮(xian)(xian)中(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)絞(jiao)汁用(yong)(yong)法(fa)(fa)(fa)的(de)(de)(de)(de)現(xian)實場景，可以(yi)從鮮(xian)(xian)榨汁液(ye)中(zhong)(zhong)(zhong)分(fen)離到(dao)納米(mi)級囊泡［22］。它們是(shi)由脂(zhi)質(zhi)(zhi)、蛋(dan)(dan)白、核酸(suan)及小分(fen)子等(deng)構(gou)成(cheng)(cheng)(cheng)(cheng)的(de)(de)(de)(de)膜(mo)結(jie)(jie)構(gou)聚集體(ti)(ti)，能(neng)很好地保留原藥(yao)(yao)(yao)(yao)材的(de)(de)(de)(de)組成(cheng)(cheng)(cheng)(cheng)和(he)功能(neng)，在(zai)治療(liao)創面(mian)、腸(chang)炎、腫瘤(liu)、肝(gan)肺(fei)損傷等(deng)方(fang)(fang)面(mian)效果(guo)顯(xian)著，且優于已報(bao)道(dao)(dao)的(de)(de)(de)(de)單一(yi)活(huo)(huo)性(xing)成(cheng)(cheng)(cheng)(cheng)分(fen)，是(shi)鮮(xian)(xian)藥(yao)(yao)(yao)(yao)起效的(de)(de)(de)(de)新藥(yao)(yao)(yao)(yao)效物質(zhi)(zhi)形式(shi)［23］。更重要(yao)的(de)(de)(de)(de)是(shi)，這些介觀尺(chi)度的(de)(de)(de)(de)脂(zhi)質(zhi)(zhi)囊泡具(ju)有(you)出色的(de)(de)(de)(de)跨膜(mo)轉(zhuan)運能(neng)力，能(neng)快(kuai)速被(bei)機(ji)體(ti)(ti)吸(xi)收［24］。此外(wai)，Chen等(deng)［25－26］還報(bao)道(dao)(dao)了(le)(le)囊泡活(huo)(huo)性(xing)miRNA的(de)(de)(de)(de)耐熱性(xing)和(he)耐胃腸(chang)道(dao)(dao)降(jiang)解性(xing)，揭示(shi)了(le)(le)經(jing)SIDT1蛋(dan)(dan)白介導(dao)入胞(bao)的(de)(de)(de)(de)體(ti)(ti)內(nei)轉(zhuan)運路徑(jing)，較(jiao)(jiao)完整地詮釋了(le)(le)古(gu)人鮮(xian)(xian)藥(yao)(yao)(yao)(yao)絞(jiao)汁用(yong)(yong)法(fa)(fa)(fa)的(de)(de)(de)(de)優勢和(he)科學內(nei)涵，對外(wai)用(yong)(yong)制(zhi)劑的(de)(de)(de)(de)設計也有(you)啟發(fa)作(zuo)(zuo)用(yong)(yong)。中(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)炭藥(yao)(yao)(yao)(yao)是(shi)中(zhong)(zhong)(zhong)醫(yi)用(yong)(yong)藥(yao)(yao)(yao)(yao)的(de)(de)(de)(de)一(yi)大特色，可內(nei)服可外(wai)用(yong)(yong)，具(ju)有(you)收斂(lian)、止血、止瀉(xie)等(deng)作(zuo)(zuo)用(yong)(yong)［27］。傳統炭藥(yao)(yao)(yao)(yao)的(de)(de)(de)(de)研究主要(yao)關注小分(fen)子成(cheng)(cheng)(cheng)(cheng)分(fen)炮制(zhi)前后(hou)的(de)(de)(de)(de)變化(hua)，但(dan)大多缺乏共性(xing)規律和(he)可靠的(de)(de)(de)(de)因果(guo)關系。近年來(lai)發(fa)現(xian)包括黃柏、荊芥(jie)、貫眾和(he)血余在(zai)內(nei)的(de)(de)(de)(de)數(shu)十種中(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)經(jing)炭化(hua)后(hou)均含有(you)＜100nm的(de)(de)(de)(de)碳點，其晶(jing)格排列較(jiao)(jiao)規則(ze)整齊(qi)且藥(yao)(yao)(yao)(yao)效顯(xian)著，可能(neng)是(shi)炭藥(yao)(yao)(yao)(yao)的(de)(de)(de)(de)共性(xing)藥(yao)(yao)(yao)(yao)效物質(zhi)(zhi)［27］。