CN114641517A - 经鼻腔给药的有效的脑递送技术 - Google Patents
经鼻腔给药的有效的脑递送技术 Download PDFInfo
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Abstract
本发明涉及经鼻腔给药的有效的脑递送技术,更详细而言,本发明通过将可以用作药物递送体的pH‑敏感型生物还原性PPA聚合物鼻腔给药而有效递送到脑,从而提供用于诊断、预防或治疗中枢神经系统脑疾病、神经退行性疾病、或脑肿瘤的效果。
Description
技术领域
本发明涉及经鼻腔给药的有效的脑递送技术,该技术通过将可以用作药物递送体的pH-敏感型生物还原性聚合物通过鼻腔给药而有效递送到脑部,从而用于诊断、预防或治疗中枢神经系统疾病、神经退行性疾病或脑肿瘤。
背景技术
病变部位的实时和非侵袭性成像对于中枢神经系统或脑肿瘤的治疗是非常适合的。例如,病变组织的非侵袭性追踪和成像可以通过日常实施的诊断程序早期发现,从而可以及时干预病变并引导患者的整体性的得到改善的预后。
作为新型递送系统,兴起了鼻腔给药(intra-nasal delivery),其可以绕过对用于治疗中枢神经系统疾病的治疗剂的递送构成最大障碍的血脑屏障(Blood-BrainBarrier)。
为了提高通过鼻腔给药向脑部递送的效率,开发了各种物质,本发明利用聚合物作为其递送体。
发明内容
本发明的目的是提供可以用作药物递送体的pH-敏感型生物还原性聚合物及其药剂学用途。
为了实现上述目的,本发明提供由下述化学式1表示的聚合物:
[化学式1]
在上述式中,
X为具有2000至10000Da的分子量的PEG,
n为1至10。
本发明还提供用于通过鼻腔给药向脑部递送药物的组合物,其包含由上述化学式1表示的聚合物作为药物递送用载体。
本发明还提供药物递送体,其包含由上述化学式1表示的聚合物、以及选自治疗剂和诊断剂中的一种以上的药物。
本发明还提供通过鼻腔给药向脑部递送药物的方法,其包括将上述药物递送体鼻腔给药到个体的步骤。
本发明还提供治疗中枢神经系统疾病、神经退行性疾病或脑肿瘤中的任一种的方法,其包括将上述药物递送体以药学有效量鼻腔给药到有需要的个体的步骤。
本发明的pH-敏感型生物还原性聚合物通过鼻腔给药来绕过血脑屏障并改善药物的生物利用度,从而可以通过降低药物的给药量来减少副作用。
另外,鼻腔给药的药物在最初不会通过进行全身循环的血流,而是通过到达脑部的目标病变部位,从而最大程度减少因过量给药引起的不良的副作用。此外,本发明可以有效地将药物递送到脑组织的各个部分,因此适用于中枢神经系统疾病、神经退行性疾病或脑肿瘤的治疗。此外,本发明的pH-敏感型生物还原性聚合物被标记为诊断用标记物并通过鼻腔给药递送到脑组织,从而可以用于中枢神经系统疾病、神经退行性疾病或脑肿瘤的诊断。
附图说明
图1表示Ad/PPA-IR780的生物体内荧光图像。
图2表示Ad/PPA-IR780复合物对原位胶质母细胞瘤的强力抗肿瘤效果。
图3表示各种器官中的活体IVIS成像和脑组织的活体NIR和光学成像。
图4表示各种Ad/高分子复合物的抗肿瘤功效。
图5表示各种Ad/高分子复合物的生物体内分布。
图6表示在原位脑肿瘤中利用生物发光成像的各种Ad/高分子复合物的抗肿瘤功效。
图7比较了各种Ad/高分子复合物的抗肿瘤功效。
图8表示Ad/PPA-IR780根据各种给药途径的抗肿瘤功效。
图9表示oAd/PPA-IR780的强力治疗性功效。
图10表示oAd/PPA-IR780的强力治疗性功效。
图11表示在具有脑肿瘤的小鼠模型中鼻腔或静脉给药PPA-PTX-IR780后,脑组织的不同区域中PTX的浓度。
图12表示在正常小鼠模型中鼻腔或静脉给药PPA-PTX-IR780后,脑组织的不同区域中PTX的浓度。
图13表示PTX在具有肿瘤的小鼠模型或正常小鼠的脑中的生物利用度。
图14表示在具有胶质母细胞瘤的小鼠模型中鼻腔给药siRNA-Cy5.5/PPA-IR780后,按脑的区域区分的siRNA分布图。
图15表示在具有脑肿瘤的小鼠模型中鼻腔或静脉给药pDNA-FITC/PPA-IR780后,pDNA强度-时间的图。
图16表示在正常小鼠模型中鼻腔或静脉给药pDNA-FITC/PPA-IR780后,pDNA强度-时间的图。
图17表示pDNA在具有肿瘤的小鼠模型或正常小鼠的脑中的生物利用度。
图18表示在正常小鼠模型中鼻腔给药pDNA-FITC/聚合物复合物后,按脑的区域区分的pDNA分布图。
图19将经鼻腔给药的oAd/PPA-Cu-64-DOTA-赫赛汀复合物的有效递送通过PET/CT成像进行显示。
图20显示在正常小鼠中经鼻腔给药的PPA-爱必妥递送效率。
图21显示鼻腔给药后PPA-IR780-PTX的生物利用度。
图22将经鼻腔给药的PPA-PTX的强力抗肿瘤功效通过MR成像进行显示。
图23是在U87MG/Fluc原位脑肿瘤模型中显示经鼻腔给药的PPA-PTX的强力抗肿瘤功效的H&E染色结果。
图24显示在U87MG/Fluc原位脑肿瘤模型中经鼻腔给药的PPA-PTX的强力抗肿瘤功效。
具体实施方式
下面,对本发明的构成具体地进行说明。
本发明涉及由下述化学式1表示的聚合物。
[化学式1]
在上述式中,
X为具有2000至10000Da的分子量的PEG,
n为1至10。
上述Y可以进一步改性以具有伯胺基。胺基可以用于药物或靶向部分的共轭。
本发明的化学式1的聚合物是一种具有生物降解性和pH敏感性的化合物,其通过细胞内pH范围(约pH6.0)中的高吸收率而流入,并将低pH的缺氧肿瘤微环境作为靶向,由(i)免疫反应可逃避位点(escapable portion from immune reactions)、(ii)电荷性位点(chargeable portion)和(iii)包含二硫键的生物还原性位点(bioreducible portion)组成。
更具体而言,上述化学式1的聚合物的又可以称为PP或PPA。
若Y为时,化学式1的聚合物由PP表示。即,PEG-Pip-N,N'-胱胺双丙烯酰胺(CBA)[PEG-Pip-N,N'-cystaminebisacrylamide(CBA)]。在本说明书中,PP也称为PPCBA。在下述实施例中,PP还称为PP5,是指使用了5kDa PEG的PP。若Y为精氨酸共轭的PEI时,化学式1的聚合物由PPA表示,并通过PEG-Pip-CBA(PP)和精氨酸共轭的PEI(PEI-Arg)的反应来合成。在本说明书中,PEI可以为具有1000至10000Da分子量的支链的PEI,精氨酸可以与PEI的伯胺共轭。Y可以进一步改性而具有伯胺基。胺基可以用于药物或靶向部分的共轭。在下述实施例中,PPA也可以由PPA2或PPA5表示,并且分别是指使用了2kDa或5kDa PEG的PPA。
在上述化学式1中,PEG作为免疫反应可逃避位点发挥作用,精氨酸是赋予聚合物正电荷的电荷性位点。精氨酸赋予聚合物正电荷,使其可以通过离子相互作用与负电荷性表面(例如,腺病毒的负电荷性表面)结合,从而形成复合物。N,N'-胱胺双丙烯酰胺(CBA)是作为包含二硫键的生物还原性位点发挥作用的部分,提供聚合物的pH敏感性的部分为哌嗪(Pip)。
例如,将PPA的合成过程简略说明如下:
首先,为了合成PEI-Arg,通过EDC/NHS的偶联反应使精氨酸和聚乙烯亚胺共轭。
