鎽樿锛?/span>鏈枃缁艰堪浜嗕翰鐤忔按鎬у湪鑽墿鎺ч噴銆佹彁楂樼敓鐗╁埄鐢ㄥ害鍜岃嵂鐗╄浇浣撶殑鍒╃敤锛屽拰鐤忔按绂诲瓙瀵瑰湪鐢熺墿鍒跺墏涓殑鐗规畩鎰忎箟銆?/span>

鍏抽敭璇嶏細浜叉按鎬э紱鐤忔按鎬э紱鑽墿鎺ч噴锛涚敓鐗╁埄鐢ㄥ害锛涜嵂鐗╄浇浣擄紱鐤忔按绂诲瓙瀵癸紱鐢熺墿鍒跺墏

鍦ㄦ柊鑽紑鍙戣繃绋嬩腑,鑽晥鏄富瑕佺洰鏍?/span>,浣嗚嵂鐗╃殑鍚告敹銆佸垎甯冦€佷唬璋€佹帓娉勫拰姣掓€?/span>(ADME/T) 绛夋€ц川涔熷悓鏍烽噸瑕?/span>^[1]銆傝嵂鐗╃殑浜叉按鎬т笌鐤忔按鎬т笉浠呭喅瀹氬叾鍦ㄤ綋鍐呯殑鍚告敹銆佸垎甯冦€佷唬璋€佹帓娉勭瓑杩囩▼锛屽悓鏃朵篃鐩存帴褰卞搷鍒拌嵂鐗╃殑浠峰€笺€傚鏋滆嵂鐗╂槸闅炬憾鎬х殑锛岀敓鐗╁埄鐢ㄥ害浣庣殑璇濓紝閫犳垚鑽墿涓嶈兘琚惛鏀惰鎺掓硠鍑哄幓锛岃€岄€犳垚娴垂锛涘鏋滆嵂鐗╀翰姘存€ц繃楂橈紝浠ｈ阿鍛ㄦ湡鐭紝鐢ㄨ嵂閲忓ぇ涓旈绻併€傚悎閫傜殑浜茬枏姘存€х爺绌堕潪甯告湁蹇呰銆傚悓鏃惰嵂鐗╁埗鍓備竴涓緢閲嶈鐨勪綔鐢ㄥ氨鏄敼鍙樿嵂鐗╀翰鐤忔按鎬ф潵杈惧埌鑽墿鐨勭悊鍖栨€ц川鏀瑰彉锛屾彁楂樼敓鐗╁埄鐢ㄥ害绛夈€?/span>

1. 浜?/span>/鐤忔按鎬т笌鑽墿鎺ч噴

楂樺垎瀛愮殑鑱氬悎鐗╀腑鏃㈡湁浜叉按鍩哄洟锛屽張鏈夌枏姘村熀鍥紝浠庤€岃〃鐜颁竴浜涙€ц川鍙敤浜庤嵂鐗╃殑缂撻噴锛屽叾閲婅嵂鏈哄埗涓昏鏄憾鍑哄拰鎵╂暎^[2]銆傜枏姘村嚌鑳舵槸鍑濊兌鍐呴儴鍚湁涓€瀹氶噺鐤忔按鐗囨柇鎴栫枏姘村熀鍥㈢殑姘村嚌鑳讹紝杩欎簺鍩哄洟鍙互鏄嚌鑳剁綉缁滀笂鐨勪晶鍩烘垨鍖呭煁鍦ㄥ嚌鑳跺唴閮ㄧ殑閾剧姸楂樺垎瀛愪晶鍩猴紝鐢变簬杩欎簺闈炴瀬鎬х殑鐤忔按鍩哄洟鍏锋湁鐤忔按缂斿悎浣滅敤锛屽苟鍦ㄦ煇浜涚壒瀹氭潯浠朵笅鍙皢鑽墿缂撴參閲婃斁^[3]銆傞噴鑽奖鍝嶅洜绱犳湁鑽墿鐨勬憾瑙ｅ害銆佽仛鍚堢墿鐨勬按鍖栭€熷害鍙婅仛鍚堢墿鐨勭矘搴︾瓑^[4]銆?/span>

