CN103429267B - 疏水分子诱导的支化聚合物集合体及其用途 - Google Patents
疏水分子诱导的支化聚合物集合体及其用途 Download PDFInfo
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Classifications
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- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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Abstract
对称和不对称的支化均聚物在表面水平被能够与水不溶性或水难溶性的药物活性剂(PAA)形成集合体的官能团进行了改性。所形成的集合体被PAA和均聚物的相互作用特异性诱导且所述集合体不同于在PAA不存在下仅由聚合物所形成的集合体或者在聚合物不存在下仅由PAA所形成的集合体。所述集合体可用于改善药物的溶解性、稳定性、释放和效力。
Description
本申请要求享有2011年1月9日提交的序列号为61/431,042的美国专利申请、2011年6月24日提交的序列号为61/500,633的美国专利申请和2011年6月29日提交的序列号为61/502,793的美国专利申请的权益,上述专利申请内容的全文各自以引用的方式纳入本说明书。
技术领域
本公开内容涉及表面改性的支化聚合物(MBP),其可为表面改性的对称支化聚合物(SBP)或者为表面改性的不对称支化聚合物(ABP),所述表面改性的支化聚合物一旦暴露于水不溶性分子或水难溶性的分子(例如药物)时就形成复合纳米颗粒或纳米集合体,其中所述药物主要分散或沉积于疏水部分或疏水位点所处的结构表面。有利的颗粒或集合体是稳定的,例如,其可变干或再水合。纳米颗粒或纳米集合体的直径范围可为约50nm至约500nm,这部分地取决于药物与聚合物比、所使用的药物、聚合物、溶剂、均聚物的用量和药物的用量。疏水相互作用、静电相互作用、金属-配体相互作用、氢键和其他分子相互作用可参与到水不溶性或水难溶性分子与均聚物之间自发的相互作用中以形成集合体。有利的颗粒或集合体具有控释性质,并因此具有以下用途:作为宿主中药物活性剂、药物等控释的载体用以提供补充物、营养物或必需品;用以治疗任意多种病症等。
背景技术
对称的支化聚合物
近年来,开发并研究了一类新的被称为树枝形聚合物(dendriticpolymer)的聚合物用于多种工业应用,其包括星爆树枝形分子(Starburstdendrimer)(或致密星形聚合物(DenseStarpolymer))和梳爆树枝形接枝分子(Combburstdendrigraft)(或超梳形支化聚合物(hypercombbranchedpolymer))。这些聚合物通常具有:(a)明确限定的核分子,(b)至少两个具有对称(等长)支链和支链接合点的同心树枝形层(代),和(c)外部表面基团,如在美国专利4,435,548、4,507,466、4,568,737、4,587,329、5,338,532、5,527,524和5,714,166号中描述的基于聚酰胺胺(PAMAM)的支化聚合物和树枝形分子。其他实例包括聚乙烯亚胺(PEI)树枝形分子,例如公开于美国专利4,631,337号中的那些;聚丙烯亚胺(PPI)树枝形分子,例如公开于美国专利5,530,092、5,610,268和5,698,662号中的那些;Frechet型聚醚和聚酯树枝形分子、核壳构造树枝形分子(tectodendrimer)及其他例如描述于“DendriticMolecules”,Newkomeetal.编辑,VCHWeinheim,1996;“DendrimersandOtherDendriticPolymers”,Frechet&Tomalia编写,JohnWiley&Sons,Ltd.,2001;和美国专利7,754,500中的树枝形分子。
通过逐步合成方法构建具有核分子和具有对称支链的同心层的梳爆树枝形接枝分子。与树枝形分子相比,生成的梳爆树枝形接枝分子或聚合物具有单分散线形聚合物结构单元(美国专利5,773,527、5,631,329和5,919,442)。此外,支化类型也不同于树枝形分子。例如,梳爆树枝形接枝分子沿着聚合物骨架形成支链接合点(链支链),而星爆树枝形分子通常在末端支化(末端支链)。由于所使用的活性聚合技术,那些聚合物结构单元(核和支链)的分子量分布(Mw/Mn)通常很窄。因此,通过接枝-接枝(graft-on-graft)方法制备的梳爆树枝形接枝分子被明确地限定为Mw/Mn比通常小于约1。
SBP,例如树枝形分子,主要通过发散或汇聚合成方法经重复的保护和脱保护步骤来制备。由于树枝形分子使用小分子作为核和支链的结构单元,因此通常限定了树枝形分子的分子量分布。对于较低代,通常获得单一分子量的树枝形分子。
除了树枝形分子和树枝形接枝分子,其他SBP包括对称的星形或梳形聚合物,例如对称的星形或梳形聚环氧乙烷(PEO)、聚乙二醇(PEG)、PEI、PPI、聚噁唑啉(POX)、聚甲基噁唑啉(PMOX)、聚乙基噁唑啉(PEOX)、聚苯乙烯、聚甲基丙烯酸甲酯、聚二甲基硅氧烷或其组合物。
不对称的支化聚合物
与SBP不同,不对称的支化聚合物(ABP),尤其是不对称的支化树枝形分子或规则ABP(reg-ABP),通常具有核、受控并被明确限定的不对称(不等长)支链和不对称的支链接合点,如在美国专利4,289,872、4,360,646和4,410,688中所描述的。
另一方面,无规ABP(ran-ABP)具有:a)无核,b)在外部和内部的官能团,c)无规/变化的支链长度和类型(即末端支链和链支链),和d)不均匀分布的内部空隙空间。
由例如PEI制备的ran-ABP的合成和机理报道如下:Jonesetal.,J.Org.Chem.9,125(1944);Jonesetal.,J.Org.Chem.30,1994(1965)和Dicketal.,J.Macromol.Sci.Chem.,A4(6),1301-1314,(1970)。由例如POX即聚(2-甲基噁唑啉)和聚(2-乙基噁唑啉)制备的ran-ABP报道如下:Litt(J.Macromol.Sci.Chem.A9(5),703-727(1975))和Warakomski(J.Polym.Sci.Polym.Chem.28,3551(1990))。ran-ABP的合成通常可包括一锅分散法或一锅汇聚法。
均聚物
均聚物可涉及由相同重复单元组成的聚合物或聚合物骨架,即,均聚物由相同的单体(例如聚乙烯亚胺树枝形分子、聚酰胺型胺树枝形分子或聚噁唑啉树枝形分子)生成。所述单体可为简单的化合物或化合物的络合物或组装物,其中络合物或组装物为均聚物中的重复单元。因此,如果组装物由三种化合物A、B和C组成,则络合物可被描述成ABC。由(ABC)-(ABC)-(ABC)……组成的聚合物为用于本公开内容目的的均聚物。均聚物可为线性的或支化的。因此,对于无规的支化PEI,虽然存在不同长度的支链以及无规存在的支链,但是所述分子是用于本公开内容目的的均聚物,因为该支化的聚合物由单一的单体——吖丙啶或氮丙啶——组成。此外,可对一个或多个单体或复合单体组分进行改性、取代、衍生化等,例如,将其改性成携带官能团。由于这些分子的骨架由单一的简单单体或复合单体组成,因此它们为用于本公开内容目的的均聚物。
水难溶性药物
小分子药物候选物和药物,以及生物分子——其可为了具体的目的而被改性或被改性为具有具体的性质——可以是水难溶性或水不溶性的。通常,需要分子具有亲水性以使其在循环系统或组织空间中存活,这一需要可限制药学活性的疏水药物候选物或药物的使用。因此,对于水难溶性的药物活性剂(PAA)的有效制剂的开发在药物开发和应用中是重要的。现有的解决方案包括通过例如化学改性或物理配制来提高药物溶解性或减少药物颗粒尺寸。
化学改性方法通常包括通过以下方法将药物转化成原药分子以增强水溶性:例如通过使用盐形式、水合或连接多种水溶性官能团,例如含氨基/亚氨基、羟基或羧基的基团;通过使用水溶性聚合物,例如PEG或PEO等。
物理配制可包括使用共溶剂和/或表面活性剂以溶解难溶性药物;涉及基于脂质或脂质体的纳米乳剂或微乳剂;在高温下不使用任何溶剂熔融药物和聚合物;使用络合剂(例如无机盐、配位金属(例如氯化六氨合钴(III))、螯合物(例如EDTA、EGTA等)、金属-烯烃或金属茂(例如二茂铁)、包合物(例如环糊精、络胆酸等)或分子络合物);以及载体中的固体分散体,例如,酸(例如柠檬酸、酒石酸、琥珀酸、HCl等)、糖(例如葡萄糖、山梨糖、蔗糖、麦芽糖、半乳糖、木糖等)、聚合材料(例如聚乙烯吡咯烷酮、PEG-400、PEG-1000、PEG-4000、PEG-6000、羧甲基纤维素、羟丙基纤维素、瓜尔胶、黄原胶、海藻酸钠、甲基纤维素、HPMC、环糊精及它们的衍生物、半乳甘露聚糖)、表面活性剂(例如,聚氧乙烯硬脂酸酯、泊洛沙姆、脱氧胆酸、吐温、司盘、Gelucire、维生素ETPGS等)、及其他(例如,季戊四醇、脲、氨基甲酸乙酯、羟烷基氮杂蒽等)。