此外(wai)，有(you)學者發(fa)現(xian)中(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)中(zhong)(zhong)(zhong)廣泛存在(zai)的(de)(de)(de)(de)綠(lv)原酸(suan)在(zai)高溫處(chu)理(li)后(hou)會自發(fa)形成(cheng)(cheng)(cheng)(cheng)一(yi)種性(xing)質(zhi)(zhi)穩定的(de)(de)(de)(de)納米(mi)結(jie)(jie)構(gou)，可通過生(sheng)(sheng)(sheng)物催化(hua)反應促(cu)進腫瘤(liu)細胞(bao)發(fa)生(sheng)(sheng)(sheng)鐵(tie)死亡，進而發(fa)揮抗腫瘤(liu)及激(ji)活(huo)(huo)腫瘤(liu)免疫微環境的(de)(de)(de)(de)作(zuo)(zuo)用(yong)(yong)［28］。Liu等(deng)［29］研究了(le)(le)納米(mi)生(sheng)(sheng)(sheng)物炭的(de)(de)(de)(de)形成(cheng)(cheng)(cheng)(cheng)過程和(he)結(jie)(jie)構(gou)特征，為(wei)揭示(shi)炭藥(yao)(yao)(yao)(yao)的(de)(de)(de)(de)藥(yao)(yao)(yao)(yao)效物質(zhi)(zhi)基礎提供了(le)(le)新思(si)路。但(dan)是(shi)目(mu)前關于不(bu)(bu)同中(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)炭化(hua)后(hou)的(de)(de)(de)(de)個性(xing)特征如何體(ti)(ti)現(xian)尚缺乏明確的(de)(de)(de)(de)證(zheng)據。以(yi)上(shang)研究均是(shi)在(zai)中(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)非分(fen)子層次發(fa)現(xian)的(de)(de)(de)(de)活(huo)(huo)性(xing)實體(ti)(ti)，也不(bu)(bu)能(neng)通過簡單的(de)(de)(de)(de)增溶、促(cu)滲原理(li)予以(yi)解釋，是(shi)結(jie)(jie)構(gou)中(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)學研究的(de)(de)(de)(de)范疇，其思(si)路方(fang)(fang)法(fa)(fa)(fa)可為(wei)外(wai)用(yong)(yong)中(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)研究所借鑒。

2．2多維作(zuo)用途徑和機制(zhi)的研究

在(zai)(zai)(zai)材料(liao)學(xue)領域(yu)，跨尺度的(de)(de)(de)(de)(de)(de)研(yan)究(jiu)(jiu)對(dui)象具(ju)有(you)獨(du)特的(de)(de)(de)(de)(de)(de)表(biao)(biao)界(jie)面性質，例如不同(tong)(tong)(tong)尺寸的(de)(de)(de)(de)(de)(de)納(na)米(mi)(mi)碳材料(liao)能誘導(dao)不同(tong)(tong)(tong)程(cheng)度的(de)(de)(de)(de)(de)(de)蛋白(bai)組裝(zhuang)(zhuang)進而(er)(er)影響宏觀(guan)效(xiao)應(ying)(ying)(ying)［30］。在(zai)(zai)(zai)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)聚(ju)集體(ti)研(yan)究(jiu)(jiu)領域(yu)也發現了(le)(le)類似現象。Li等［2］研(yan)究(jiu)(jiu)了(le)(le)黃連解毒(du)湯中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)主要成(cheng)(cheng)(cheng)分(fen)小檗(bo)堿與(yu)(yu)黃芩苷、漢黃芩苷的(de)(de)(de)(de)(de)(de)相互作用(yong)(yong)(yong)行為，證明(ming)(ming)二者可分(fen)別組裝(zhuang)(zhuang)形成(cheng)(cheng)(cheng)納(na)米(mi)(mi)粒(li)和(he)納(na)米(mi)(mi)纖維，并且2種構象在(zai)(zai)(zai)抗菌(jun)活性方面表(biao)(biao)現出(chu)明(ming)(ming)顯差(cha)異，納(na)米(mi)(mi)粒(li)的(de)(de)(de)(de)(de)(de)活性強于(yu)小檗(bo)堿，而(er)(er)納(na)米(mi)(mi)纖維的(de)(de)(de)(de)(de)(de)活性則比(bi)小檗(bo)堿弱。