为了合成PEG-Pip-CBA(PP),使PEG-丙烯酸酯(5kDa)、N,N'-胱胺双丙烯酰胺(CBA)和哌嗪(Pip)反应,然后添加PEI-Arg来合成PPCBA-PEI-Arg(PPA)。其中,PEG-丙烯酸酯包括各种活化的PEG-丙烯酸酯,例如,可以使用甲氧基-、邻吡啶基二硫化物(ortho pyridyldisulfide(OPSS))、COOH-、NH2-、或马来酰亚胺-PEG丙烯酸酯。在一个具体例中,EPG-丙烯酸酯可以为甲氧基-PEG-丙烯酸酯。作为备选方案,为了聚乙二醇化,可以使用其它PEG衍生物代替PEG-丙烯酸酯。
更具体而言,本发明的聚合物由下述化学式2表示:
[化学式2]
在上述式中,
n为1至10,
m为44至228(PEG具有2000至10000Da的分子量)。
Y进一步改性而具有伯胺基。胺基可以用于药物或靶向部分的共轭。
本发明的PPA聚合物为pH敏感型,特别是将缺氧条件下的肿瘤细胞的微环境作为靶向,因此可以将药物递送到肿瘤细胞。此外,由于表面带正电荷,可以用作通过与具有负电荷性表面的靶成分结合来将药物等递送到生物体内的载体。因此,除了肿瘤细胞以外,PPA聚合物还可以将药物递送到靶向病变部位。
另外,本发明的pH-敏感型聚合物可以通过鼻腔给药绕过血脑屏障而流入到脑组织,因此可以用作药物载体。
因此,作为本发明的另一实施方式,本发明提供用于通过鼻腔给药向脑部递送药物的组合物,其包含由上述化学式1表示的聚合物作为药物递送用载体。
作为本发明的另一实施方式,本发明提供药物递送体,其包含由上述化学式1表示的聚合物、以及选自治疗剂和诊断剂中的一种以上的药物。
本发明的PPA聚合物可以作为用于药物递送的载体使用,可以将肿瘤的微环境作为靶向,或者通过与靶成分结合而将药物递送到除肿瘤细胞以外的靶向病变部位,并且与光敏剂结合而递送到肿瘤细胞,在照射700-900nm波长范围的近红外线时,可以通过光热疗法来杀死肿瘤细胞。
另外,本发明的PPA聚合物于表面与诊断剂结合并通过鼻腔给药绕过脑血屏障而流入到脑组织,因此可以用作脑部疾病的诊断。
上述药物递送体可以优选为鼻腔给药用药物递送体。本发明的PPA聚合物通过鼻腔给药绕过脑血屏障而流入到脑组织,从而可以有效递送药物。
本发明的药物递送体可以包括PPA聚合物和药物的复合物形态。
上述治疗剂可以为选自基因递送系统、光敏剂和药物活性成分中的一种以上。
可以适用利用于常规基因治疗的所有基因递送系统,优选可以使用质粒;腺病毒(Lockett LJ,et al.,Clin.Cancer Res.3:2075-2080(1997))、腺相关病毒(Adeno-associated viruses:AAV,Lashford LS.,et al.,Gene Therapy Technologies,Applications and Regulations Ed.A.Meager,1999)、逆转录病毒(Gunzburg WH,et al.,Retroviral vectors.Gene Therapy Technologies,Applications and RegulationsEd.A.Meager,1999)、慢病毒(Wang G.et al.,J.Clin.Invest.104(11):R55-62(1999))、单纯疱疹病毒(Chamber R.,et al.,Proc.Natl.Acad.Sci USA 92:1411-1415(1995))、牛痘病毒(Puhlmann M.et al.,Human Gene Therapy 10:649-657(1999))、呼肠孤病毒、痘病毒、塞姆利基森林病毒、麻疹病毒(Measles virus)等病毒载体;内含上述裸重组DNA分子或质粒的脂质体(Methods in Molecular Biology,Vol 199,S.C.Basu and M.Basu(Eds.),Human Press 2002)或类脂质体。
i.腺病毒
腺病毒由于中等的基因组大小、操作方便、高滴度、广泛的靶细胞和优异的感染性而广泛用作基因递送载体。基因组的两端包含100-200bp的ITR(inverted terminalrepeat,反向末端重复序列),它是DNA复制和包装中必不可少的顺式元件。基因组的E1区域(E1A和E1B)编码调节转录和宿主细胞基因转录的蛋白质。E2区域(E2A和E2B)编码参与病毒DNA复制的蛋白质。
在目前开发的腺病毒载体中,广泛使用缺乏E1区域的复制缺陷型腺病毒。另一方面,E3区域从常规的腺病毒载体中被去除而提供插入外源基因的位点(Thimmappaya,B.etal.,Cell,31:543-551(1982)和Riordan,J.R.et al.,Science,245:1066-1073(1989))。因此,待转运到细胞内的靶核苷酸序列优选插入缺失的E1区域(E1A区域和/或E1B区域,优选E1B区域)或E3区域,更优选插入缺失的E1区域。在本说明书中,与病毒基因组序列相关所使用的用语“缺失”不仅包括相应序列完全缺失,还具有部分缺失的意思。
腺病毒具有42种不同的血清型和A-F亚组。其中,属于C亚组的2型和5型腺病毒是用于获得本发明的腺病毒载体的最优选的起始物质。2型和5型腺病毒的生化和遗传信息是众所周知的。
通过腺病毒转运的外源基因以与附加体相同的方式复制,因此对宿主细胞的遗传毒性非常低。因此判断利用了本发明的腺病毒基因递送系统的基因治疗是非常安全的。
ii.逆转录病毒
逆转录病毒广泛用作基因递送载体,因为可以将自身基因插入宿主的基因组,转运大量的外源遗传物质,并且可以感染的细胞谱较广。
为了构建逆转录病毒载体,待转运到细胞内的靶核苷酸序列插入逆转录病毒基因组而代替插入逆转录病毒的序列,从而产生复制缺陷型病毒。为了产生病毒体,构建了包含gag、pol和env基因但没有LTR(long terminal repeat,长末端重复序列)和Ψ序列的包装细胞株(Mann et al.,Cell,33:153-159(1983))。将包含待转运的靶核苷酸序列、LTR和Ψ序列的重组质粒引入上述细胞株时,Ψ序列能够产生重组质粒的RNA转录物,并且该转录物被包装成病毒,病毒排出到培养基(Nicolas and Rubinstein"Retroviral vectors,"In:Vectors:A survey of molecular cloning vectors and their uses,Rodriguez andDenhardt(eds.),Stoneham:Butterworth,494-513(1988))。收集、浓缩含有重组逆转录病毒的培养基并用作基因递送系统。
发表了利用了第二代逆转录病毒载体的基因递送。(Kasahara et al.Science,266:1373-1376(1994))制造了莫洛尼鼠白血病病毒(MMLV)的突变体,其中,将EPO(erythropoietin,促红细胞生成素)序列插入包膜位点而产生了具有新型结合特征的嵌合蛋白质。本发明的基因递送系统也可以根据上述第二代逆转录病毒载体的构建策略进行制造。
iii.AAV载体
腺相关病毒(AAV)可以感染非分裂细胞,由于具有可以感染各种类型的细胞的能力,因此适于本发明的基因递送系统。关于AAV载体的制造和用途的详细说明详细地记载于美国专利第5139941号和第4797368号。