其他已知的策略包括降低药物颗粒尺寸,例如,微粉化,可使用研磨技术,例如使用喷射式研磨机或转子定子胶体研磨机来降低颗粒尺寸;随着增加表面积来提高溶解速率;纳米悬浮液,其为纯药物颗粒的亚微米胶体分散液,其可通过被表面活性剂稳定;均质化,其通常涉及常规均化机、超声破碎仪和高剪切流体处理器;湿磨法,其中活性药物在表面活性剂的存在下通过研磨被粉碎或通过将溶于挥发性有机溶剂中的药物喷射至加热的水溶液中被粉碎;使用超临界流体;改变多晶形;使用共晶体混合物;使用自微乳化的释药系统等。
然而,这些处理可损害药理活性。
虽然药物通常可通过各种途径释放,包括口服、鞘内、直肠、鼻内、真皮下、硬膜下、肌内、经皮、局部、吸入、注射等,但是静脉给药可使药物在循环系统中迅速且恰好地平衡,这可实现有效的局部浓度。稳定和可控的药物释放制剂不仅可避免刚给药后过高的血清水平还可使药物在血管内室逐渐释放。
大于7μm的微颗粒通常从循环系统中被“血液过滤器官”例如,脾、肺和肝清除。因此,较小的纳米颗粒(例如50-500nm)通常具有更长的血液循环时间。
药物活性剂(PAA)(例如药物)的实例包括但不限于氮芥(chlormethine)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、塞替派(thiotepa)、环磷酰胺(cyclophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、二氯甲基二乙胺(meclilorethamine)、美法仑(melphalan)、尿嘧啶氮芥(uramustine)、lonuistine、链脲佐菌素(streptozotocin)、达卡巴嗪(decarbazine)、丙卡巴肼(procarbazine)、替莫唑胺(temozolainide)、顺铂(cisplatin)、卡铂(carboplatin)、奥沙利铂(oxaliplatin)、沙铂(satraplatin)、(SP-4-3)-(顺)-胺二氯-[2-甲基吡啶]-铂(II)、甲氨蝶呤(methotrexate)、培美曲塞(permetrexed)、雷替曲塞(raltitrexed)、三甲曲沙(trimetrexate)、喜树碱(camptothecin)、喜树碱衍生物(例如伊立替康(irinotecan)、拓扑替康(topotecan)等)、克拉利宾(cladribine)、克拉屈滨(chlorodeoxyadenosine)、克罗拉滨(clofarabine)、氟达拉滨(fludarabine)、6-巯基嘌呤(mercaptopurine)、喷司他汀(pentostatin)、硫代鸟嘌呤(thioguanine)、阿扎胞苷(azacitidine)、卡培他滨(capecitabine)、阿糖胞苷(cytarabine)、依达赛特(edatrexate)、氟尿苷(floxuridine)、5-氟尿嘧啶(5-fluorouracil)、吉西他滨(gemcitabine)、曲沙他滨(troxacitabine)、博来霉素(bleomycin)、放线菌素D(dactinomycin)、阿霉素(adriamycin)、放线菌素(actinomycin)、光神霉素(mithramycin)、丝裂霉素(mitomycin)、米托蒽醌(mitoxantrone)、泊非霉素(porfiromycin)、柔红霉素(daunorubicin)、阿霉素(doxorubicin)、脂质体阿霉素、表阿霉素(epirubicin)、依达比星(idarubicin)、戊柔比星(valrubicin)、苯芥胆甾醇(phenesterine)、他莫昔芬(tamoxifen)、piposulfancamptothesin、L-门冬酰胺酶(L-asparaginase)、PEG-L-门冬酰胺酶、紫杉醇(paclitaxel)、多西他赛(docetaxel)、泰素帝(taxotere)、长春碱(vinblastine)、长春新碱(vincristine)、长春地辛(vindesine)、长春瑞滨(vinorelbine)、伊立替康(irinotecan)、拓扑替康(topotecan)、安吖啶(amsacrine)、依托泊甙(etoposide)、替尼泊甙(teniposide)、氟羟甲睾酮(fluoxymesterone)、睾内酯(testolactone)、比卡鲁胺(bicalutamide)、环丙氯地孕酮(cyproterone)、氟他胺(flutamide)、尼鲁米特(nilutamide)、氨鲁米特(aminoglutethimide)、瑞宁得(anastrozole)、依西美坦(exemestane)、福美斯坦(formestane)、来曲唑(letrozole)、地塞米松(dexamethasone)、强的松(prednisone)、己烯雌酚(diethylstilbestrol)、氟维司群(fulvestrant)、雷洛昔芬(raloxifene)、托瑞米芬(toremifene)、布舍瑞林(buserelin)、戈舍瑞林(goserelin)、亮丙瑞林(leuprolide)、曲普瑞林(triptorelin)、醋酸甲羟孕酮(medroxyprogesteroneacetate)、醋酸甲地孕酮(megestrolacetate)、左甲状腺素(levothyroxine)、碘塞罗宁(liothyronine)、六甲蜜胺(altretamine)、三氧化二砷、硝酸镓、羟基脲、左旋咪唑(levamisole)、米托坦(mitotane)、奥曲肽(octreotide)、丙卡巴肼(procarbazine)、苏拉明(suramin)、沙利度胺(thalidomide)、甲氧沙林(methoxsalen)、卟吩姆钠(sodiumporfimer)、硼替佐米(bortezomib)、盐酸厄洛替尼(erlotinibhydrochloride)、吉非替尼(gefitinib)、甲磺酸伊马替尼(imatinibmesylate)、semaxanib、阿达帕林(adapalene)、蓓萨罗丁(bexarotene)、反式维甲酸、9-顺式视黄酸和N-(4-羟基苯基)维甲酰酚胺、阿伦单抗(alemtuzumab)、贝伐珠单抗(bevacizumab)、西妥昔单抗(cetuximab)、替伊莫单抗(ibritumomabtiuxetan)、利妥昔单抗(rituximab)、托西莫单抗(trastuzumab)、吉妥珠单抗奥唑米星(gemtuzumabozogamicin)、托西莫单抗(tositumomab)、干扰素-α2a、干扰素-α等,及其衍生物和修饰物,条件是所述药物或其衍生物难溶于水或不溶于水。将一些上述分子改性为更加溶于水。出于本公开内容的目的,可将所述分子改性或改变以除去一些导致产生更小亲水性且更多疏水性(即难溶于水或不溶于水)的药学活性分子或生物活性分子的修饰。
因此,通常不能常规给予(例如,通过静脉注射或口服给药)水不溶性或水难溶性PAA,或者对酸环境敏感的那些PAA。在一些情况下,所述药物的肠胃外给药可通过以下实现:用水性液体(如生理盐水)将脂溶性药物乳化——通常在表面活性剂或乳化剂的存在下——以产生给药用的乳剂。
例如,紫杉醇是水不溶性药物。紫杉醇由Bristol-MyersSquibb以销售。紫杉醇来自太平洋紫杉的短叶红豆杉(Taxusbrevifolia)(Wanetal.,J.Am.Chem.Soc.93:2325(1971))。紫杉烷,包括紫杉醇和多西他赛(也作为出售),用于治疗多种癌症,包括乳腺癌、卵巢癌和肺癌,以及结肠癌和头颈癌等。
然而,紫杉醇的较差水溶性妨碍了其广泛的应用。当前,使用乙醇:(聚乙氧基化蓖麻油)的1:1的溶液配制及其无商标药以溶解药物。的存在与严重的超敏反应相关,因此需要患者服用类固醇药(例如地塞米松)和抗组胺药。
或者,共轭的紫杉醇——例如其通过将紫杉醇与人血清白蛋白混合制备——已经取消了注射类固醇药和抗组胺药的需要。然而,却产生了不需要的副作用,例如,严重的心血管事件,包括胸痛、心脏骤停、室上性心动过速、水肿、血栓形成、肺血栓栓塞、肺栓塞、高血压等,这阻碍了具有高心血管风险的患者使用该药。
水难溶性药物与表面改性的支化聚合物一起给药
虽然支化聚合物(包括SBP和ABP)已经用于药物释放,但是,这些尝试主要集中在药物与聚合物的化学连接,或者通过单分子包封将所述药物物理地包封于内部(美国专利:5,773,527、5,631,329、5,919,442和6,716,450)。
例如,认为树枝形分子和树枝形接枝分子使用单分子包封方法可物理性地捕获生物活性分子,如对于致密星形聚合物描述于美国专利5,338,532、5,527,524和5,714,166以及对于超梳形支化聚合物描述于美国专利5,919,442。类似地,使用SBP进行多种药物的单分子包封以形成“树枝形分子盒”报道于Tomaliaetal.,Angew.Chem.Int.Ed.Engl.,1990,29,138和“DendrimersandOtherDendriticPolymers”,Frechet&Tomalia编辑,JohnWiley&Sons,Ltd.,2001,387-424。