類似現象在(zai)(zai)(zai)其他多(duo)(duo)成(cheng)(cheng)(cheng)分(fen)組裝(zhuang)(zhuang)體(ti)系(xi)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)也有(you)報道［31］，表(biao)(biao)明(ming)(ming)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)多(duo)(duo)分(fen)散體(ti)系(xi)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)的(de)(de)(de)(de)(de)(de)分(fen)子(zi)(zi)、團(tuan)簇、微納(na)米(mi)(mi)聚(ju)集體(ti)等不同(tong)(tong)(tong)物(wu)態(tai)形式(shi)均可能產生(sheng)不同(tong)(tong)(tong)的(de)(de)(de)(de)(de)(de)效(xiao)應(ying)(ying)(ying)輸出(chu)，這(zhe)是(shi)導(dao)致(zhi)經典量效(xiao)曲線(xian)偏(pian)移的(de)(de)(de)(de)(de)(de)重要因素，驗證了(le)(le)結構中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)學(xue)研(yan)究(jiu)(jiu)的(de)(de)(de)(de)(de)(de)必(bi)要性。同(tong)(tong)(tong)時(shi)提示，當中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)外用(yong)(yong)(yong)時(shi)需要關注(zhu)不同(tong)(tong)(tong)成(cheng)(cheng)(cheng)分(fen)間的(de)(de)(de)(de)(de)(de)組裝(zhuang)(zhuang)行為及(ji)其聚(ju)集形式(shi)，在(zai)(zai)(zai)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)配伍、加(jia)工和(he)制(zhi)劑等環節應(ying)(ying)(ying)加(jia)強對(dui)晶型(xing)(xing)、團(tuan)簇等在(zai)(zai)(zai)內(nei)(nei)的(de)(de)(de)(de)(de)(de)各類凝(ning)聚(ju)態(tai)類型(xing)(xing)開展監測和(he)控(kong)制(zhi)，以提高中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)質控(kong)和(he)新(xin)藥(yao)(yao)(yao)(yao)創制(zhi)的(de)(de)(de)(de)(de)(de)科學(xue)性。近(jin)年來，在(zai)(zai)(zai)生(sheng)物(wu)界(jie)內(nei)(nei)部和(he)跨界(jie)調(diao)(diao)控(kong)領域(yu)涌現出(chu)很多(duo)(duo)不同(tong)(tong)(tong)于(yu)傳統(tong)起效(xiao)途(tu)徑的(de)(de)(de)(de)(de)(de)新(xin)機(ji)制(zhi)，值得為中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)外用(yong)(yong)(yong)研(yan)究(jiu)(jiu)所(suo)借鑒(jian)。RNA依賴性RNA聚(ju)合酶(RDR)在(zai)(zai)(zai)植物(wu)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)對(dui)小RNA介(jie)導(dao)的(de)(de)(de)(de)(de)(de)免(mian)疫(yi)反應(ying)(ying)(ying)至關重要，但(dan)在(zai)(zai)(zai)脊(ji)椎(zhui)動物(wu)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)不存(cun)在(zai)(zai)(zai)。