对于AAV作为基因递送系统的研究公开于LaFace et al,Viology,162:483486(1988),Zhou et al.,Exp.Hematol.(NY),21:928-933(1993),Walsh et al,J.Clin.Invest.,94:1440-1448(1994)和Flotte et al.,Gene Therapy,2:29-37(1995)。
通常,AAV病毒是将包含在旁边具有两个AAV末端重复序列的靶基因序列(待转运到细胞内的靶核苷酸序列)的质粒(McLaughlin et al.,J.Virol.,62:1963-1973(1988)和Samulski et al.,J.Virol.,63:3822-3828(1989))和包含没有末端重复序列的野生型AAV编码序列的表达质粒(McCarty et al.,J.Virol.,65:2936-2945(1991))共转化而制造的。
iv.其它病毒载体
其它病毒载体也可以用作本发明的基因递送系统。来源于牛痘病毒(PuhlmannM.et al.,Human Gene Therapy 10:649-657(1999);Ridgeway,"Mammalian expressionvectors,"In:Vectors:A survey of molecular cloning vectors and theiruses.Rodriguez and Denhardt,eds.Stoneham:Butterworth,467-492(1988);Baichwaland Sugden,"Vectors for gene transfer derived from animal DNA viruses:Transient and stable expression of transferred genes,"In:Kucherlapati R,ed.Gene transfer.New York:Plenum Press,117-148(1986)和Coupar et al.,Gene,68:1-10(1988))、慢病毒(Wang G.et al.,J.Clin.Invest.104(11):R55-62(1999))或单纯疱疹病毒(Chamber R.,et al.,Proc.Natl.Acad.Sci USA 92:1411-1415(1995))的载体也可以用作可以将靶核苷酸序列转运到细胞内的转运系统。
除此以外,作为病毒载体,有呼肠孤病毒、痘病毒、塞姆利基森林病毒和麻疹病毒(Measles virus)等。
v.脂质体
脂质体通过分散在水相中的磷脂自动形成。将外源DNA分子由脂质体成功转运到细胞内的例子公开于Nicolau和Sene,Biochim.Biophys.Acta,721:185-190(1982)以及Nicolau et al.,Methods Enzymol.,149:157-176(1987)。另一方面,作为在利用了脂质体的动物细胞的转化中利用最多的试剂,有脂质体(Lipofectamine,Gibco BRL)。内含待转运的靶核苷酸序列的脂质体通过内吞作用、吸附到细胞表面或者与浆细胞膜融合等机制而与细胞相互作用,从而将靶核苷酸序列转运到细胞内。
在本发明的一个具体例中,上述基因递送系统可以为重组腺病毒。
随着重组腺病毒作为基因递送载体的各种优点凸显,其在癌症基因治疗中的使用频率具有正在稳步增加的趋势。特别是,在准备利用基因治疗剂治疗癌症时,具有不需要长期且持续地治疗基因的表达的优点。此外,由于用作载体的病毒引发的宿主的免疫反应不是大问题或反而可以发挥优势,因此重组腺病毒作为癌症治疗用基因递送体正备受关注。
上述重组腺病毒可以为复制缺陷型腺病毒或溶瘤腺病毒。
复制缺陷型腺病毒插入治疗用基因而不是腺病毒的复制所必需的E1基因(全部或部分)而进行重组,使其不能在导入了腺病毒的细胞内复制。
溶瘤腺病毒为E1B 55kDa基因部分性缺失的腺病毒,只能在p53功能性失活的细胞中增殖。在p53的功能被抑制的癌细胞中,病毒的增殖活跃,相反,在正常细胞中,病毒的增殖被抑制。因此,溶瘤腺病毒不影响正常细胞而可以选择性地只杀死癌细胞,因此在癌症治疗中特别有利。
在本发明的一个具体例中,重组腺病毒具有失活的E1B 19kDa基因、E1B 55kDa基因或E1B 19kDa/E1B 55kDa基因,优选具有失活的E1B 19kDa和E1B 55kDa基因。
在本说明书中,与基因相关而使用的用语“失活”是指其基因不正常进行转录和/或解码,从而通过该基因而编码的正常的蛋白质的功能没有表现出来。例如,失活E1B19kDa基因是在其基因中发生突变(置换、附加、部分缺失或全部缺失)而不能产生活性的E1B 19kDa蛋白质的基因。在缺失E1B 19kDa基因时,可能增加细胞凋亡,在缺失E1B 55kDa基因时,具有肿瘤细胞特异性(参照:韩国专利申请第2002-0023760号)。
根据本发明的一个具体例,本发明的重组腺病毒可以包含活性的E1A基因。包含E1A基因的重组腺病毒具有能够复制的特性。根据本发明的更优选的具体例,本发明的重组腺病毒包含失活的E1B 19kDa/E1B 55kDa基因和活性的E1A基因。
在本发明的一个具体例中,基因递送系统可以是缺失E1位点的复制-缺陷型(replication-incompetent)的选择性地杀伤肿瘤的腺病毒。
另外,上述载体优选进一步包含选择标记。本发明中的用语“选择标记(selectionmarker)”用于便于选择通过引入shRNA表达盒而转化的细胞。作为可以在本发明的载体中使用的选择标记,只要是可以容易地检测或测定是否引入载体的基因,就没有特别限定,但作为赋予药物抗性、营养需求性、对细胞毒剂的抗性或表面蛋白质的表达等可选择表型的代表性的标记,例如,有GFP(绿色荧光蛋白质)、嘌呤霉素(puromycin)、新霉素(Neomycin:Neo)、潮霉素(hygromycin:Hyg)、组氨醇脱氢酶(histidinol dehydrogenase gene:hisD)或鸟嘌呤磷酸核糖基转移酶(guanine phosphosribosyltransferase:Gpt)等。
另外,上述光敏剂可以选自卟啉系(phorphyrins)化合物、二氢卟酚系(chlorins)化合物、菌绿二氢卟吩系(bacteriochlorins)化合物、酞菁系(phthalocyanines)化合物、萘酞菁系(naphthalocyanines)化合物和5-氨基乙酰丙酸酯系(5-aminolevuline esters)化合物。
优选地,可以是在700-900nm波长范围的近红外线下表现出光热效应的IR-780、Cu-64-DOTA等。
另外,本发明的药物活性成分的种类没有特别限定,例如,可以例举出选自抗癌药、抗生素、激素、激素拮抗剂、白细胞介素、干扰素、生长因子、肿瘤坏死因子、内毒素、淋巴毒素、尿激酶、链激酶、组织纤溶酶原激活剂、蛋白酶抑制剂、烷基磷酸胆碱、放射性同位素标记成分、表面活性剂、心血管系统药物和神经系统药物中的一种以上。