具有疏水核和亲水壳的支化核壳聚合物可通过分子包封用以捕获水难溶性药物。具有亲水核和疏水壳的无规支化和超支化核壳结构通过单分子包封和预形成的纳米胶束也用以运载药物(美国专利6,716,450和Liuetal.,Biomaterials2010,10,1334-1341)。然而所述单分子结构和预形成的胶束结构在不存在药物的情况下产生。
观察到嵌段共聚物——例如杂臂形(miktoarm)聚合物(即Y形/AB2型星形聚合物)和线性(A)-树枝形(B)嵌段共聚物——与紫杉醇形成立体复合物(Nederbergetal.,Biomacromolecules2009,10,14601468和Luoetal.,BioconjugateChem.2010,21,1216)。所述嵌段共聚物与常规脂质或AB-型线性嵌段共聚物极其相似,所述常规脂质或AB-型线性嵌段共聚物为熟知的用于产生胶束的表面活性剂。
然而,所述支化嵌段共聚物难于制备,并因此不适于大规模生产。
目前没有改性的支化均聚物的描述,所述改性的支化均聚物一旦暴露于水难溶性或水不溶性药物后就会自发地形成适于药物控释的稳定的集合体。
发明内容
在一个方面,本公开内容涉及改性的支化聚合物(MBP)提高水不溶性或水难溶性药物活性剂(PAA)(例如药物)的溶解性的用途。所述MBP可包括对称的支化聚合物和不对称的支化聚合物。
在本公开内容的另一方面,所述对称的支化聚合物(SBP)在聚合物中具有规则的对称支链。在本公开内容的另一方面,所述不对称的支化聚合物(ABP)具有无规的不对称支链或者具有规则的不对称支链。所述无规的ABP还可具有末端支化和链支化类型的混合物。
在本公开内容的另一方面,ABP和SBP均可在给定时间被至少一种能够形成额外支链的分子或基团进一步改性,从而可获得新的材料性质,其中还可以进一步连接额外的官能团。所有改性的聚合物可被定义为改性的对称或不对称支化聚合物。
在本公开内容的另一方面,未经改性的和经改性的支化聚合物可通过分散法或汇聚法制备,并且可使用分步合成法或一步合成法。
在本公开内容的另一方面,所述SBP包括但不限于,聚酰胺胺树枝形分子;聚乙烯亚胺树枝形分子;聚丙烯亚胺树枝形分子;聚醚树枝形分子;聚酯树枝形分子;梳形支化/星形支化聚合物,例如,聚酰胺胺、聚环氧乙烷(PEO)、聚乙二醇(PEG)、聚甲基噁唑啉、聚乙基噁唑啉、聚甲基丙烯酸甲酯(PMA)、聚苯乙烯、聚丁二烯、聚异戊二烯和聚二甲基硅氧烷;梳形支化树枝形接枝分子,例如,聚乙基噁唑啉、聚甲基噁唑啉、聚乙烯亚胺、聚酰胺胺等。
在本公开内容的又一方面,所述SBP可具有内部空隙空间,而所述ABP可具有不均匀分布的空隙空间。
在本公开内容的另一方面,杂合的支化聚合物也可用于产生所述感兴趣的药物诱导的集合体或纳米颗粒,所述杂合的支化聚合物包括上述的SBP,例如树枝形分子或树枝形接枝分子;和ABP,例如,规则和无规支化的聚合物,以及星形支化和梳形支化聚合物,或其组合物。
在本公开内容的另一方面,素数支化聚合物被官能团改性,所述官能团例如但不限于,NH2、NHR、NR2、NR3 +、COOR、COOH、COO-、OH、C(O)R、C(O)NH2、C(O)NHR或C(O)NR2,其中R可为任意的脂族基团、芳族基团或其结合;脂族基团(例如烃链)——可被支化——可包含一个或多个双键和/或三键和/或可被取代;芳族基团,其可含有多个环,其可以是稠合或者孤立的,所述环可以为各种尺寸和/或可含有取代基;全氟碳链;糖类和/或多糖类,其可为各种环尺寸,所述环可含有杂原子(例如硫或氮原子),其可被取代,其可含有一种以上的糖类,其可以是支化的和/或可被取代;聚乙二醇等。
所述MBP的分子量可以在约500至超过5,000,000、约500至约1,000,000、约1,000至约500,000,或约2,000至约100,000的范围。
在本公开内容的另一方面,所述对称和不对称聚合物的表面被改性以使得表面基团的物理性质与感兴趣的PAA更相容,从而使PAA与MBP的表面基团区域/结构域更易混溶。
在一个实施方案中,用疏水的官能团将支化聚合物改性,所述疏水的官能团为,例如,脂族链(例如包含1至约22个碳的线性或支化的烃链)、芳族结构(例如含有一个或多个芳环,所述芳环可以是稠合的)或其结合。
相对于已知的药物载体,本公开内容的PAA不在所述支化聚合物结构中被物理捕获。相反,所述PAA可位于或分散于各支化聚合物的含表面官能团的结构域/区域中。
生成感兴趣的结构可任选地通过例如冻干或其他干燥形式——其可以进一步稳定感兴趣的结构——来保存。一旦将其重新溶于水或缓冲溶液中就可获得直径在约50至约500nm范围尺寸的纳米颗粒。
多重的、经常官能化的支链的存在能形成分子内交联和分子间交联,所述交联可稳定含PAA的纳米颗粒。一旦稀释,所述物理集合体或纳米颗粒就解构以控制的速率释放药物。
在本公开内容的另一方面,所述支化聚合物可包括靶向部分/基团,其包括但不限于,抗体或其抗原结合部分、抗原、同源碳水化合物(例如唾液酸)、细胞表面受体配体、被细胞表面受体结合的部分、结合细胞表面糖类的部分、细胞外基质配体、细胞质受体配体、生长因子、细胞因子、肠促胰岛素、激素、凝集素、凝集素配体(例如,半乳糖、半乳糖衍生物、N-乙酰基半乳糖胺、甘露糖、甘露糖衍生物等)、维生素(例如叶酸或生物素)、抗生物素蛋白、链霉亲和素、中和亲和素、DNA、RNA等。所述靶向的纳米颗粒在优选的治疗位置释放药物,由此增加了局部有效浓度并且可使不良副作用最小化。
在本公开内容的另一方面,在形成用于靶向药物释放的复合纳米颗粒之前,将靶向部分/基团和官能团连接至支化聚合物,所述官能团包括疏水官能团、亲水官能团和/或离子官能团。
在本公开内容的另一方面,还可通过所述感兴趣的结构运载诊断剂(例如造影剂)用于例如体内成像。在一个实施方案中,所述诊断剂为水难溶性或水不溶性诊断剂,因此不需要药物形成感兴趣的结构。
在一些实施方案中,显像剂为包含金属的或者是顺磁的显像剂,例如磁共振成像材料,所述显像剂可在所述基于纳米复合物的颗粒的所述支化聚合物中沉积或被捕获。
在本公开内容的另一个方面,所述含有诊断材料的纳米颗粒还可包括靶向部分/基团,这使得所述纳米颗粒以靶向特定位置用以诊断。
在其他实施方案中,感兴趣的结构包含第二或更多PAA。所述第二或更多PAA可以是或可以不是水难溶性或水不溶性的。
在本公开内容的另一方面,所述纳米颗粒可载有多种相似的PAA或可载有具有不同功能或活性的PAA,例如各种类型的药物以形成组合疗法或鸡尾酒疗法。为了治疗多种疾病或一般用途(例如,为了化妆品或非处方药产品),所述药物可以包括但不限于,小分子药物、无机药物和基于生物分子的药物,例如肽、蛋白质、抗体或其抗原结合部分、酶、疫苗等。
在本公开内容的另一方面,所述基于纳米颗粒的药物制剂还可用于药物发现和开发,其中可快速地筛选和测试多种治疗制剂。
本公开内容的其他特征和优势描述于以下的具体实施方式和附图中,并且在以下的具体实施方式和附图中是显而易见的。
附图说明
以下的附图说明和各自的图是说明例证了本公开内容的各个实施方案的非限制性实例。
图1示出了包括树枝形分子、星形聚合物、树枝形接枝形聚合物和梳形聚合物的SBP。所有SBP均具有核,所述核为球形或线性。
图2示出了对称支化的PPI树枝形分子的化学结构。
图3示出了对称支化PPI树枝形分子的化学改性反应。数字8、16、32等表示在树枝形分子表面上活性基团的数目。
图4A和4B示出了具有不对称支链接合点和类型的无规APB(A)和规则ABP(B)。
图5示出了无规不对称支化PEI均聚物的化学结构。
图6A和6B示出了合成方案。图6A代表无规不对称支化PEI均聚物的化学改性反应。图6B示出了在聚合物焦点处具有伯氨基的疏水改性的无规支化聚(2-乙氧基噁唑啉)的一锅法合成。引发剂/表面基团(I)为溴代烃。该反应打开了噁唑啉环。
图7示出了在支化聚合物(SBP和ABP)的表面结构域或区域处或在其中负载的药物。在该图和其他附图中,R表示表面基团;实心圆表示感兴趣的药物。
图8示出了一类含有药物分子和支化聚合物的基于复合物的纳米颗粒。
图9示出了一种处于支化聚合物(SBP和ABP)的疏水表面基团处的水不溶性或水难溶性药物。在该图和其他附图中,细波浪线表示疏水表面基团。
图10示出了多种还带有至少一种靶向基团或部分(例如抗体)的含药物的纳米颗粒,所述靶向基团或部分在此且在其他附图中以“Y”表示。
图11示出了带有磁性成像造影剂和靶向部分或基团(例如抗体)的含药物的纳米颗粒。在该图和其他附图中,M表示成像材料,例如磁共振成像造影剂。
图12示出了带有放射(Rad)剂和靶向部分或基团(例如抗体)的含药物的纳米颗粒。
图13示出了仅含聚合物的集合体和聚合物-药物集合体的尺寸比较,其中聚合物在盐水中的浓度为25mg/mL,药物在盐水中的浓度为5mg/mL。所述聚合物是经疏水改性的无规支化PEOX并且所述药物是紫杉醇。
图14示出了仅含聚合物的集合体和聚合物-药物集合体的尺寸比较,其中聚合物在盐水中的浓度为2.5mg/mL,药物在盐水中的浓度为0.5mg/mL。所述聚合物是经疏水改性的无规支化PEOX并且所述药物是紫杉醇。
图15示出了仅含聚合物的集合体和聚合物-药物集合体的尺寸比较,其中聚合物在盐水中的浓度为250μg/mL,药物在盐水中的浓度为50μg/mL。所述聚合物是经疏水改性的无规支化PEOX并且所述药物是紫杉醇。