有(you)研(yan)究(jiu)(jiu)人員將來自植物(wu)的(de)(de)(de)(de)(de)(de)RDR1蛋白(bai)成(cheng)(cheng)(cheng)功表(biao)(biao)達(da)在(zai)(zai)(zai)哺乳(ru)動物(wu)細(xi)胞(bao)(bao)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)，顯著抑(yi)(yi)制(zhi)了(le)(le)10種不同(tong)(tong)(tong)癌細(xi)胞(bao)(bao)系(xi)的(de)(de)(de)(de)(de)(de)細(xi)胞(bao)(bao)增殖，但(dan)未影響5種非癌細(xi)胞(bao)(bao)系(xi)［32］。這(zhe)體(ti)現了(le)(le)系(xi)統(tong)間跨界(jie)調(diao)(diao)控(kong)的(de)(de)(de)(de)(de)(de)新(xin)作用(yong)(yong)(yong)模式(shi)，為同(tong)(tong)(tong)樣來源于(yu)植物(wu)的(de)(de)(de)(de)(de)(de)草(cao)藥(yao)(yao)(yao)(yao)外用(yong)(yong)(yong)于(yu)人體(ti)的(de)(de)(de)(de)(de)(de)起效(xiao)方式(shi)提供了(le)(le)啟發。除了(le)(le)直(zhi)接作用(yong)(yong)(yong)于(yu)效(xiao)應(ying)(ying)(ying)靶(ba)位(wei)，有(you)學(xue)者發現磷脂(zhi)酸可通過作用(yong)(yong)(yong)于(yu)遠端附睪白(bai)色脂(zhi)肪組織，誘導(dao)衍生(sheng)的(de)(de)(de)(de)(de)(de)IL－6分(fen)泌以對(dui)抗對(dui)乙(yi)酰氨基(ji)(ji)酚誘導(dao)的(de)(de)(de)(de)(de)(de)肝(gan)損(sun)傷，而(er)(er)對(dui)原發病(bing)部位(wei)———肝(gan)臟無影響［33］;無獨(du)有(you)偶(ou)，最近(jin)的(de)(de)(de)(de)(de)(de)一項研(yan)究(jiu)(jiu)表(biao)(biao)明(ming)(ming)，EP2抑(yi)(yi)制(zhi)劑通過阻斷外周血(xue)髓細(xi)胞(bao)(bao)EP2受體(ti)而(er)(er)改(gai)善腦認(ren)知障礙，但(dan)抑(yi)(yi)制(zhi)劑本身并沒有(you)穿越血(xue)腦屏障的(de)(de)(de)(de)(de)(de)能力［34］。類似的(de)(de)(de)(de)(de)(de)，基(ji)(ji)于(yu)腸道菌(jun)代(dai)謝物(wu)、細(xi)胞(bao)(bao)因子(zi)(zi)、外泌體(ti)等中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)間媒介(jie)的(de)(de)(de)(de)(de)(de)間接起效(xiao)方式(shi)在(zai)(zai)(zai)很多(duo)(duo)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)的(de)(de)(de)(de)(de)(de)調(diao)(diao)控(kong)方式(shi)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)也有(you)報道［21，35］。苗(miao)明(ming)(ming)三團(tuan)隊［36］認(ren)為皮膚(fu)是(shi)外周的(de)(de)(de)(de)(de)(de)神經－內(nei)(nei)分(fen)泌－免(mian)疫(yi)器官，與(yu)(yu)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)樞神經系(xi)統(tong)具(ju)有(you)相同(tong)(tong)(tong)的(de)(de)(de)(de)(de)(de)神經外胚層來源;中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)外用(yong)(yong)(yong)可通過局部微作用(yong)(yong)(yong)、微刺激、微吸(xi)收方式(shi)，舒達(da)體(ti)表(biao)(biao)與(yu)(yu)體(ti)內(nei)(nei)聯通的(de)(de)(de)(de)(de)(de)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)樞神經－內(nei)(nei)分(fen)泌－免(mian)疫(yi)網絡，達(da)到燮理調(diao)(diao)平的(de)(de)(de)(de)(de)(de)治療(liao)效(xiao)果(guo)。該“體(ti)表(biao)(biao)機(ji)制(zhi)”學(xue)說(shuo)與(yu)(yu)吳尚先的(de)(de)(de)(de)(de)(de)思(si)想基(ji)(ji)本一致(zhi)，也是(shi)一種遠程(cheng)間接的(de)(de)(de)(de)(de)(de)調(diao)(diao)控(kong)模式(shi)，這(zhe)就為外用(yong)(yong)(yong)中(zhong)(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)的(de)(de)(de)(de)(de)(de)起效(xiao)機(ji)制(zhi)研(yan)究(jiu)(jiu)提供了(le)(le)新(xin)的(de)(de)(de)(de)(de)(de)思(si)路。