上述中的抗癌药可以例举出贝伐单抗(bevacizumab)、替莫唑胺(temozolomide)、亚硝基脲(nitrosourea)、顺铂(cisplatin)、PCV(丙卡巴肼(procarbazine)+CCNU+长春新碱(vincristine))、长春碱(vinblastine)、长春新碱(vincristine)、长春氟宁(vinflunine)、长春地辛(vindesine))、长春瑞滨(vinorelbine)、卡巴他赛(cabazitaxel)、多西他赛(docetaxel)、拉洛他赛(larotaxel)、奥他赛(ortataxel)、紫杉醇(paclitaxel)、替司他赛(tesetaxel)、伊沙匹隆(ixabepilone)、赫赛汀(herceptin)、爱必妥(erbitux)、环磷酰胺(Cyclophosphamide)、多柔比星(Doxorubicin)、依托泊苷(Etoposide)、拓扑替康(Topotecan)、卡铂(carboplatin)、丙卡巴肼(procarbazine)、氮芥(mechlorethamine)、异环磷酰胺(ifosfamide)、马法兰(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(bisulfan)、放线菌素(dactinomycin)、柔红霉素(daunorubicin)、博来霉素(bleomycin)、普利霉素(plicomycin)、丝裂霉素(mitomycin)、他莫昔芬(tamoxifen)、反式铂(transplatinum)、5-氟尿嘧啶(5-fluorouracil)、或甲氨蝶呤(methotrexate)等。
本发明的药物递送体可以通过PPA5聚合物的肿瘤靶向性而用于脑肿瘤的预防或治疗,可以通过与其它靶成分的结合而将药物递送到靶向病变部位,因此可以用于中枢神经系统疾病或神经退行性疾病的预防或治疗。
上述中枢神经系统疾病可以例举出认知障碍、智力障碍、小脑症、癫痫、神经发育障碍、痴呆、自闭症谱系障碍、唐氏综合症、雷特综合征、脆性X综合征等。
上述神经退行性疾病可以为缺血性脑卒中(ischemic stroke)、创伤性脑损伤、急性播散性脑脊髓炎(acute disseminated encephalomyelitis)、肌萎缩侧索硬化症(amyotrophic lateral sclerosis,ALS)、色素性视网膜炎(retinitis pigmentosa)、轻度认知障碍、阿尔茨海默氏病、匹克氏病、老年痴呆、进行性核上性麻痹(progressivesupranuclear palsy)、皮层下痴呆、威尔逊病、多发性梗塞(multiple infarct disease)、动脉硬化性痴呆(arteriosclerotic dementia)、AIDS相关痴呆、小脑变性(cerebellardegeneration)、脊髓小脑变性综合征(spinocerebellar degeneration syndromes)、弗里德赖希共济失调(Friedreichs ataxia)、毛细血管扩张性共济失调(ataxiatelangiectasia)、癫痫相关的脑损伤、脊髓损伤、不安腿综合征(restless legssyndrome)、亨廷顿氏病、帕金森病、纹状体黑质变性(striatonigral degeneration)、脑血管炎(cerebral vasculitis)、线粒体脑肌病(mitochondrial encephalomyopathies)、神经元蜡样脂褐质沉积症(neuronal ceroid lipofuscinosis)、脊髓性肌肉萎缩症(spinalmuscular atrophies)、与中枢神经系统相关的溶酶体贮积症(lysosomal storagedisorder)、脑白质营养不良(leukodystrophies)、尿素循环缺陷障碍(urea cycle defectdisorder)、肝性脑病(hepatic encephalopathies)、肾性脑病(renalencephalopathies)、代谢性脑病(metabolic encephalopathies)、卟啉症(porphyria)、细菌性脑膜炎(bacterial meningitis)、病毒性脑膜炎(viral meningitis)、脑膜脑炎(meningoencephalitis)、朊病毒病(prion diseases)、神经毒性化合物中毒(poisoningswith neurotoxic compounds)、格林巴利综合征(Guillain Barre syndrome)、慢性炎症性神经病(chronic inflammatory neuropathies)、多发性肌炎(polymyositis)、皮肌炎(dermatomyositis)或辐射引起的脑损伤(radiation-induced brain damage)等。
上述脑肿瘤(brain tumor或encephaloma)是指发生在大脑皮层和脑膜中的肿瘤。上述脑肿瘤可以为神经胶质瘤(glioma)、少突胶质细胞瘤(oligodendroglioma)、胶质母细胞瘤(glioblastoma)、胶样囊肿(colloid cyst)、表皮样囊肿(epidermoid cyst)、脑膜瘤(meningioma)、血管母细胞瘤(hemangioblastoma)、淋巴瘤(lymphoma)、垂体腺瘤(pituitary adenoma)、转移性肿瘤(metastatic tumor)、或它们的组合。例如,神经胶质瘤是多形性胶质母细胞瘤(glioblastoma multiforme:GBM)。上述脑肿瘤可以是原发性脑肿瘤或从其它癌转移的肿瘤。
另外,本发明的PPA聚合物可以标记有诊断剂(诊断用标记物),被标记物标记的聚合物可以在生物体内进行追踪,从而实现对中枢神经系统疾病、神经退行性疾病或脑肿瘤的光学检测和成像。
上述诊断剂只要是可以探知并识别靶细胞的物质就可以不受限制地使用。例如,可以穿透生物体的近红外荧光物质,例如,可以例举出花青、别藻蓝蛋白(allophycocyanin)、荧光素(fluorescein)、四甲基罗丹明(tetramethylrhodamine)、氟硼荧(BODIPY)或阿莱克萨(Alexa)等;钙-47(Calcium-47)、碳-11(Carbon-11)、碳-14(Carbon-14)、铬-51(Chromium-51)、钴-57(Cobalt-57)、钴-58(Cobalt-58)、铒-169(Erbium-169)、氟-18(Fluorine-18)、镓-67(Gallium-67)、镓-68(Gallium-68)、氢-3(Hydrogen-3)、铟-111(Indium-111)、碘-123(Iodine-123)、碘-131(Iodine-131)、锝-99m(Technetium-99m)等放射性药物;或MRI造影剂等。
本发明的药物递送体施用于从诊断对象分离的组织或细胞,并且PPA聚合物和/或诊断剂可以用于检测信号而获得影像。为了检测这种信号,可以利用磁共振成像设备或光学成像设备。上述磁共振成像设备是如下的一种装置:将生物体置于强磁场中,照射特定频率的电波,将能量吸收到生物体组织中存在的氢等的原子核中,制造成高能量状态后,中断上述电波,使上述氢等的原子核能释放,将这种能量转换为信号,并用电脑进行处理而成像。由于磁波或电波不受骨骼干扰,对于坚硬的骨骼周围或者脑或骨髓中的肿瘤,可以从纵向、横向、任意的角度获得清晰的三维断层图像。特别是,上述磁共振成像设备优选T2自旋-自旋弛豫磁共振成像设备。
本发明的药物递送体可以进一步包括药学上可接受的载体,并且可以与载体一起制剂化。本发明中的用语“药学上可接受的载体”是指不刺激生物体且不妨碍给药化合物的生物活性和特性的载体或稀释剂。作为以液相溶液制剂化的药物递送体中可接受的药物载体,是无菌和生物相容的,可以使用盐水、无菌水、林格溶液、缓冲盐水、白蛋白注射液、葡萄糖溶液、麦芽糖糊精溶液、甘油、乙醇、以及混合使用这些成分中的1种成分以上,可以根据需要而添加抗氧化剂、缓冲剂、抑菌剂等其它常规添加剂。此外,可以另外添加稀释剂、分散剂、表面活性剂、粘合剂和润滑剂,从而制成水溶液、悬浮液、乳浊液等注射用制剂;丸剂;胶囊剂;颗粒剂或片剂。