杩樻湁锛?/span>N-寮備笝鍩轰笝鐑叞鑳烘按鍑濊兌(PN IPAAm)鍦ㄥ叾鏈€浣庝复鐣屾憾瑙ｆ俯搴?/span>(LCST)闄勮繎瀛樺湪鍙€嗙殑涓嶈繛缁殑浣撶Н鐩歌浆鍙樸€傚綋鐜娓╁害绋嶇◢楂樹簬LCST鏃讹紝鍏朵綋绉細绐佺劧鍓х儓鏀剁缉;褰撶幆澧冩俯搴﹂檷鍒?/span>LCST浠ヤ笅鏃?/span>, 姘村嚌鑳朵細閲嶆柊婧惰儉銆傚鏁扮爺绌惰€?/span>^[5] 璁や负PN IPAAm娓╂晱鎬т笌鍏跺垎瀛愮粨鏋勪腑鐨勭枏姘存€у紓涓欏熀鍜屼翰姘存€ч叞鑳哄熀鏈夊叧,瀹冧滑鍒嗗埆浣嶄簬鍑濊兌缃戠粶涓翰/鐤忔按鍖哄煙,涓斿瓨鍦ㄤ翰/鐤忔按骞宠　銆?/span>Ichikawa绛?/span>^[6]鏍规嵁姝ゆ€ц川璁捐浜嗕竴绉嶅井鑳跺泭锛屽埄鐢ㄦ俯搴︾殑鍙樺寲鎺у埗鑽墿鐨勯噴鏀俱€?/span>

    涓€浜涗笉婧朵簬姘存垨姘存憾鎬ф瀬灏忕殑楂樺垎瀛愯仛鍚堢墿銆佹棤姣掑鏂欑瓑涔熷彲鐢ㄤ簬缂撻噴鏉愭枡锛屽涔欏熀绾ょ淮绱?/span>(EC)銆佽仛涔欑儻銆佽仛涓欑儻銆佽仛纭呮哀鐑峰拰鑱氭哀涔欑儻绛?/span>^[7]銆備互EC涓洪鏋舵潗鏂欍€佺緹涓欏熀鐢插熀绾ょ淮绱犱负鑷村瓟鍓傚彲鍒跺緱闀挎晥鑼剁⒈鐗?/span>^[8]銆?/span>

缂撻噴浣滅敤杈呮枡鐨勯€夋嫨鍜屽簲鐢ㄥ浜庡埗鍓傜殑缂撻噴浣滅敤鏄竴涓噸瑕佺殑褰卞搷鍥犵礌锛岀紦閲婂埗鍓傚湪寰堝ぇ绋嬪害涓婁緷璧栦簬杈呮枡鐨勫悎鐞嗛€夋嫨鍜屽簲鐢?/span>^[9]銆?/span>

姝ゅ锛岀撼绫虫帶閲婄郴缁熺殑杞戒綋鏉愭枡澶氭槸鐤忔按鎬х殑锛屽舰鎴愮殑绾崇背绮掓槗琚泲鐧借川鍚搁檮鍜岀綉鐘跺唴鐨郴缁熸崟鎹夛紝鐢ㄨ仛涔欎簩閱囦慨楗扮撼绫崇矑琛ㄩ潰鏀瑰杽鍏朵翰姘存€э紝鍙互鍏嬫湇姝ょ己鐐?/span>^[10]銆?/span>

2. 浜?/span>/鐤忔按鎬т笌鐢熺墿鍒╃敤搴?/span>

褰卞搷鐢熺墿鍒╃敤搴︾殑鑽墿涓昏鏈変袱绫伙細涓€绫绘槸闅炬憾鎬ц嵂鐗╋紝鐢变簬棰楃矑澶у皬鎴栧姞鍏ヨ祴鍨嬪墏涓嶅悓,铏界劧鍙ｆ湇鍓傞噺鐩稿悓,鐤楁晥鍗存湁寰堝ぇ宸紓銆傚彟涓€绫绘槸瀹夊叏鑼冨洿杈冪獎鐨勮嵂鐗?/span>,鏈夋晥鍓傞噺鍜屼腑姣掑墏閲忛潪甯告帴杩戯紝鍚告敹閲忕殑澶氬皯鐩存帴褰卞搷鍒扮敤鑽畨鍏紝鎵€浠ユ€庢牱鎻愰珮涓婅堪鑽墿鐨勭敓鐗╁埄鐢ㄥ害鏄嵂鍓傜爺绌剁殑闅剧偣^[11]銆傞毦婧舵€ц嵂鐗╁湪娑堝寲娑蹭腑鐨勬憾鍑洪€氬父涓哄叾鍚告敹鐨勯檺閫熼樁娈点€傚洜姝?/span>,鎻愰珮闅炬憾鎬ц嵂鐗╃殑婧惰В搴﹀拰婧跺嚭閫熷害甯告垚涓烘敼鍠勫叾鍙ｆ湇缁欒嵂鐢熺墿鍒╃敤搴︾殑棣栬姝ラ銆?/span>