3結語

中(zhong)(zhong)(zhong)(zhong)(zhong)醫藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)歷數(shu)千年(nian)而(er)賡續至今，對(dui)它的(de)(de)(de)(de)(de)認識(shi)和研(yan)究(jiu)也(ye)鐫刻著(zhu)時(shi)代(dai)(dai)(dai)的(de)(de)(de)(de)(de)烙印(yin)。現(xian)代(dai)(dai)(dai)化(hua)學(xue)(xue)(xue)與(yu)(yu)生(sheng)物(wu)(wu)(wu)(wu)學(xue)(xue)(xue)的(de)(de)(de)(de)(de)發展(zhan)將(jiang)中(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)從樸素抽(chou)象(xiang)的(de)(de)(de)(de)(de)言語(yu)描述(shu)帶入(ru)清晰明確的(de)(de)(de)(de)(de)分(fen)(fen)(fen)子(zi)(zi)世界(jie);而(er)隨著(zhu)生(sheng)物(wu)(wu)(wu)(wu)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)的(de)(de)(de)(de)(de)興起，主(zhu)流(liu)的(de)(de)(de)(de)(de)小分(fen)(fen)(fen)子(zi)(zi)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)物(wu)(wu)(wu)(wu)單極格局正在被大(da)分(fen)(fen)(fen)子(zi)(zi)和介觀尺(chi)度的(de)(de)(de)(de)(de)活性(xing)物(wu)(wu)(wu)(wu)質(zhi)所打破，納(na)米藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)物(wu)(wu)(wu)(wu)、抗(kang)體偶聯(lian)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)物(wu)(wu)(wu)(wu)以及CAR－T為代(dai)(dai)(dai)表的(de)(de)(de)(de)(de)活細胞(bao)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)物(wu)(wu)(wu)(wu)不(bu)(bu)斷刷新著(zhu)傳統藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)物(wu)(wu)(wu)(wu)的(de)(de)(de)(de)(de)邊界(jie)。即使是(shi)小分(fen)(fen)(fen)子(zi)(zi)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)物(wu)(wu)(wu)(wu)領(ling)域，多分(fen)(fen)(fen)子(zi)(zi)組(zu)合(he)的(de)(de)(de)(de)(de)雞(ji)尾酒(jiu)療(liao)法已被發現(xian)具有(you)多重優勢。例如抑制同(tong)一(yi)致癌(ai)途徑的(de)(de)(de)(de)(de)3種或4種抑制劑聯(lian)用(yong)(yong)時(shi)，只需(xu)20%單藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)劑量就(jiu)能(neng)(neng)完全阻斷腫瘤細胞(bao)增殖，且不(bu)(bu)會產生(sheng)耐(nai)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)性(xing)和毒性(xing)［37］;而(er)另一(yi)研(yan)究(jiu)使用(yong)(yong)3種小分(fen)(fen)(fen)子(zi)(zi)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)物(wu)(wu)(wu)(wu)共同(tong)作(zuo)用(yong)(yong)可將(jiang)小鼠多能(neng)(neng)干細胞(bao)誘(you)導成(cheng)(cheng)(cheng)具有(you)全能(neng)(neng)特性(xing)的(de)(de)(de)(de)(de)干細胞(bao)［38］。