作为包含本发明的药物递送体作为有效成分的鼻腔给药用剂型,可以制成注射用形态、或者能够通过呼吸道吸入的气雾剂等喷雾用制剂。为了制成注射用剂型,将本发明的药物递送体与稳定剂或缓冲剂一起在水中混合而制造溶液或悬浮液,可以将它制成安瓶或小瓶的单位给药用制剂。在制成气雾剂等喷雾用制剂时,可以与添加剂一起配合推进剂等以使得水分散的浓缩物或湿粉被分散。
本发明的药物递送体可以通过鼻-脑递送用药物递送装置而被喷射到鼻-脑给药途径。
上述鼻-脑递送用药物递送装置可以使用公知的喷雾器形态。
本发明的药物递送体可以作为单一疗法使用,但也可以与其它常规的化学疗法或放射疗法一同使用,在实施这种组合疗法时,能更有效地治疗疾病。
因此,作为本发明的另一实施方式,本发明提供一种通过鼻腔给药向脑部递送药物的方法,其包括将上述药物递送体鼻腔给药到个体的步骤。
作为本发明的另一实施方式,本发明提供治疗中枢神经系统疾病、神经退行性疾病或脑肿瘤中的任一种的方法,其包括将上述药物递送体以药学有效量鼻腔给药到有需要的个体的步骤。
本发明的用语“药学有效量”是指足以以医学治疗上可适用的合理的收益/风险比治疗疾病的量。本发明的药物递送体的合适的给药量根据制剂化方法、给药方式、患者的年龄、体重、性别、疾病症状程度、饮食、给药时间、排泄频率和反应敏感性等因素而不同,通常,熟练的医生可以容易地确定并开出对目标治疗有效的给药量。一般来说,本发明的药物递送体包含1Х105-1Х1015pfu/ml的聚合物或聚合物-基因递送系统、光敏剂或药物活性成分的复合物,通常,将1×1010pfu每两天注射一次持续2周。
本发明的用语“个体”可以包含患有疾病的马、羊、猪、山羊、骆驼、羚羊、狗等动物或人,其症状可以通过将根据本发明的药物递送体进行给药而好转。通过将根据本发明的药物递送体给药到个体,从而可以有效地预防和治疗疾病。根据本发明的上述治疗方法可以是治疗除了人类以外的动物的方法,但并不限定于此。即,考虑到人类患有可以通过将根据本发明的药物递送体进行给药而症状好转的疾病时,也可以充分地用于对人类的治疗。
下面,通过本发明的实验例详细地进行说明。下述实验例只例示本发明,本发明的范围不限定于下述实验例。本实验例用于使本发明的公开完整,是为了向本发明所属技术领域的技术人员完整告知发明的范畴而提供的,本发明只由权利要求的范围来限定。
实施发明的方式
<实施例1>PPCBA-PEI-Arg的合成
(1)聚(乙烯亚胺)-精氨酸(PEI-Arg)的合成
根据参考文献,使精氨酸与聚乙烯亚胺共轭(Journal of Colloid andInterface Science 348(2010)360-368,Biomaterials 31(2010)8759-8769)。通过使精氨酸氨基酸(350mg,2.0mmol)的羧酸基团在PBS(磷酸盐盐水缓冲液(phosphate salinebuffer),pH=7.4(PBS,3.0mL)中与EDC/NHS(EDC,384mg,2.0mmol和NHS=230mg,2.0mmol)试剂在4℃偶联4小时,从而进行了活化。然后,添加聚乙烯亚胺(polyethylenimine(PEI)(360mg,0.2mmol)),使精氨酸活化,反应在室温下进行了18小时。将反应产物对双蒸水透析1天(MWCO 1.0kDa)而去除未反应的化合物,进行冻干,从而得到了白色物质PEI-Arg。化学结构通过1H NMR(600MHz,D2O)进行了确认。确认了PEI的特征峰(2.0至3.0ppm)和精氨酸的峰(1.66-(-HCCH2CH2CH2NH-);1.86(-HCCH2CH2CH2NH-);3.24(-HCCH2CH2CH2NH-);3.86(-HCCH2CH2CH2NH-)。
(2)PPCBA-PEI-Arg(PPA)的合成
为了生成pH-敏感型和生物还原性聚合物,将mPEG-丙烯酸酯(125mg,0.025mM(PEG=5.0kDa或2.0kDa;Laysan Bio,Inc))和N,N’-胱胺双丙烯酰胺(N,N’-cystaminebisacrylamide)(71.5mg,0.275mM)(PolySciences Inc.,Warrington,PA)溶解于甲醇(5.0mL)。接着,添加哌嗪(19.5mg)(Sigma-Aldrich),反应混合物在100%氮气氛下,在50℃-60℃,在黑暗条件下搅拌48小时,在室温下冷却后,添加PEI-Arg(12mg)。将最终的反应混合物在室温下搅拌一天,最终将聚合物对双蒸水透析一天(MWCO3.5kDa,Pro Spectrum,透析膜(dialysis membrane))后,进行冻干,从而得到了白色物质PPCBA-PEI-Arg。PPCBA-PEI-Arg的化学结构通过与m PEG和PEI-Arg的特征峰一同在相当于哌嗪的-N(CH2-CH2)亚甲基质子和CBA的-S-CH2-CH2-NH-CO-质子的2.3-2.8和3.6ppm处的共振峰并利用1H NMR(600MHz,D2O)进行了确认。
(3)细胞株和细胞培养
从美国典型培养物保藏中心(American Type Culture Collection)(ATCC,马纳萨斯(Manassas),VA)购入U87MG-Fluc细胞株,在包含10%FBS(Gibco BRL)和HEPES(GibcoBRL)的DMEM(Gibco BRL,Grand Island,NY)培养基中,以37℃、5%CO2的条件进行了培养。
(4)腺病毒(Ad)制备
在E1位点的CMV启动子调节下,使用了表达GFP(green fluorescent protein,绿色荧光蛋白)的非复制性Ad(dE1/GFP)和溶瘤Ad(DWP418,RdB/IL-12/Decorin或HE5cT-Rd19-k35/Decorin;oAd),并且基本上使用了与本发明发明人在以往研究中记载的方法相同的方法(Kim,E.et al.Hum.Gene Ther.2003,14,14151428;Kim,J.H.etal.J.Natl.Cancer Inst.2006,98,14821493;Choi,J.W.et al.Gene Ther.2013,20,880892;Kim,P.H.et al.Biomaterials 2011,32,93289342)。使所有的Ad在HEK293细胞中繁殖,然后进行了CsCl(Sigma,St Louis,MI)浓度梯度纯化。在OD260测定中使吸光度1等于1012VP/ml而计算了病毒粒子(VP)的数量。对HEK293细胞利用有限稀释测验法确定了病毒滴度(感染滴度(Infectious titers),PFU/mL)。dE1/GFP和DWP418的病毒颗粒/PFU比率分别为29:1和81:1。基于病毒滴度计算了MOI。
(5)Ad/PPA复合物制备
为了制作Ad/PPA复合物,将Ad粒子(2×1010VP/PBS,pH7.4)与不同浓度的PPA聚合物混合。其结果,每个聚合物的Ad粒子的摩尔比为1Х105和1Х106。在使用前,将溶液在室温下培养30分钟。
(6)统计分析