   2.1 鍚堟垚姘存憾鎬у墠浣撹嵂鐗┿€€閫氳繃鎴愰叝銆佹垚鐩愩€佹垨杩涜鍒嗗瓙缁撴瀯淇グ褰㈡垚浠ュ叡浠烽敭缁撳悎浜叉按鎬уぇ鍒嗗瓙鐨勫墠浣撹嵂鐗┿€傚鍏剁７閰搁叝鍓嶈嵂涓庡師鑽湪浜轰綋鍐呯殑鍚告敹,鍙戠幇鏃犺鍦ㄩ珮鍓傞噺( > 100mg·kg^-1) 鎴栦綆鍓傞噺( < 100mg·kg^-1) 涓?/span>,鍓嶈嵂杈冧箣鍘熻嵂鐨勭敓鐗╁埄鐢ㄥ害鐨嗘湁绾?/span>19 %鐨勬彁楂?/span>^[12]銆備篃鏈変汉鐮旂┒琛ㄦ槑^[13]锛氭垚閰兘澧炲姞鑽墿鐨勯叝婧舵€т絾骞朵笉鑳芥彁楂樼敓鐗╁埄鐢ㄥ害銆?/span>

2.2 鍒跺鎴愮幆绯婄簿鍖呭悎鐗?/span>  闅炬憾鎬ц嵂鐗╀笌β-CD褰㈡垚鍖呭悎鐗╁悗锛岃嵂鐗╁垎瀛愯鍖呭惈浜?beta;-CD鍒嗗瓙绌鸿厰涓紝鍏锋湁寰堥珮鐨勫垎鏁ｅ害锛屽悓鏃剁敱浜?beta;-CD 鐨勪翰姘存€э紝浣垮寘鍚堢墿鍏锋湁鑹ソ鐨勫彲娑︽箍鎬э紝鑽墿寰楀埌浜嗗婧讹紝鍏朵綋澶栨憾鍑虹壒鎬у拰浜轰綋鐢熺墿鍒╃敤搴︿粠鑰屾敼鍠勩€傚閰礇鑺殑β-CD 鍖呭悎鐗╁湪5min 鍐呭叏閮ㄦ憾鍑?/span>,鑰屽師鑽矇鏈湪鐩稿悓婧跺嚭浠嬭川涓?/span>60min 鍐呭彧婧跺嚭50. 1 %;鍙ｆ湇缁欒嵂鍚庯紝鍖呭悎鐗╃殑C _max銆?/span>AUC0锝?/span>8h鍒嗗埆杈冨師鑽矇鏈彁楂?/span>6鍊嶅拰3鍊?/span>^{[14銆?/span>15]} 銆?/span>

2.3 鍒跺鎴愬浐浣撳垎鏁ｄ綋  甯搁€夌敤浜叉按鎬ф垨涓や翰鎬ц浇浣撴潗鏂欍€備互涓嶅悓杞戒綋鏉愭枡鍒舵垚鐨勫浐浣撳垎鏁ｄ綋瀵硅嵂鐗╂憾鍑虹殑褰卞搷涓嶅悓^[16]銆傞毦婧舵€ц嵂鐗╀笌閫傚疁杞戒綋褰㈡垚鐨勫浐浣撳垎鏁ｄ綋涓紝鑽墿浠ュ井鏅舵€併€佹棤瀹氬瀷鎬併€佽兌浣撳垎鏁ｆ€佹垨鍒嗗瓙鍒嗘暎鎬佸瓨鍦紝鎻愰珮鐢熺墿鍒╃敤搴︺€?/span>