图16示出了仅含聚合物的集合体和聚合物-药物集合体的尺寸比较,其中聚合物在盐水中的浓度为25μg/mL,药物在盐水中的浓度为5μg/mL。所述聚合物是经疏水改性的无规支化PEOX并且所述药物是紫杉醇。
图17总结了药物和药物集合体的细胞毒性比较数据。将MCF-7人乳腺癌细胞暴露于多种浓度的药物和药物集合体中并且测定其存活率。
图18总结了药物和药物集合体的细胞毒性比较数据。将H460人肺癌上皮细胞暴露于多种浓度的药物和药物集合体中并且测定其存活率。
具体实施方式
在本公开内容中,将药物溶解性定义为相对于用于溶解一份药物所需要的溶剂份数,<30(可溶)、30-100(难溶)、>100(不溶)。
出于本公开内容的目的,将词,例如,“约”、“基本上”等定义为不大于所述数值或数字的20%的值的范围。“均聚物”如上定义。
感兴趣的药物
在本公开内容中所描述的PAA包括任意化学药物/基于小分子的药物、无机系列药物、生物药物/基于大分子的药物、其改性物和/或衍生物及其结合,其中,所述药物是水难溶性的或水不溶性的。因此,感兴趣的药物可为小分子、其盐,其中所述分子被改性成水难溶性的或水不溶性的,或者可为被改性成水不溶性或水难溶性的生物分子。
化学药物/小分子药物可包括试图用于实施本公开内容的任意基本上水难溶性或水不溶性的药物活性剂,其包括PAA、药物、显像剂、诊断剂、具有营养价值的药剂、补充物、维生素、生活类化学品等。所述药物的一些可需要转换成更不溶于水的形式,例如,将PAA从盐形式转换成非盐形式或从带电荷的分子转换成不带电荷的分子。
PAA的合适的实例包括水难溶性或水不溶性药物,其包括,生长剂、AIDS佐剂、酗酒制剂,例如用于治疗酒精依赖或用于戒酒的药剂、阿尔茨海默病治疗剂、肌肉萎缩性侧索硬化症(AmyotrophicLateralSclerosis)治疗剂、镇痛药、麻醉剂、抗惊厥药、抗糖尿病药、解毒药、抗纤维化治疗药、抗组胺药、抗感染药(例如抗生素、抗病毒药、抗真菌药、抗阿米巴药、抗寄生虫药、抗疟疾药、抗麻风病药等)、抗肿瘤药、抗帕金森药、抗风湿药、食欲刺激剂、生物反应调节剂、生物制品、血液调节剂(例如,抗凝血剂、集落刺激因子、止血剂、血浆增量剂、凝血酶抑制剂等)、骨代谢调节剂、心脏保护剂、心血管药(如肾上腺素能阻滞剂、肾上腺素能刺激剂、ACE抑制剂、抗心律失常药、降血脂药、钙通道阻滞剂、利尿药、升压药等)、CNS刺激药、胆碱酯酶抑制剂、避孕药、生育治疗药、排卵刺激药、囊性纤维化处置剂、解毒剂、诊断剂、膳食补充剂、多巴胺受体激动剂、子宫内膜异位症处置剂、酶、勃起功能障碍治疗药、足部护理产品、GI剂(例如抗酸药、止泻药、止吐药、抗气胀药(antiflatulant)、肠道排泄药、消化酶、组胺受体激动剂、轻泻药、质子泵抑制剂、前列腺素等)、高雪氏症(Gaucher’sDisease)治疗剂、痛风治疗剂、顺势治疗药、皮肤处理剂、维生素、营养素、激素、高钙血症处置剂、低钙血症处置治疗剂、免疫调节剂、免疫抑制剂、左卡尼汀缺乏治疗剂、肥大细胞稳定剂、偏头痛治疗剂、运动病产品(例如,苯海拉明(benadryl)和非那根(phenergan))、解充血剂、抗组胺药、止咳药、多发性硬化症治疗剂、肌肉松弛剂、经鼻制剂(例如,抗炎药、戒烟辅助药物、食欲抑制剂、核苷类似物、肥胖处置剂、眼用制剂(例如,抗生素、抗青光眼剂、人工泪液、润滑剂等)、性助剂、润滑剂、骨质疏松症治疗剂、经耳制剂(例如抗感染药和溶耵聍剂(cerumenolytic))、矿物质、催产剂、副交感神经抑制剂(parasympatholytic)、拟副交感神经药、动脉导管未闭剂(patentductusarteriosusagent)、磷酸盐结合剂、卟啉剂、前列腺素、精神治疗剂、放射线造影剂、呼吸剂(例如,消炎药、镇咳剂、支气管扩张剂、解充血剂、祛痰药、白三烯拮抗剂、表面活性剂等)、盐替代品、镇静剂、安眠药、皮肤和粘膜制剂(例如,痤疮治疗剂)、肛门直肠治疗剂(例如,痔疮治疗剂和灌肠剂)、止汗剂、止痒剂、抗银屑病药、抗皮脂溢剂、烧伤治疗药、清洁剂、脱色剂、润肤剂、头发生长延缓剂、头发生长刺激剂、角质剥脱剂、头发问题治疗剂、嘴和喉咙问题治疗剂、洗发水、感光剂、疣治疗剂、伤口护理治疗剂等、非处方药和产品(例如,除臭剂、秽语综合征药(Tourette’sSyndromeagent)、震颤治疗剂、泌尿道药(例如,酸化剂、碱化剂(alkalinizer)、镇痉药、良性前列腺增生治疗药、草酸钙结石预防剂、遗尿处置剂等)、阴道用制剂(例如,抗感染药、激素等)、血管扩张剂、眩晕治疗药、威尔森氏症(Wilson’sDisease)治疗药等。
本文所列的为感兴趣的药以及可以被改性的药物形式,例如,盐。出于本发明的目的,如本领域已知将任意所述离子化或亲水形式改性以除去所述官能团、改性物等从而获得水难溶性或水不溶性的药物未改性形式或其他形式。药物活性剂、药物等的实例包括在本文中所列的那些,例如,止痛药/退烧药(例如,阿斯匹林、对乙酰氨基酚、布洛芬、甲氧萘丙酸钠(naproxensodium)、盐酸丁丙诺啡(buprenorphinehydrochloride)、盐酸丙氧芬(propoxyphenehydrochloride)、萘磺酸丙氧芬(propoxyphenenapsylate)、盐酸哌替啶(meperidinehydrochloride)、盐酸氢吗啡酮(hydromorphonehydrochloride)、硫酸吗啡(morphinesulfate)、盐酸羟考酮(oxycodonehydrochloride)、磷酸可待因(codeinephosphate)、重酒石酸双氢可待因(dihydrocodeinebitartrate)、盐酸喷他佐辛(pentazocinehydrochloride)、二酒石酸氢可酮(hydrocodonebitartrate)、酒石酸左啡诺(levorphanoltartrate)、二氟尼柳(diflunisal)、水杨酸三乙醇胺(trolaminesalicylate)、盐酸纳布啡(nalbuphinehydrochloride)、甲芬那酸(mefenamicacid)、酒石酸布托啡诺(butorphanoltartrate)、水杨酸胆碱(cholinesalicylate)、布他比妥(butalbital)、柠檬酸苯托沙敏(phenyltoloxaminecitrate)、柠檬酸苯海拉明(diphenhydraminecitrate)、左美丙嗪(methotrimeprazine)、盐酸桂美君(cinnamedrinehydrochloride)、眠尔通(meprobamate)等);麻醉剂(例如,环丙烷、安氟醚(enflurane)、氟烷(halothane)、异氟烷(isoflurane)、甲氧氟烷、一氧化二氮、丙泊酚(propofol)等);平喘药(例如,氮卓斯汀(azelastine)、酮替芬(ketotifen)、曲呫诺(traxanox)、氨来呫诺(amlexanox)、色甘酸(cromolyn)、异丁司特(ibudilast)、孟鲁司特(montelukast)、奈多罗米(nedocromil)、奥沙米特(oxatomide)、普鲁司特(pranlukast)、塞曲司特(seratrodast)、甲磺司特(suplatasttosylate)、噻拉米特(tiaramide)、扎鲁司特(zafirlukast)、齐留通(zileuton)、倍氯米松(beclomethasone)、布地奈德(budesonide)、地塞米松、氟尼缩松(flunisolide)、曲安奈德(triamcinoloneacetonide)等);抗生素(例如,新霉素(neomycin)、链霉素(streptomycin)、氯霉素(chloramphenicol)、头孢菌素(cephalosporin)、氨苄青霉素(ampicillin)、青霉素(penicillin)、四环素(tetracycline)等);抗抑郁药(例如,奈福泮(nefopam)、奥昔哌汀(oxypertine)、盐酸多塞平(doxepinhydrochloride)、阿莫沙平(amoxapine)、盐酸曲唑酮(trazodonehydrochloride)、盐酸阿米替林(amitriptylinehydrochloride)、盐酸马普替林(maprotilinehydrochloride)、硫酸苯乙肼(phenelzinesulfate)、盐酸地昔帕明(desipraminehydrochloride)、盐酸去甲替林(nortriptylinehydrochloride)、硫酸苯环丙胺(tranylcyprominesulfate)、盐酸氟西汀(fluoxetinehydrochloride)、盐酸多塞平(doxepinhydrochloride)、盐酸丙咪嗪(imipraminehydrochloride)、双羟萘酸丙咪嗪(imipraminepamoate)、去甲替林(nortriptyline)、盐酸阿米替林(amitriptylinehydrochloride)、异卡波肼(isocarboxazid)、马来酸三甲丙咪嗪(trimipraminemaleate)、盐酸普罗替林(protriptylinehydrochloride)等);抗糖尿病药(例如,双胍(biguanide