将数据表示为平均值±标准偏差(SD)。通过双尾学生t检验(SPSS13.0软件;SPSS,芝加哥,IL)进行了统计分析,P值小于0.05时被认为具有统计学意义。
<实验例1>Ad/PPA-IR780的生物体内荧光图像
为了分析Ad/PPA-IR780复合物的生物体内分布,通过鼻腔途径注射复合物,在给药后5分钟、6h、12h、18h、24h、48h进行了NIR成像。
图1显示了信号在注射后5分钟至18h保持相似,然后,以时间依赖性方式逐渐减少直到48h。随着Ad/PPA-IR780复合物流入肿瘤组织,许多荧光信号保持在荷瘤脑区:照射后5分钟达到了肿瘤区域中的最大荧光强度。该结果表明Ad/PPA-IR780复合物是适合通过鼻腔途径来靶向脑肿瘤的治疗剂。
<实验例2>Ad/PPA-IR780复合物的强力抗癌效果
为了构建脑肿瘤模型,利用汉密尔顿注射器将稳定表达萤火虫萤光素酶基因的人类胶质母细胞瘤细胞株U87MG-Fluc立体定向注射到脑部。为了非侵袭性监测肿瘤生长,每间隔6天实施了生物发光成像。在第21天鼻腔注射Ad/PPA5-IR780复合物后,在给药后第6小时对脑肿瘤进行了激光照射。
如图2所示,在肿瘤细胞注射后的第30天,在经Ad/PPA5-IR780(7.26Х106p/s)处理的小鼠的原位脑肿瘤中获得的荧光素酶信号显著低于在载体处理组中所观察到的信号,且显示出比PBS(9.48Х108p/s)低131倍的肿瘤荧光强度。此结果表明Ad/PPA5-IR780复合物可以诱导高凝聚性原位胶质母细胞瘤的肿瘤生长抑制。
<实验例3>用于肿瘤靶向化和抗肿瘤效果监测的活体成像
进行活体生物发光成像,从而评价了原位肿瘤的荧光强度。
如图3所示,与PBS-处理组(1.26Х109p/s)相比,Ad/PPA5-IR780-处理组(7.64Х106p/s)的荧光强度低了165倍。此结果确认了鼻腔给药的Ad/PPA5-IR780复合物的强力抗肿瘤效果。
另外,通过活体NIR成像和光学照片比较而再次确认了Ad/PPA5-IR780复合物的强力抗肿瘤功效。
<实验例4>Ad/PPA-IR780的抗肿瘤功效和生物体内分布
使用U87MG-Fluc原位胶质母细胞瘤模型来比较了利用Ad和各种类型的IR780-结合的聚合物的纳米复合物的各种鼻腔给药的治疗性功效和生物体内分布图。所有的处理均在细胞注射后的第6天通过鼻腔途径而给药。对于所有的肿瘤,在处理鼻腔给药后的第6小时进行了激光照射。
如图4所示,在肿瘤细胞注射后的第13天,从给药Ad/PPA5-IR780、Ad/PPA2-IR780、Ad/PP-IR780的小鼠的原位肿瘤中获得的荧光素酶信号由于PP而减少了。
为了评价生物体内的各种Ad/聚合物复合物的生物体内分布图,在肿瘤细胞注射后的第6天,在第一次鼻腔给药治疗剂后,每24小时进行一次NIR成像。
如图5所示,经Ad/PPA2-IR780或Ad/PPA5-IR780处理的小鼠与经Ad/PAMAM(G2)-IR780处理的小鼠相比,在脑组织中显示出更高的荧光强度;给药Ad/PAMAM(G2)-IR780后,在脑区域检测到极少荧光甚至没有检测到荧光。此结果表明通过鼻腔注射的有效的脑递送是基于PPA的聚合物的一般功能。
<实验例5>Ad/PPA-IR780的抗肿瘤功效:生物发光成像
在细胞注射后的第6天,通过生物发光成像确认了原位脑肿瘤的建立。为了处理,对小鼠(肿瘤光子值接近1Х106p/s)每3天共3次鼻腔注射20μl的PBS、裸Ad(5Х1010VP)、Ad/APP(APP公开于Biomaterials 33(2012)8122-8130)、Ad/PP5-PTX-爱必妥或Ad/PPA5-IR780(1Х105、1Х106;聚合物:Ad摩尔比)。在鼻腔给药后6h,对所有的肿瘤照射了激光。
如图6所示,在肿瘤细胞注射后的第20天,由经Ad/PPA5-IR780(1Х105摩尔比)处理的小鼠的原位肿瘤中获得的荧光素酶信号与其它处理组相比,更加有效地衰减,与Ad/APP、Ad/PP5-PTX-爱必妥、或Ad/PPA5-IR780(1Х106摩尔比)相比,分别显示出更高3.40-、2.32-或1.44-倍的治疗性功效。这些结果表明基于PP的pH-敏感型聚合物(PP和PPA)可以通过鼻腔注射而有效地将Ad递送到脑部。
<实验例6>Ad/PPA-IR780的抗肿瘤功效和不同的给药途径
为了比较不同的Ad/聚合物复合物的抗肿瘤效果,将Ad/PAMAM-PEG、Ad/PPSA(PPSA公开于KR10-2016-0103078)、Ad/APP或Ad/PPA5-IR780每隔3天共3次鼻腔给药到小鼠。一组的小鼠通过静脉途径接受了Ad/PPA5-IR780(命名为Ad/PPA5-IR780(I.V.)组)。对所有的肿瘤进行处理后,在第6h照射了激光。
如图7所示,在肿瘤细胞注射后的第26天,由经Ad/PPA5-IR780(I.N.注射)处理的小鼠的原位肿瘤中获得的荧光素酶信号显著低于其它组,与经Ad/PAMAM-PEG、Ad/PPSA、Ad/APP或Ad/PPA5-IR780(I.V.注射)处理的组相比,分别显示出更低30.5-、29.5-、9.66-、或27.9-倍的肿瘤荧光,从而表明与通过静脉递送相比,PPA5-IR780-介导的鼻腔递送诱导了更加良好的治疗性功效。
另外,如图8所示,作为研究生物体内分布的结果,从Ad/PPA5-IR780(I.N.注射)获得的荧光信号在整个观察期间在脑中被检出,相反,在静脉给药Ad/PPA5-IR780时,在脑组织中没有检出信号。这表明鼻腔给药对于脑肿瘤中Ad/PPA5-IR780的积累及其强力抗肿瘤效果是重要的。
<实验例7>oAd/PPA-IR780在原位(orthotopic)脑癌模型中的强力治疗性功效
为了评价溶瘤Ad(oAd)和利用IR780的光热治疗在生物体内的联合治疗性功效,对表达荧光素酶的原位脑肿瘤静脉(I.V.)注射oAd/PPA5-IR780,或者鼻腔(I.N.)注射PBS、oAd或oAd/PPA5-IR780。在注射后的第24小时,对肿瘤照射808nm激光3分钟。
如图9所示,通过鼻腔给药oAd/PPA5-IR780和激光照射联合,与其它组相比,诱导了明显更高的抗肿瘤效果。在肿瘤细胞注射后的第27天,由经激光照射(9.8Х105+/-2.1Х105p/s)和oAd/PPA5-IR780(I.N.)联合处理的小鼠的原位脑肿瘤中获得的荧光素酶信号与其它处理组相比,明显衰减(P<0.01),与经激光(6.6Х107+/-2.7Х107p/s)和PBS处理、无激光(4.0Х107+/-8.6Х106p/s)经oAd/PPA5-IR780(I.V.)处理、经激光(4.8Х107+/-2.4Х107p/s)和oAd处理、或者无激光(7.3Х106+/-2.1Х106p/s)经oAd/PPA5-IR780(I.N.)处理的结果相比,分别显示出67.5-、40.8-、101.8-、49.2-、或7.5-倍更低的荧光素酶信号(图10)。这些结果验证了鼻腔给药后oAd/PPA5-IR780与激光处理联合的强力治疗性功效。
<实验例8>鼻腔给药PPA-IR780-PTX后脑组织中PTX的分布图
为了测定与PPA-IR780聚合物结合的PTX是否可以有效地递送到脑组织,通过静脉或鼻腔途径中的任一种而给药PTX-结合的聚合物突变体(PPA5-PTX-IR780)。在注射后的第0.5h、1h、2h和6h时获取脑组织,通过LC-MS/MS测定了脑组织的不同解剖区中的PTX的量。