梳理藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)物(wu)(wu)(wu)(wu)的(de)(de)(de)(de)(de)衍化(hua)規律不(bu)(bu)難看出，藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)物(wu)(wu)(wu)(wu)研(yan)發正在朝(chao)多成(cheng)(cheng)(cheng)分(fen)(fen)(fen)、跨尺(chi)度、多途徑方(fang)向發展(zhan)，這與(yu)(yu)傳統中(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)的(de)(de)(de)(de)(de)作(zuo)用(yong)(yong)特點不(bu)(bu)謀(mou)而(er)合(he)，特別是(shi)與(yu)(yu)結(jie)構(gou)中(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)學(xue)(xue)(xue)統轄的(de)(de)(de)(de)(de)研(yan)究(jiu)維度高(gao)度契(qi)合(he)。就(jiu)像音樂遠非(fei)音符的(de)(de)(de)(de)(de)組(zu)合(he)，文(wen)學(xue)(xue)(xue)不(bu)(bu)止于文(wen)字(zi)的(de)(de)(de)(de)(de)組(zu)合(he)，有(you)著(zhu)千年(nian)積淀的(de)(de)(de)(de)(de)中(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)也(ye)必然是(shi)有(you)著(zhu)超(chao)越化(hua)學(xue)(xue)(xue)成(cheng)(cheng)(cheng)分(fen)(fen)(fen)組(zu)合(he)的(de)(de)(de)(de)(de)更(geng)深層次奧秘，需(xu)要研(yan)究(jiu)者不(bu)(bu)斷挖掘和探索。正如過去(qu)數(shu)十年(nian)在小分(fen)(fen)(fen)子(zi)(zi)化(hua)學(xue)(xue)(xue)維度的(de)(de)(de)(de)(de)深耕(geng)細作(zuo)夯實了中(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)的(de)(de)(de)(de)(de)化(hua)學(xue)(xue)(xue)基礎，結(jie)構(gou)中(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)學(xue)(xue)(xue)的(de)(de)(de)(de)(de)研(yan)究(jiu)思路(lu)將(jiang)豐富中(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)多成(cheng)(cheng)(cheng)分(fen)(fen)(fen)互作(zuo)的(de)(de)(de)(de)(de)物(wu)(wu)(wu)(wu)理結(jie)構(gou)基礎及其關聯(lian)作(zuo)用(yong)(yong)機制，對(dui)更(geng)好地揭示包括外用(yong)(yong)中(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)在內(nei)的(de)(de)(de)(de)(de)中(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)科學(xue)(xue)(xue)內(nei)涵(han)、促進中(zhong)(zhong)(zhong)(zhong)(zhong)藥(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)(yao)現(xian)代(dai)(dai)(dai)化(hua)都有(you)較廣泛的(de)(de)(de)(de)(de)參考(kao)價(jia)值。

作者:喬(qiao)宏志 陳熹 陳軍 狄留慶(qing) 單位(wei):南京中(zhong)醫藥大學(xue)藥學(xue)院(yuan) 江蘇省中(zhong)藥高效給藥系(xi)統工程(cheng)技術研究中(zhong)心 南京大學(xue)生命科學(xue)學(xue)院(yuan) 江蘇省中(zhong)醫外用藥開發(fa)與(yu)應用工程(cheng)研究中(zhong)心