)、激素、磺酰脲衍生物等);抗真菌药(例如,灰黄霉素(griseofulvin)、酮康唑(ketoconazole)、两性霉素B(amphotericinB)、制霉菌素(nystatin)、杀假丝菌素(candicidin)等);抗高血压药(例如,心得安(propanolol)、普罗帕酮(propafenone)、氧希洛尔(oxyprenolol)、硝苯地平(nifedipine)、利血平(reserpine)、樟磺咪芬(trimethaphancamsylate)、盐酸酚苄明(phenoxybenzaminehydrochloride)、盐酸优降宁(pargylinehydrochloride)、地舍平(deserpidine)、二氮嗪(diazoxide)、单硫酸胍乙啶(guanethidinemonosulfate)、米诺地尔(minoxidil)、瑞西那明(rescinnamine)、硝普钠(sodiumnitroprusside)、蛇根萝芙木(rauwolfiaserpentina)、阿舍西隆(alseroxylon)、甲磺酸酚妥拉明(phentolaminemesylate)、利血平等);抗炎药(例如,非甾体化合物,例如,吲哚美辛、萘普生、布洛芬、雷米那酮、吡罗昔康等;甾族化合物,例如,可的松、地塞米松、氟扎可特(fluazacort)、氢化可的松(hydrocortisone)、泼尼松龙(prednisolone)、泼尼松(prednisone)等);抗肿瘤药(例如,阿霉素、环磷酰胺、放线菌素、博来霉素、柔红霉素、多柔比星、表柔比星、丝裂霉素、甲氨喋呤、氟尿嘧啶、卡铂、卡氮芥(carmustine,BCNU)、甲基-CCNU、顺铂、依托泊甙、干扰素、喜树碱及其衍生物、苯芥胆甾醇(phenesterine)、泰素(Taxol)及其衍生物、多西他赛(taxotere)及其衍生物、长春碱、长春新碱、他莫昔芬(tamoxifen)、依托泊甙、哌泊舒凡(piposulfan)等);抗焦虑药(例如,劳拉西泮(lorazepam)、盐酸丁螺环酮(buspironehydrochloride)、普拉西泮(prazepam)、盐酸利眠宁(chlordiazepoxidehydrochloride)、奥沙西泮(oxazepam)、氯草酸钾(clorazepatedipotassium)、地西泮(diazepam)、双羟萘羟嗪(hydroxyzinepamoate)、盐酸羟嗪(hydroxyzinehydrochloride)、阿普唑仑(alprazolam)、氟哌利多(droperidol)、哈拉西泮(halazepam)、氯美扎酮(chlormezanone)、硝苯呋海因(dantrolene)等);免疫抑制剂(例如,环孢霉素(cyclosporine)、硫唑嘌呤(azathioprine)、咪唑立宾(mizoribine)、FK506(他克莫司(tacrolimus))等);抗偏头痛药(例如,酒石酸麦角胺(ergotaminetartrate)、盐酸心得安、半乳糖二酸异美汀(isometheptenemucate)、氯醛比林(dichloralphenazone)等);镇静剂/催眠药(例如,巴比妥类药(例如,苯巴比妥(pentobarbital)、戊巴比妥钠(pentobarbitalsodium)、司可巴比妥钠(secobarbitalsodium)等)或苯二氮卓类药(例如,盐酸氟西泮、三唑仑、替马西泮(tomazeparm)、盐酸咪达唑仑(midazolamhydrochloride)等);抗心绞痛药物(例如,β-肾上腺素能阻滞剂、钙通道阻滞剂(例如,硝苯地平、盐酸地尔硫卓(diltiazemhydrochloride)等)、硝酸盐(例如,硝酸甘油、硝酸异山梨酯、季戊四醇四硝酸酯、丁四硝酯(erythrityltetranitrate)等))、抗精神病药(例如,氟哌啶醇(haloperidol)、琥珀酸洛沙平(loxapinesuccinate)、盐酸洛沙平(loxapinehydrochloride)、硫利达嗪(thioridazine)、盐酸硫利达嗪、替沃噻吨(thiothixene)、盐酸氟奋乃静(fluphenazinehydrochloride)、氟奋乃静癸酸酯(fluphenazinedecanoate)、氟奋乃静庚酸酯(fluphenazineenanthate)、盐酸三氟拉嗪(trifluoperazinehydrochloride)、盐酸氯丙嗪(chlorpromazinehydrochloride)、奋乃静、柠檬酸锂、丙氯拉嗪(prochlorperazine)等);抗躁狂药(如碳酸锂);抗心律失常药(如溴苄铵(bretyliumtosylate)、盐酸艾司洛尔(esmololhydrochloride)、盐酸维拉帕米(verapamilhydrochloride)、胺碘酮(amiodarone)、盐酸恩卡尼(encainidehydrochloride)、地高辛(digoxin)、洋地黄毒苷(digitoxin)、盐酸美西律(mexiletinehydrochloride)、磷酸丙吡胺(disopyramidephosphate)、盐酸普鲁卡因胺(procainamidehydrochloride)、硫酸奎尼丁(quinidinesulfate)、葡萄糖酸奎尼丁(quinidinegluconate)、聚半乳糖醛酸奎尼丁(quinidinepolygalacturonate)、醋酸氟卡胺(flecainideacetate)、盐酸妥卡胺(tocainidehydrochloride)、盐酸利多卡因(lidocainehydrochloride)等);抗关节炎药(如保泰松(phenylbutazone)、舒林酸(sulindac)、青霉胺、双水杨酸(salsalate)、吡罗昔康(piroxicam)、咪唑硫嘌呤(azathioprine)、吲哚美辛、甲氯灭酸钠(meclofenamatesodium)、硫代苹果酸金钠(goldsodiumthiomalate)、酮洛芬(ketoprofen)、金诺芬(auranofin)、硫金代葡萄糖(aurothioglucose)、托美丁钠(tolmetinsodium)等);抗痛风药(例如,秋水仙碱(colchicine)、别嘌呤醇(allopurinol)等);抗凝血药(例如,肝素(heparin)、肝素钠、华法林钠(warfarinsodium)等);溶血栓药(例如,尿激酶(urokinase)、链激酶(streptokinase)、阿替普酶(altoplase)等);抗纤维蛋白溶解药(例如,氨基己酸);血液流变剂(例如,己酮可可碱(pentoxifylline));抗血小板药(例如,阿斯匹林、安匹林(empirin)、ascriptin等);抗惊厥药(例如,丙戊酸、双丙戊酸钠、苯妥英(phenytoin)、苯妥因钠、氯硝西泮、扑米酮、苯巴比妥、苯巴比妥钠、卡马西平、异戊巴比妥钠(amobarbitalsodium)、甲琥胺(methsuximide)、美沙比妥(metharbital)、普罗米那(mephobarbital)、美芬妥英(mephenytoin)、苯琥胺(phensuximide)、甲乙双酮(paramethadione)、乙妥英(ethotoin)、苯乙酰脲(phenacemide)、丙烯戊巴比妥钠(secobarbitolsodium)、氯草酸钾、三甲双酮(trimethadione)等);抗帕金森药(例如,乙琥胺等);抗组胺剂/止痒剂(例如,盐酸羟嗪、盐酸苯海拉明、马来酸氯苯吡胺、马来酸溴苯那敏、盐酸赛庚啶(cyproheptadinehydrochloride)、特非那定(terfenadine)、富马酸氯马斯汀(clemastinefumarate)、盐酸曲普利啶(triprolidinehydrochloride)、马来酸卡比沙明(carbinoxaminemaleate)、盐酸双苯拉林(diphenylpyralinehydrochloride)、酒石酸苯茚胺(phenindaminetartrate)、马来酸阿扎他定(azatadinemaleate)、盐酸曲吡那敏(tripelennaminehydrochloride)、马来酸右氯苯那敏(dexchlorpheniraminemaleate)、盐酸甲地嗪(methdilazinehydrochloride)、酒石酸异丁嗪(trimprazinetartrate)等);对钙调节有用的药(例如,降钙素(calcitonin)、甲状旁腺激素(parathyroidhormone)等);抗细菌剂(例如,硫酸丁胺卡那霉素(amikacinsulfate)、氨曲南(aztreonam)、氯霉素(chloramphenicol)、棕榈酸氯霉素、氯霉素琥珀酸钠、盐酸环丙沙星(ciprofloxacinhydrochloride)、盐酸克林霉素(clindamycinhydrochloride)、克林霉素棕榈酸酯、磷酸克林霉素、甲硝唑(metronidazole)、盐酸甲硝唑、硫酸庆大霉素(gentamicinsulfate)、盐酸林可霉素(lincomycinhydrochloride)、硫酸妥布霉素(