如图11所示,在患有荷脑瘤的小鼠模型中,脑亚区中PTX的量在0.5h内不规则升高,在鼻腔注射后的第2h达到正常。在鼻腔注射2h后,肿瘤内PTX的浓度在脑亚区中最高。
在正常小鼠模型中,PPA5-PTX-IR780的鼻腔注射诱导PTX有效流入到脑组织,与由图11中的荷瘤小鼠中观察到的类似(图12);在两只小鼠中观察到类似的生物体内分布图案,但正常小鼠中PTX的总量与荷瘤小鼠相比稍微更低。这些结果表明肿瘤的存在对于PPA5-PTX-IR780的有效的脑递送不是必需的。重要的是,这些结果表明PPA5-IR780聚合物骨架可以作为用于治疗中枢神经系统疾病、神经退行性疾病或脑肿瘤的药物递送体来利用。
鼻腔递送PPA5-PTX-IR780后,通过利用从图11和图12中获得的值计算DTP(nose-to-brain direct transport,鼻向脑直接递送)和DTE(drug targeting efficiency,药物靶向效率)来分析PTX的DTP(鼻向脑直接递送)效率。DTP%表示通过嗅觉途径直接递送到脑部的药物的比率。PPA5-PTX-IR780表现出最高的DTE%(肿瘤模型中为1620.95+/-38.81、以及在正常模型中为1019.17+/-28.39)和DTP%(肿瘤模型中为93.83+/-0.97、以及在正常模型中为90.18+/-0.96),通过鼻腔途径的PPA5-PTX-IR780给药由于通过鼻腔的嗅觉区域进行有效递送,从而显示出比静脉注射更好地向脑部递送治疗剂。
如图13所示,在比较肿瘤模型和正常模型时,肿瘤模型中通过鼻腔途径递送到脑部的PTX的量更高。
<实验例9>鼻腔给药siRNA-Cy5.5/PPA-IR780后siRNA的脑分布
为了评价siRNA是否可以通过PPA5-IR780聚合物经鼻腔递送,为了鼻腔给药,使Cy5.5-标记的siRNA(siRNA-Cy5.5)与PPA5-IR780形成了复合物。在注射0.5h、1h、2h和6h后,使用荧光读数器测试了脑组织中siRNA-Cy5.5的存在。
如图14所示,经鼻腔给药的Cy5.5-标记的siRNA的荧光强度在2h的照射后,在原位脑肿瘤中达到了最高的水平;肿瘤区域中的该时间的强度比脑中其它所有区域中观察到的都高。这些结果表明使用PPA-IR780作为递送体,也可以将siRNA通过鼻腔途径有效递送到肿瘤中。
<实验例10>鼻腔给药pDNA-FITC/PPA-IR780后,pDNA的脑分布
为了测定pDNA是否通过鼻腔递送到脑部并评价其递送效率,为了鼻腔递送,使FITC-标记的pDNA(pDNA-FITC)与PPA5-IR780形成了复合物。通过静脉和鼻腔途径给药pDNA-FITC/PPA5-IR780复合物。在注射后的0.5h、1h、2h和6h,使用荧光读数器测试了脑组织中pDNA的存在。
如图15所示,与静脉给药相比,在脑部的不同部位中观察到了明显更高水平的经鼻腔给药的FITC-标记的pDNA。重要的是,pDNA的最高量在注射2至6h后的肿瘤组织中被检出,从而验证了PPA5-IR780促进pDNA良好地流入肿瘤。
在正常小鼠模型中,鼻腔给药pDNA-FITC/PPA5-IR780诱导pDNA有效流入脑组织,而与从图15的荷瘤小鼠中观察到的类似(图16);在两只小鼠中观察到了类似的生物体内分布图案,但正常小鼠的pDNA的总量与荷瘤小鼠相比稍微更低(图17)。这些结果表明肿瘤的存在对于通过PPA5-IR780有效脑递送pDNA不是必需的。
为了评价PPA5-IR780聚合物中的哪些成分对于通过鼻腔途径有效流入脑部是重要的,生成了PPA5-IR780的不具有pH-反应性或IR780部分中的任一种的若干聚合物衍生物。对于不具有pH-反应性的衍生物的生成,将作为pH-反应部分的哌嗪置换为不具有pH-反应性的二硫苏糖醇(DTT)部分,从而生产了P(DTT)PA5-IR780。此外,对于PPA5-IR780和P(DTT)PA5-IR780两者生产了不具有光敏剂的对照组聚合物,最终分别生产了PPA5和P(DTT)PA5聚合物。为了比较PPA5-IR780和不具有一个或两个功能性部分的其衍生物的脑递送效率,使pDNA-FITC与P(DTT)PA5、P(DTT)PA5-IR780、PPA5、或PPA5-IR780聚合物形成复合物,然后通过鼻腔途径给药。在注射后的0.5h、1h、2h和6h,使用荧光读数器测试在脑组织的不同区域中pDNA的存在。
如图18所示,与经与非-pH反应性聚合物形成复合物的pDNA-FITC处理的组(组2和3)进行比较,经与pH反应性聚合物形成复合物的pDNA-FITC处理的小鼠(组4和5)中的FITC强度更高。此外,这些结果表明经鼻腔给药的pDNA/聚合物复合物的脑流入效率不依赖于光敏性IR780部分,比如组2和4在脑组织的不同区域显示出与组3和5类似的积累。而且,这些结果表明pH敏感性对于通过鼻腔途径的治疗剂的有效的聚合物-介导递送是重要的。
<实验例11>经鼻腔给药的oAd/PPA-Cu-64-DOTA-赫赛汀复合物的有效递送:PET/CT成像
通过PET/CT成像测定了通过鼻腔给药、腹腔给药和静脉给药而向脑部递送oAd/PPA-Cu-64-DOTA-赫赛汀复合物的效率。
如图19所示,在注射后的第1h,与其它递送方法相比,鼻腔递送在脑区域显示出最强的信号。
<实验例12>PPA-爱必妥在正常小鼠中的递送
利用LC-MS/MS实验,比较了在静脉给药和鼻腔给药时的结合有治疗抗体的PPA向脑部的递送效率。
如图20所示,通过治疗抗体与PPA5的结合,与对照组的通过PBS或静脉给药(IV)的递送相比,在鼻腔给药的实验组中可以有效地向脑部递送。此外,比较脑组织中随时间的给药效率,结果在给药后2小时后检测到最高的比率,该比率为初始给药量的20%。
<实验例13>鼻腔给药后PPA-IR780-PTX的生物利用度
利用LC-MS/MS实验比较了在静脉给药和鼻腔给药时的结合有作为治疗药物的PTX的PPA-IR780向脑部的递送效率。
如图21所示,PTX通过鼻腔递送成功地递送到脑部的不同区域。此外,在脑组织中检测到高达初始给药量的12%的高比率。
<实验例14>PPA-PTX的强力抗肿瘤功效:MR成像
如图22所示,通过MR成像,显示出PPA5-PTX的鼻腔递送比PTX I.V.递送和PTXI.N.递送更加良好的抗肿瘤功效,并且显示出PPA5-PTX(I.N.)诱导了脑肿瘤的完全消退。
另外,在U87MG/Fluc原位脑肿瘤模型中,在注射后第13天进行H&E染色,结果PTX浓度(I.N.递送)的1/25给药量诱导了脑肿瘤的完全消退(图23)。
另外,如图24所示,在U87MG/Fluc原位脑肿瘤模型中,PPA5-PTX的鼻腔递送显示出比PTX I.V.递送和PTX I.N.递送更加良好的抗肿瘤功效,PTX浓度(I.N.递送)的1/25给药量显示出比静脉递送更加良好的功效。
产业上的利用可能性
本发明可以适用于中枢神经系统疾病、神经退行性疾病或脑肿瘤的诊断和治疗领域。
Claims (18)
3.根据权利要求2所述的药物递送体,其中,药物递送体用于鼻腔给药。
4.根据权利要求2所述的药物递送体,其中,所述聚合物和所述药物以形成复合物的形态包含。
5.根据权利要求2所述的药物递送体,其中,治疗剂为选自基因递送系统、光敏剂和药物活性成分中的一种以上。
6.根据权利要求5所述的药物递送体,其中,基因递送系统为(i)裸重组DNA分子、(ii)质粒、(iii)病毒载体、以及(iv)内含所述裸重组DNA分子或质粒的脂质体或类脂质体的形态。