3. 浜?/span>/鐤忔按鎬т笌鑽墿杞戒綋

鑽墿杞戒綋鏄寚鑳芥敼鍙樿嵂鐗╁湪浣撳唴鐨勫垎甯冨苟灏嗚嵂鐗╄緭閫佸埌闈跺櫒瀹樼殑鐗╄川銆?/font>

3.1 琛ㄩ潰娲绘€у墏鍦ㄨ嵂鐗╄浇浣撲腑鐨勫埄鐢?/span>  琛ㄩ潰娲绘€у墏鐢变簬鍏剁粨鏋勪笂鏃㈡湁浜叉按鍩哄洟涔熸湁鐤忔按鍩哄洟锛岄潬灏鹃摼鐤忔按鐩镐簰浣滅敤鍜屽ご鍩虹殑鍋舵瀬鐩镐簰浣滅敤锛岃〃闈㈡椿鎬у墏鍦ㄦ憾娑蹭腑鍙紨鍚堝舰鎴愬绉嶈秴鍒嗗瓙鑷粍瑁呬綋缁撴瀯锛屽鑳舵潫(micelle)銆佸井涔虫恫(microemulsion)銆佸泭娉?/span>(vesicle)銆佹恫鏅?/span>(1iquid-crysta1)绛夈€傝繖浜涜〃闈㈡椿鎬у墏鐨勭紨鍚堢粨鏋勬墍鍏锋湁鐨勫唴鑵斿拰鐣岄潰鑶滃叿鏈夊寘杞借嵂鐗╁垎瀛愮殑鑳藉姏锛屽悓鏃跺張涓庣敓鐗╄啘鏈夎壇濂界殑娓楅€忔€?/span>^[17]銆傚叾涓紝澶у垎瀛愯兌鏉熶綔涓鸿嵂鐗╁拰DNA杞戒綋搴旂敤鍓嶆櫙骞块様^[18]銆?/span>

3.2 鍒嗗瓙浼炰綔涓鸿嵂鐗╄浇浣?/span>  鍒嗗瓙浼炲嵆妯′豢浼炵殑缁撴瀯鍜屽姛鑳界殑鍒嗗瓙鍙互灏嗚嵂鐗╁垎瀛愬湪涓庡叾涓嶇浉瀹圭殑鐜閲屽睆钄借捣鏉ャ€傚垎瀛愪紴鍦ㄤ笉鍚岀殑鐜涓牴鎹灞忚斀鐨勫寲鍚堢墿鐨勬€ц川,鑳藉鍛堢幇涓嶅悓鐨勬瀯璞°€傚綋琚睆钄界殑鏄翰姘存€у寲鍚堢墿鏃讹紝鍦ㄦ按婧舵恫涓?/span>,鏆撮湶鏋勮薄鍑虹幇锛涘湪闈炴瀬鎬ф憾娑蹭腑,灞忚斀鏋勮薄鍑虹幇銆傚綋琚睆钄界殑鏄枏姘存€у寲鍚堢墿鏃?/span>,鍦ㄦ按婧舵恫涓?/span>,灞忚斀鏋勮薄鍑虹幇锛涘湪闈炴瀬鎬ф憾娑蹭腑,鏆撮湶鏋勮薄鍑虹幇^[19]銆傝繖鏄垎瀛愪紴鑳藉杈呭姪鑽墿杈撻€佺殑鍏堝喅鏉′欢銆?/span>

鍒嗗瓙浼炰富瑕佹湁涓夐儴鍒嗙粍鎴愩€?/span>Regen绛夐€夌敤鑳嗛吀鍜屼簹绮捐兒鍒嗗埆浣滀负鍒嗗瓙浼炵殑浼為潰鍜屼腑蹇冩敮鎾戞灦锛岃灞忚斀鐨勫寲鍚堢墿(鐢?/span>T琛ㄧず)鏄翰姘存垨鐤忔按鎬х殑鑽墿鍒嗗瓙銆傝儐閰告槸鑳嗘眮閰哥殑涓昏鎴愬垎锛屽畠鏄竴绉嶄袱浜叉€у垎瀛愶紝鑳介€氳繃缇у熀涓庡叾瀹冪墿璐ㄥ舰鎴愮粨鍚堢墿銆備簹绮捐兒鍒嗗瓙鍚湁涓変釜姘ㄥ熀锛屼袱绔拰涓棿鐨勬皑鍩哄彲浠ュ垎鍒笌浼為潰銆佺洰鏍囧垎瀛愮浉杩炴帴銆傝儐閰稿拰浜氱簿鑳哄潎瀛樺湪浜庡摵涔冲姩鐗╃粏鑳炰腑锛屽叿鏈夌敓鐗╃浉瀹规€у拰鍙檷瑙ｆ€?/span>^[20]銆傝儐閰搞€佷簹绮捐兒浠ュ強鏃犻潰鈪犮€佸崟闈⑩叀銆佷袱闈⑩參銆佸洓闈⑩叄绛夊悇绉嶅垎瀛愪紴鐨勭粨鏋勫鍥?/span>1鎵€绀恒€?/span>

鍒嗗瓙浼炲皢鑽墿鍒嗗瓙鍦ㄤ笌鍏朵笉鐩稿鐨勭幆澧冮噷灞忚斀璧锋潵锛屾敼鍙樹簡鑽墿鍒嗗瓙鐨勭墿鐞嗗拰鍖栧鎬ц川锛屼粠鑰屽緢濂藉湴瑙ｅ喅浜嗚嵂鐗╁垎瀛愮┛閫忕敓鐗╄啘浠ュ強姘存憾瑙ｅ害銆佺ǔ瀹氭€х瓑闂^[21]銆?/span>