tobramycinsulfate)、盐酸万古霉素(vancomycinhydrochloride)、硫酸多粘菌素B(polymyxinBsulfate)、多粘菌素E甲磺酸钠(colistimethatesodium)、硫酸多粘菌素E(colistinsulfate)等);抗病毒药(例如,干扰素γ、齐多夫定(zidovudine)、盐酸金刚烷胺(amantadinehydrochloride)、三唑核苷(ribavirin)、阿昔洛韦(acyclovir)等);抗细菌药(如头孢菌素(如头孢唑啉钠(cefazolinsodium)、头孢拉定(cephradine)、头孢克洛(cefaclor)、头孢匹林钠(cephapirinsodium)、头孢唑肟钠(ceftizoximesodium)、头孢哌酮钠(cefoperazonesodium)、头孢替坦二钠(cefotetandisodium)、cefutoximeazotil、头孢噻肟钠(cefotaximesodium)、一水头孢羟氨苄(cefadroxilmonohydrate)、头孢他啶(ceftazidime)、头孢氨苄(cephalexin)、头孢噻吩钠(cephalothinsodium)、头孢氨苄盐酸盐一水合物、头孢孟多酯钠(cefamandolenafate)、头孢西丁钠(cefoxitinsodium)、头孢尼西钠(cefonicidsodium)、头孢雷特(ceforanide)、头孢曲松钠(ceftriaxonesodium)、头孢他啶(ceftazidime)、头孢羟氨苄(cefadroxil)、头孢拉定(cephradine)、头孢呋辛钠(cefuroximesodium)等)、青霉素类药(如氨苄西林(ampicillin)、阿莫西林(amoxicillin)、苄星青霉素G(penicillinGbenzathine)、环己西林(cyclacillin)、氨苄西林钠(ampicillinsodium)、青霉素GK、青霉素VK、哌拉西林钠(piperacillinsodium)、苯唑西林钠(oxacillinsodium)、盐酸巴氨西林(bacampicillinhydrochloride)、氯唑西林钠(cloxacillinsodium)、替卡西林二钠(ticarcillindisodium)、阿洛西林钠(azlocillinsodium)、羧苄西林茚满钠(carbenicillinindanylsodium)、普鲁卡因青霉素G(penicillinGprocaine)、甲氧苯青霉素钠(methicillinsodium)、萘夫西林钠(nafcillinsodium)等)、红霉素类(例如,琥乙红霉素(erythromycinethylsuccinate)、红霉素、依托红霉素(erythromycinestolate)、乳糖酸红霉素(erythromycinlactobionate)、硬脂酸红霉素(erythromycinstearate)、琥乙红霉素(erythromycinethylsuccinate)等)、四环素类抗生素(例如,盐酸四环素、盐酸强力霉素(doxycyclinehyclate)、盐酸米诺环素(minocyclinehydrochloride)等)等);抗感染药(例如,GM-CSF);支气管扩张药(例如,拟交感神经药(例如,盐酸肾上腺素、硫酸奥西那林(metaproterenolsulfate)、硫酸特布他林(terbutalinesulfate)、异丙他林(isoetharine)、甲磺酸异丙他林、盐酸异丙他林、硫酸沙丁胺醇、沙丁胺醇、比托特罗(bitolterol)、盐酸异丙肾上腺素甲磺酸酯、硫酸特布他林(terbutalinesulfate)、双酒石酸肾上腺素、硫酸奥西那林、肾上腺素、双酒石酸肾上腺素);抗胆碱能药(例如,溴化异丙托品(ipratropiumbromide));黄嘌呤(例如,氨茶碱(aminophylline)、二羟丙茶碱(dyphylline)、硫酸奥西那林、氨茶碱);肥大细胞稳定剂(例如,色甘酸钠);吸入型糖皮质激素(例如,氟尼缩松(flunisolide)、丙酸氯地米松一水合物等)、沙丁胺醇、二丙酸倍氯米松(BDP)、溴化异丙托品、布地奈德(budesonide)、酮替酚、沙美特罗(salmeterol)、昔萘酸沙美特罗(xinafoate)、硫酸特布他林、曲安西龙(triamcinolone)、茶碱(theophylline)、奈多罗米钠(nedocromilsodium)、硫酸奥西那林、albuterol、氟尼缩松等);激素(例如,雄激素(例如,达那唑(danazol)、环戊丙酸睾酮(testosteronecypionate)、氟甲睾酮(fluoxymesterone)、乙基睾酮(ethyltostosterone)、庚酸睾酮(testosteroneenanthate)、甲基睾酮(methyltestosterone)、氟甲睾酮、环戊丙酸睾酮等)、雌激素(例如,雌二醇(estradiol)、雌酮硫酸酯哌嗪(estropipate)、共轭雌激素等)、孕激素(例如,醋酸甲氧基孕酮、醋酸炔诺酮(norethindroneacetate)等)、糖皮质激素(例如,曲安西龙、倍他米松、倍他米松磷酸钠、地塞米松、地塞米松磷酸钠、醋酸地塞米松、强的松、醋酸甲基强的松龙悬浮液、曲安奈德(triamcinoloneacetonide)、甲基强的松龙、强的松龙磷酸钠、甲基强的松龙琥珀酸钠、氢化可的松琥珀酸钠、甲基强的松龙琥珀酸钠、羟氟烯索(triamcinolonehexacatonide)、氢化可的松、环戊丙酸氢化可的松、强的松龙、醋酸氟氢可的松、醋酸帕拉米松、prednisolonetebulate、醋酸强的松龙、强的松龙磷酸钠、氢化可的松琥珀酸钠等)、甲状腺激素(例如,左甲状腺素钠)等糖皮质激素)等激素;降糖药(例如,人胰岛素、纯化的牛胰岛素、纯化的猪胰岛素、格列本脲(glyburide)、氯磺丙脲(chlorpropamide)、格列吡嗪(glipizide)、甲苯磺丁脲(tolbutamide)、妥拉磺脲(tolazamide)等);降血脂药(例如,氯贝丁酯(clofibrate)、右甲状腺素钠(dextrothyroxinesodium)、普罗布考(probucol)、洛伐他汀(lovastatin)、烟酸(niacin)等);蛋白质(例如,DNA酶、褐藻酸酶(alginase)、超氧化物歧化酶(superoxidedismutase)、脂酶(lipase)等);核酸(例如,编码任何治疗上有用的蛋白质(包括任何本文所描述的蛋白质等)的正义核酸或反义核酸);对红细胞生成有用的药(例如,促红细胞生成素(erythropoietin));抗溃疡或抗反流剂(例如,法莫替丁、西米替丁、盐酸雷尼替丁等);止吐剂或抗呕剂(例如,盐酸氯苯甲嗪(meclizinehydrochloride)、大麻隆(nabilone)、丙氯拉嗪、茶苯海明(dimenhydrinate)、盐酸异丙嗪(promethazinehydrochloride)、硫乙拉嗪(thiethylperazine)、东莨菪碱(scopolamine)等);脂溶性维生素(例如,维生素A、D、E、K等);以及其他药物,例如,米托坦(mitotane)、visadine、halonitrosourea、蒽环霉素(anthrocycline)、玫瑰树碱(ellipticine)等。
试图用于实施本公开内容的诊断剂的实例包括但不限于,例如,磁共振成像造影剂(例如,各种金属离子(例如,用于功能性MRI的基于钆的化合物、碳氟化合物、脂溶性顺磁化合物等)、超声造影剂、放射造影剂(例如,常规放射性核素(如碘、铜、氟、镓、铊等),其可以与载体(例如,碘-辛烷、卤代烃、renografin等)络合,以及其他诊断剂,其不能不经某些物理和/或化学改性而被容易地被释放以满足其基本上水不溶性性质。金属和放射性核素可被运至或结合至蛋白质、脂质、核酸、螯合剂(例如小分子)或其结合。
试图用于实施本公开内容的具有营养价值或生活价值的药剂的实例包括氨基酸、糖、脂质、蛋白质、碳水化合物、油(例如鱼油)、脂溶性维生素(例如维生素A、D、E、K等)、矿物质、补充物、脂肪、润肤剂、鞣剂、保湿剂等,或其结合。
纳米复合物或纳米集合体
纳米复合物是两种以上材料或组分(例如聚合物和PAA分子)的物理混合物。在本公开内容中,这样的混合物可含有不同的固态或液态的纳米级相或域,其形成于PAA和支化均聚物分子之间。纳米复合物可包括块状基体(例如支化均聚物和PAA)与纳米二维相的结合,其由于结构和化学(例如由PAA和支化聚合物的表面基团所形成的域,以及由支化聚合物的内部所形成的域)的不相似性可以呈现出不同的特性。由于所述域/相的溶解性可以不同,因此一旦将纳米复合物溶解在水溶液中,各相中的一相可比其他相或其他多相溶解更迅速,这使得复合物集合体逐渐破裂,进而使复合组分分级且可控地释放以及任选地,所述组分中的一种或多种重新形成一种新的形式,例如,新的集合体。
在本公开内容中描述的集合体的尺寸在约10至约500nm的直径范围内,或者直径为约30nm至约300nm。集合体可以呈现出与在微米颗粒或块状材料中观察到的显著不同的尺寸相关的特性。