7.根据权利要求6所述的药物递送体,其中,病毒载体为选自重组腺病毒、腺相关病毒即AAV、逆转录病毒、慢病毒、单纯疱疹病毒、牛痘病毒、呼肠孤病毒、痘病毒、塞姆利基森林病毒和麻疹病毒中的一种以上。
8.根据权利要求5所述的药物递送体,其中,光敏剂为选自卟啉系化合物、二氢卟酚系化合物、菌绿二氢卟吩系化合物、酞菁系化合物、萘酞菁系化合物和5-氨基乙酰丙酸酯系化合物中的一种以上。
9.根据权利要求5所述的药物递送体,其中,药物活性成分为选自抗癌药、抗生素、激素、激素拮抗剂、白细胞介素、干扰素、生长因子、肿瘤坏死因子、内毒素、淋巴毒素、尿激酶、链激酶、组织纤溶酶原激活剂、蛋白酶抑制剂、烷基磷酸胆碱、放射性同位素标记成分、表面活性剂、心血管系统药物和神经系统药物中的一种以上。
10.根据权利要求9所述的药物递送体,其中,抗癌药为选自贝伐单抗、替莫唑胺、亚硝基脲、顺铂、PCV、长春碱、长春新碱、长春氟宁、长春地辛、长春瑞滨、卡巴他赛、多西他赛、拉洛他赛、奥他赛、紫杉醇、替司他赛、伊沙匹隆、赫赛汀、爱必妥、环磷酰胺、多柔比星、依托泊苷、拓扑替康、卡铂、丙卡巴肼、氮芥、异环磷酰胺、马法兰、苯丁酸氮芥、白消安、放线菌素、柔红霉素、博来霉素、普利霉素、丝裂霉素、他莫昔芬、反式铂、5-氟尿嘧啶和甲氨蝶呤中的一种以上,所述PCV为丙卡巴肼+CCNU+长春新碱。
11.根据权利要求2所述的药物递送体,其中,药物递送体用于中枢神经系统疾病、神经退行性疾病或脑肿瘤中的任一种的预防或治疗。
12.根据权利要求11所述的药物递送体,其中,中枢神经系统疾病为选自认知障碍、智力障碍、小脑症、癫痫、神经发育障碍、痴呆、自闭症谱系障碍、唐氏综合症、雷特综合征和脆性X综合征中的任一种。
13.根据权利要求11所述的药物递送体,其中,神经退行性疾病为选自缺血性脑卒中、创伤性脑损伤、急性播散性脑脊髓炎、肌萎缩侧索硬化症即ALS、色素性视网膜炎、轻度认知障碍、阿尔茨海默氏病、匹克氏病、老年痴呆、进行性核上性麻痹、皮层下痴呆、威尔逊病、多发性梗塞、动脉硬化性痴呆、AIDS相关痴呆、小脑变性、脊髓小脑变性综合、弗里德赖希共济失调、毛细血管扩张性共济失调、癫痫相关的脑损伤、脊髓损伤、不安腿综合征、亨廷顿氏病、帕金森病、纹状体黑质变性、脑血管炎、线粒体脑肌病、神经元蜡样脂褐质沉积症、脊髓性肌肉萎缩症、与中枢神经系统相关的溶酶体贮积症、脑白质营养不良、尿素循环缺陷障碍、肝性脑病、肾性脑病、代谢性脑病、卟啉症、细菌性脑膜炎、病毒性脑膜炎、脑膜脑炎、朊病毒病、神经毒性化合物中毒、格林巴利综合征、慢性炎症性神经病、多发性肌炎、皮肌炎和辐射引起的脑损伤中的任一种。
14.根据权利要求11所述的药物递送体,其中,脑肿瘤为神经胶质瘤、少突胶质细胞瘤、胶质母细胞瘤、胶样囊肿、表皮样囊肿、脑膜瘤、血管母细胞瘤、淋巴瘤、垂体腺瘤、转移性肿瘤或者它们的组合。
15.根据权利要求2所述的药物递送体,其中,诊断剂为近红外荧光物质、放射性药物或造影剂。
17.一种通过鼻腔给药向脑部递送药物的方法,其中,包括将权利要求2所述的药物递送体鼻腔给药到个体的步骤。
18.一种治疗中枢神经系统疾病、神经退行性疾病或脑肿瘤中的任一种的方法,其中,包括将权利要求2所述的药物递送体以药学有效量鼻腔给药到有需要的个体的步骤。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103566379A (zh) * | 2013-09-30 | 2014-02-12 | 中国药科大学 | 一种“胞内触发”式还原敏感型药物联合基因靶向共传递体的制备及应用 |
CN107614019A (zh) * | 2015-03-09 | 2018-01-19 | 加利福尼亚大学董事会 | 用于组合抗癌疗法的聚合物‑药物结合物 |
CN108135966A (zh) * | 2015-08-31 | 2018-06-08 | 汉阳大学校产学协力团 | 包含腺病毒蛋白vi衍生肽的用于细胞内递送的组合物和包含它的抗癌药物组合物 |
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US4797368A (en) | 1985-03-15 | 1989-01-10 | The United States Of America As Represented By The Department Of Health And Human Services | Adeno-associated virus as eukaryotic expression vector |
US5139941A (en) | 1985-10-31 | 1992-08-18 | University Of Florida Research Foundation, Inc. | AAV transduction vectors |
KR20020023760A (ko) | 2001-12-15 | 2002-03-29 | 심재석 | 가상 CD ROM 드라이브 및 가상 Disk 드라이브를 이용한소프트웨어 설치, 실행 및 사용권 라이센스 관리 프로그램제작 방법 |
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WO2015163622A1 (ko) * | 2014-04-22 | 2015-10-29 | 한양대학교 산학협력단 | 항암치료용 pH 민감성 및 생환원성 폴리머-바이러스 복합체 |
WO2017083794A1 (en) * | 2015-11-12 | 2017-05-18 | Board Of Regents Of The University Of Nebraska | Polyethylene glycol-conjugated glucocorticoid prodrugs and compositions and methods thereof |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103566379A (zh) * | 2013-09-30 | 2014-02-12 | 中国药科大学 | 一种“胞内触发”式还原敏感型药物联合基因靶向共传递体的制备及应用 |
CN107614019A (zh) * | 2015-03-09 | 2018-01-19 | 加利福尼亚大学董事会 | 用于组合抗癌疗法的聚合物‑药物结合物 |
CN108135966A (zh) * | 2015-08-31 | 2018-06-08 | 汉阳大学校产学协力团 | 包含腺病毒蛋白vi衍生肽的用于细胞内递送的组合物和包含它的抗癌药物组合物 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115737598A (zh) * | 2022-10-08 | 2023-03-07 | 中山大学 | 一种纳米粒子簇Al-PHNPs-PAMAM的制备及其在治疗脑部疾病中的应用 |
CN115737598B (zh) * | 2022-10-08 | 2024-04-19 | 中山大学·深圳 | 一种纳米粒子簇Al-PHNPs-PAMAM的制备及其在治疗脑部疾病中的应用 |
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