3.3 鏉愭枡鏀规€х敤浣滆嵂鐗╄浇浣?/span>  甯歌鐨勮仛涔抽吀(PLA)浜叉按鎬ф敼鎬ф潗鏂欐湁鑱氫箼浜岄唶(PEG)^[22]銆佽仛涔?/span>(PVA)^[23]銆佽憽鑱氱硸(dextran)^[24]銆佸３鑱氱硸(chitosan)^[25]绛夈€?/span>PEG鐨勫紩鍏ヤ笉浣嗘彁楂樹簡PLA鐨勪翰姘存€э紝鍚屾椂杩樿祴浜堟潗鏂欐柊鐨勭壒鎬у拰鍔熻兘锛屽畠鍙互鍑忓皯鐢熺墿浣撳唴铔嬬櫧璐ㄥ湪鏉愭枡琛ㄩ潰鐨勫惛闄勫拰缁嗚優鐨勯粡闄勶紝鍦ㄤ綋鍐呬笉鏄撹鍏嶇柅绯荤粺璇嗗埆銆?/span>PEG鏀规€?/span>PLA鍏辫仛鐗╁彲鏈夋晥鍦拌皟鎺ц浇浣撶殑浜茬枏姘存€с€佽嵂鐗╅噴鏀鹃€熺巼鍜岃浇鑽巼^[26]銆?/span>

4. 鐤忔按绂诲瓙瀵逛笌鐢熺墿鍒跺墏

绂诲瓙鍖栧悎鐗╁叿鏈夐珮姘存憾鎬т笉浠呭洜涓虹數鑽凤紝涔熷洜涓哄弽绂诲瓙涓€鑸负鏄撴按鍖栫瀛愶紝濡傛灉灏嗗弽绂诲瓙浠ョ數鑽风浉鍚岃€屼笉鏄撴按鍖栫殑鍖栧悎鐗╁彇浠ｏ紝鍒欒嵂鐗╃殑姘存憾鎬т細鍙戠敓鏄庢樉鍙樺寲銆傜枏姘寸瀛愬(HIP)浠ュ甫鐩稿悓鐢佃嵎鐨勭瀛愭€ц〃闈㈡椿鎬у墏鍙栦唬鏋佹€у弽绂诲瓙锛屼粠鑰屾敼鍙樺叾婧惰В鐗规€?/span>^[27]銆?/span>

   Powers绛夋渶鍏堢爺绌朵簡HIP鐨勭枏姘寸壒鎬э紝鍙戠幇杩欑娌夋穩鍙互鍒嗛厤杩涘叆寮辨瀬鎬ф憾鍓傚姝ｈ緵閱囦腑[28]銆?/span>HIP鐨勬剰涔変箣涓€鏄鍔犵敓鐗╁ぇ鍒嗗瓙鐨勯€忚啘鑳藉姏锛屽鍔犻€忕毊鑳藉姏^[29]銆傞『閾傛槸搴旂敤骞挎硾鐨勬姉鐧岃嵂锛屼絾姣掓€ц緝澶э紝浠ヤ簩杈涚兎鍩虹：閰搁挔鍙栦唬鍏朵腑鐨?/span>Cl ^– 閰嶅熀锛屽埗鎴?/span>HIP鍚庯紝鍏舵按婧舵€у鍔?/span>4涓暟閲忕骇銆傝優鍐呰嵂鐗╂祿搴︿笂鍗?/span>3锛?/span>5鍊嶏紝鏄剧ず浜嗚緝浣庣殑IC₅₀^[30]銆?/span>

5. 鎬荤粨

楂樺垎瀛愯仛鍚堢墿涓€鑸叿鏈変袱浜茬壒鎬э紝鎵€浠ュ湪鐢ㄤ簬鑽墿鐨勬帶閲婏紝鎻愰珮鐢熺墿鍒╃敤搴﹀拰浣滀负鑽墿杞戒綋閮藉叿鏈夊緢澶т綔鐢紝鐩墠涔熸槸鑽墿鍒跺墏涓爺绌舵瘮杈冩椿璺冪殑棰嗗煙銆傚彂瑙夋柊鐨勯珮鑱氱墿鍜岄珮鑱氱墿涓庤嵂鐗╃殑鏈夋晥缁撳悎锛屾彁楂樼ǔ瀹氭€х瓑涓哄伐涓氬寲鐢熶骇鏈嶅姟銆?/font>

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