具有对称支链的SBP示于图1,其中所有感兴趣的均聚物均具有壳并且呈现由遍及均聚物的末端支链或链支链组成的对称支链接合点。所述官能团主要存在于外部。
经改性的SBP可通过例如,将官能团化学连接至下列物质上而获得:例如,对称支化的PAMAM或PPI树枝形分子(购自Aldrich)、聚醚树枝形分子、聚酯树枝形分子、梳形支化/星形支化聚合物(例如,含有PEO、PEG、PMOX或PEOX的那些)、聚苯乙烯和梳形支化树枝形接枝分子(例如含有PEOX、PMOX或PEI的那些)。
用于制造所述SBP/树枝形分子的合成方法是已知的(参见,例如,“DendrimersandOtherDendriticPolymers,”Frechet&Tomalia,eds.,JohnWiley&Sons,Ltd.,2001),其使用市售的试剂(例如,各代的PPI树枝形分子,图2),或者大量SBP是市售可得的。梳形支化聚合物和梳爆形聚合物的合成是已知的(参见,例如,美国专利5,773,527、5,631,329和5,919,442)。
SBP的较高支化密度使得聚合物具有明确限定的内部空隙空间且在分子水平上密实,这使得这些分子适合作为实体的载体,所述实体为例如被捕获或包封于其中的指示器或PAA。
表面改性可增加所得的经改性的SBP的特性和用途。例如,经合适的改性,水不溶性SBP可变为水溶性的,而具有高电荷密度的SBP可被改性成在聚合物上或在聚合物表面上带有非常低的电荷或不带电荷。另一方面,水溶性SBP可被疏水表面基团改性以提高在其表面上溶解水不溶性或水难溶性药物的能力。
在本公开内容的一个实施方案中,所述SBP(例如,对称支化PEI树枝形分子、PPI树枝形分子、PAMAM树枝形分子或对称支化PEI树枝形接枝分子)可被不同类的例如伯胺基团通过例如Michael加成或将丙烯酸酯加成到均聚物的胺基团上的加成反应来改性。因此,例如,通过Michael加成反应,可以将丙烯酸甲酯引入到PEI、PPI和聚赖氨酸(PLL)均聚物的伯和/或仲氨基上。然后所述酯基团可被进一步衍生化,例如,通过酰胺化反应。因此,例如,与例如1,2-乙二胺的酰胺化反应可以产生氨基加成在新形成支链末端处。对所述均聚物的其他改性可以使用已知的化学知识进行,例如提供于HandbookofPolymerSynthesis(PartA),Kricheldorf,ed.,NewYork,MarcelDekker,1994;和“DendrimersandOtherDendriticPolymers,”Frechet&Tomalia,eds.,JohnWiley&Sons,Ltd.,2001中。
一旦进行此类加成,就形成改性的SBP,例如改性PEI、PPI、PAMAM树枝形分子或PEI树枝形接枝分子。作为SBP(例如PPI和PEI)的延伸,所得到的改性SBP也是对称支化的。根据溶剂环境(即pH或极性),表面官能基团可带有不同的电荷和/或电荷密度和/或疏水基团。基于这些特征性质,随后可以进一步调整分子形状和表面官能团位置(即表面官能团反折叠)。
在本公开内容的另一个实施方案中,可使用多种合成方案中的任何一种来制备所述改性的SBP,所述合成方案例如已知满足与均聚物上的合适位点反应。此外,多种试剂中的任何一种都可用于所选择的合成方案中,以得到多种改性物或均聚物骨架的加成物中的任何一种。因此,例如,在上述胺的Michael加成反应的情况下,可使用多种取代基中的任何一种的加成,例如,在烷基化反应阶段,例如使用多种丙烯酸酯试剂中的任何一种,例如包含烃取代基的丙烯酸酯,所述取代基为例如包含1至约22个碳的饱和或不饱和的烃,该烃可以是取代的、脂族的、芳族的、成环的、在一个或多个键上饱和的或其结合。因此,合适的反应物包括,丙烯酸甲酯、丙烯酸乙酯、丙烯酸丙酯、丙烯酸丁酯、丙烯酸戊酯、丙烯酸己酯、丙烯酸庚酯、丙烯酸辛酯、丙烯酸壬酯、丙烯酸癸酯、丙烯酸十一烷基酯、丙烯酸十二烷基酯等,或其混合物。类似地,在上述举例说明的实例的酰胺化阶段,可以使用多种胺中的任何一种。例如,可使用1,2-乙二胺、单乙醇胺、三(羟甲基)氨基甲烷、烷基胺、烯丙基胺、或任何氨基改性的聚合物,包括那些含PEG、PEO的聚合物、全氟聚合物、聚苯乙烯、聚乙烯、聚二甲基硅氧烷、聚丙烯酸酯、聚甲基丙烯酸甲酯等以及其混合物。
这种合成策略将不仅可使所述分子对称增长(其中可引入更多具有不同化学组成的支链),而且将可使多种官能团在所述结构外部加成。可以使用相同的或不同的合成方法将所述前体均聚物连续改性,直至得到具有合适分子量和官能团的所需要的SBP。此外,可通过使用构建该均聚物的合适单体和适当的改性反应将此类聚合物的疏水性能和亲水性能以及电荷密度进行调整以满足具体的应用需要。
在本公开内容的另一个实施方案中,如果使用分散合成方法,则对称星形支化或梳形支化均聚物(例如,聚(2-取代的噁唑啉),包括,例如,聚(2-甲基噁唑啉)、聚(2-乙基噁唑啉)、聚(2-丙基噁唑啉)和聚(2-丁基噁唑啉)、PEI、PEO/二醇、聚乙烯吡咯烷酮、聚磷酸酯、聚乙烯醇或聚苯乙烯)的链末端可被另一种小分子或聚合物改性以在均聚物链末端产生多种官能团,包括伯胺、仲胺或叔胺、羧酸酯、羟基、脂族基团(例如烃链)、芳族基团、氟烷基、芳基、PEG、PEO、乙酸酯、酰胺和/或酯基团。或者,如果使用汇聚合成方法,还可使用多种引发剂以在链末端引入相同类型的官能团(DendriticMolecules,Newkomeetal.,eds.,VCH,Weinheim,1996;DendrimersandOtherDendriticPolymers,Frechet&Tomalia,eds.,JohnWiley&Sons,Ltd.,2001;和J.Macromol.Sci.Chem.A9(5),pp.703-727(1975))。
具有不对称支链的ABP示于图4A和4B,其中一些感兴趣的聚合物不具有核并且呈现出了遍及整个均聚物的由链支链和末端支链构成的不对称支链接合点。官能团经常既存在于外部也存在于内部。然而,当使用较大官能团(例如,较大的疏水基团或亲水基团)时,所述官能团经常可优先地并且可能必然地连接在ABP的外部,例如,这可能是由于位阻效应。因此,可使用此类表面MBP用于溶解不溶性或难溶性药物或与其形成集合体。
所述改性的ABP可通过,例如,将官能团化学连接至规则ABP(例如,聚赖氨酸(如支化PLL))、无规ABP(例如PEI(购自Aldrich,Polysciences或BASF,商品名为LuposalTM)或聚噁唑啉)上,所述改性的ABP可根据Litt的方法(J.Macromol.Sci.Chem.A9(5),第703-727页(1975))制备。其他ABP可包括但不限于,聚丙烯酰胺、聚磷酸酯、聚乙烯吡咯烷酮、聚乙烯醇等。
可使用多种已知的起始材料用于制造所述改性的ABP。所述单体和聚合物可以低廉的成本大量市售。例如,一种这类可用于合成感兴趣的均聚物的前体单体为PEI。无规不对称支化PEI的合成是已知的(Jonesetal.,J.Org.Chem.9,125(1944))。具有各种分子量的PEI可从不同来源商购,例如,Aldrich,Polysciences和BASF(商品名为LuposalTM)。所述无规不对称支化PEI主要通过具有环张力的环状亚胺单体的阳离子开环聚合而制备,所述单体为例如氮丙啶(吖丙啶)和氮杂环丁烷(2-甲基吖丙啶),在上述反应中使用Lewis酸或Bronsted酸作为引发剂(Dermeretal.,“EthylenediamineandOtherAziridines”,AcademicPress,NewYork,(1969);和Pell,J.Chem.Soc.71(1959))。由于许多所述方法基本上是一锅法,因此可容易地制备大量无规ABP。无规支化聚(2-取代的噁唑啉)聚合物可使用Litt的方法(J.Macromol.Sci.Chem.A9(5),第703-727页(1975))制备。
用于制造ABP的合成方法通常在大分子内产生多种支链接合点。换言之,末端和链支链接合点混合分布于整个分子结构中。与树枝形分子和树枝形接枝分子相比,无规ABP的支化密度可更低,并且分子结构可更开放。虽然所述支化类型是无规的,但是伯胺、仲胺和叔胺基团的平均比例可相对符合约1:2:1的比例,如Dicketal.,J.Macromol.Sci.Chem.,A4(6),1301-1314(1970)和Lukovkin,Eur.Polym.J.9,559(1973)所述。
所述支链接合点的存在可使无规ABP(例如不对称支化PEI)形成具有可能的球状、卵状或类似构造的大分子。在球状结构内,在大分子的内部存在多种尺寸的由不完全的支链接合点形成的口袋(pocket)。不同于其中内部口袋总是位于分子的中心核周围的树枝形分子和树枝形接枝分子,无规ABP的口袋不均匀地分布在整个分子中。结果,无规ABP具有外部官能团和不均匀分布的内部官能团,所述官能团可以进一步与多种分子反应,从而形成新的大分子结构,即为感兴趣的改性的无规ABP。
虽然所述规则ABP具有核,但是其官能团也分布在外部和内部,这与无规ABP非常相似。一种这样的均聚物为PLL,其可如在美国专利4,289,872、4,360,646和4,410,688中所描述的进行制造。这类均聚物还可以对于无规ABP类似的方式进行改性,如在本说明书中所教导的,并且如本领域已知的。
在本公开内容的一个实施方案中,所述ABP(例如,无规不对称支化PEI或规则不对称支化PLL)被不同种类的伯胺基团通过例如Michael加成或将丙烯酸酯加成到聚合物的胺基团上的加成反应来改性。因此,例如,通过Michael加成反应,可以将丙烯酸甲酯基或如在本文中提供的其他丙烯酸酯引入到例如PEI、PPLL均聚物的伯和/或仲氨基上。然后所述酯基团可被进一步衍生化,例如,通过酰胺化反应。因此,例如,与例如1,2-乙二胺的酰胺化反应可以产生在新形成支链末端处的氨基的加成。对所述聚合物的其他改性可以使用已知的化学知识进行,例如在HandbookofPolymerSynthesis(PartA),Kricheldorf,ed.,NewYork,MarcelDekker,1994;和“DendrimersandOtherDendriticPolymers,”Frechet&Tomalia,eds.,JohnWiley&Sons,Ltd.,2001中提供的那些。
一旦进行此类加成就形成改性的ABP,例如改性PEI或PLL均聚物。作为ABP(例如PEI和PLL)的延伸,所得到的改性ABP也是不对称支化的。根据溶剂环境(即pH或极性),表面官能基团可带有不同的电荷和电荷密度。基于这些特征性质,随后可以进一步调整分子形状和官能团位置(即官能团反折叠)。
在另一个实施方案中,可使用多种合成方案中的任何一种来制备所述改性的ABP,所述合成方案例如已知满足与均聚物上的合适位点的反应。此外,多种反应试剂中的任何一种均可用于所选择的合成方案中,以得到多种改性物或均聚物骨架的加成物中的任一种。因此,例如,在上述胺的Michael加成反应的情况下,在烷基化反应阶段可使用多种取代基中的任一种例如与丙烯酸酯加成的加成,如上文中提供,所述丙烯酸酯可包含饱和的或不饱和的烃,例如包含1至约22个碳的饱和或不饱和的烃,该烃可以是脂族的、支化的、饱和的、芳族的、成环的,或其结合。合适的反应物包括,丙烯酸甲酯、丙烯酸乙酯、丙烯酸丙酯、丙烯酸丁酯、丙烯酸戊酯、丙烯酸己酯、丙烯酸庚酯、丙烯酸辛酯、丙烯酸壬酯、丙烯酸癸酯、丙烯酸十一烷基酯、丙烯酸十二烷基酯等,或其混合物。类似地,在上述举例说明的实例的酰胺化阶段,多种胺中的任何一种可用于本文提供的和本领域已知的方法中。例如,可使用乙二胺、单乙醇胺、三(羟甲基)氨基甲烷、烷基胺、烯丙基胺、或任何氨基改性的聚合物,包括聚乙二醇(PEG)、全氟聚合物、聚苯乙烯、聚乙烯、聚二甲基硅烷、聚丙烯酸酯、聚甲基丙烯酸甲酯等,以及其混合物。此外,可通过使用以下方法实现将疏水基团以及亲水基团连接至改性ABP:例如环氧化反应、酰胺化反应、Michael加成反应(包括使用-SH或NH2基团与马来酰亚胺反应)、醛/酮-胺/肼偶联反应、碘/碘乙酰-SH偶联反应、羟胺-醛/酮偶联反应,所述疏水基团包括脂族(例如C1至约C22的烃)基团、芳族基团、聚乙烯聚合物、聚苯乙烯聚合物、全氟聚合物、聚二甲基硅氧烷、聚丙烯酸酯、聚甲基丙烯酸甲酯;所述亲水基团包括OH基团、亲水聚合物,例如PEOX、PEG、PEO等。所述合成策略不仅使引入更多口袋的分子不对称地生长,还实现了在结构的内部和外部多个官能团的加成。可使用相同的或不同的合成方法将所述均聚物进一步改性直至得到具有合适分子量和官能团的所需要的ABP。此外,可通过使用构建该均聚物的合适单体和适当的改性反应将此类均聚物的疏水和亲水性能以及电荷密度进行调整以满足具体应用的需要。
在本公开内容的另一个实施方案中,无规ABP(例如聚噁唑啉)的焦点(在汇聚合成期间从多个反应链末端汇合)可被另一种小分子封端或与其反应,以在均聚物链的末端产生多种官能团,所述官能团包括伯胺、仲胺或叔胺、羧酸酯、羟基、烷基、氟烷基、芳基、PEG、乙酸酯、酰胺和/或酯基团。或者,也可使用多种引发剂从而在汇聚合成期间在聚合反应开始的表面基团处引入相同类型的官能团(J.Macromol.Sci.Chem.A9(5),pp.703-727(1975))。
在支化聚合物的焦点处具有伯胺基团的烷基表面改性的、无规支化聚(2-乙基噁唑啉)可通过使用上述Litt和Warakomski方法来制备。例如,可使用CH3(CH2)17-Br作为2-乙基噁唑啉聚合反应的引发剂,通过阳离子开环方法以生成无规支化聚合物,随后用N-叔丁氧羰基哌嗪(N-Boc-哌嗪)或1,2-乙二胺(EDA)淬灭。使用大过量的EDA封端使得经疏水改性的支化聚(2-乙基噁唑啉)聚合物在焦点被伯胺基团官能化(图6B)。或者,被N-叔丁氧羰基哌嗪(N-Boc-哌嗪)封端的疏水改性的支化的聚(2-乙基噁唑啉)聚合物还可脱保护以在焦点处形成伯氨基团。如果不进行封端,则一旦溶于水(例如含1NNa2CO3),聚合物的焦点就可被水解成羟基基团。
将伯胺基团引入至经疏水改性的支化聚(2-噁唑啉)均聚物中提高了药物溶解性并且产生了PAA诱导的集合体,同时伯胺基团也使得多种靶向基团连接至疏水改性的支化聚(2-噁唑啉)聚合物(图10),所述靶向基团为,例如,抗体、其抗原结合部分、抗原、或结合对中的一员。这类含有所述靶向基团及其改性物的集合体或纳米颗粒可在与PAA的集合体上提供靶向能力并且使PAA能够优先释放或者仅在所需的治疗位置释放。
如本说明书所教导的,可使用MBP——例如经疏水改性的均聚物,包括SBP和ABP——以生成表面改性的支化聚合物用于溶解水不溶性或水难溶性PAA,或者用于与水不溶性或水难溶性PAA形成PAA诱导的纳米颗粒,例如紫杉醇、喜树碱、多柔比星(doxorubin)、达拉根(dolargin)、洛哌丁胺、筒箭毒碱、布洛芬、地西泮、萘普生、卡马西平、灰黄霉素,硝苯地平、植物甾醇、奥美拉唑、多潘立酮、齐多夫定、两性霉素B等,以及在本说明书中描述的药物,和已知为或者被改性为水难溶性或水不溶性的。在这样的反应中,所述亲水性或两亲性核可为聚(2-噁唑啉)、聚(2-取代噁唑啉)(包括聚(2-甲基噁唑啉)、聚(2-乙基噁唑啉)、聚(2-丙基噁唑啉)、聚(2-丁基噁唑啉)等)、PEG、PEO、聚磷酸酯等。疏水壳可包括脂族烃(例如C1至约C22的烃)、芳族烃、聚乙烯聚合物、聚苯乙烯聚合物、全氟聚合物、聚二甲基硅氧烷、聚丙烯酸酯、聚甲基丙烯酸甲酯等。另一方面,不对称支化的PLL、PEI或PEOX均聚物还可被列于上文的疏水表面基团改性以提高水不溶性或水难溶性PAA的溶解性。
支化均聚物的支化密度(例如从低代(例如星形和梳形均聚物)到高代的树枝形分子和树枝形接枝分子),以及疏水表面基团的覆盖量(例如0%至100%覆盖)可显著影响均聚物的溶解性,而均聚物的溶解性反过来也影响溶解或吸收疏水PAA的能力。例如,支化密度和疏水基团覆盖量的增加会使均聚物与疏水PAA更相容。
在一些情况下,具有约1至约30重量%或更多的表面疏水组分的ABP和SBP对溶解或分散水难溶性或水不溶性PAA(例如紫杉醇)是有效的。此外,所使用的支化均聚物(例如,POX、PEOX、PMOX、PEO/PEG、聚丙烯酰胺、聚磷酸酯、聚乙烯吡咯烷酮和聚乙烯醇)溶于水和各种有机溶剂,从而有助于形成各种含PAA的纳米颗粒或集合体。良好的水溶性连同在水性溶液(含或不含其他有机溶剂)中的良好的疏水性药物混溶性使所述均聚物对提高水难溶性PAA的溶解性是有用的。例如,通过减少配制步骤、缩短加工时间以及减少使用目前用于制药工业中的复杂且昂贵的设备的需要从而简化了感兴趣的均聚物的制造过程并降低了生产成本。如果需要额外的支化密度,可首先使用本文所述的其他基团对SBP或ABP进行改性,然后,例如,与其他疏水官能团连接以提高PAA溶解性。
一旦将疏水改性的SBP或ABP与水不溶性或水难溶性PAA混合,就会形成尺寸与仅由聚合物形成的集合体不同的独特的物理集合体(图13-15)。当均聚物和PAA浓度降低时,所述聚合物PAA集合体的尺寸和分布变得与仅含聚合物的集合体更为相似,这表明PAA从诱导的集合体或纳米颗粒中释放。仅含聚合物的集合体的较宽的尺寸分布与由脂质组成的其他结构(无论是否与PAA结合)所观察到的尺寸分布相似。另一方面,感兴趣的PAA诱导的集合体具有特定的窄尺寸分布的尺寸,即,生成了具有某种尺寸的独特的集合体。由于在集合体中PAA的浓度降低、在集合体中的均聚物浓度降低、集合体浓度降低或其任意结合,因此,如通过集合体尺寸的降低和/或更宽的集合体尺寸分布所证明的,感兴趣的集合体释放了PAA。更宽的尺寸分布可以产生于多种尺寸的仅含均聚物的集合体和聚合物PAA集合体的混合物,而该混合物是由于PAA释放所致,直至观察到的仅有的集合体是那些具有仅含均聚物的集合体的特性的集合体。换言之,在PAA被引入宿主中例如循环系统中后,其逐渐释放。这一机理对于多种药物释放应用,并且其中可能需要延迟释放或缓慢释放特性的药物释放应用是重要的,所述药物释放应用包括静脉内(IV)、口服、经皮、经眼、肌内等给药方式。
所述PAA诱导的集合体还可与靶向部分或基团连接形成集合体从而使靶向基团与感兴趣的纳米复合物颗粒一起纳入(图10),所述靶向部分或基团包括但不限于抗体(或其抗原结合部分)、抗原、同源碳水化合物(例如唾液酸)、细胞表面受体配体、结合细胞表面受体的部分、结合细胞表面糖类的部分、细胞外基质配体、细胞质受体配体、生长因子、细胞因子、肠促胰岛素、激素、凝集素、凝集素靶标(例如,半乳糖、半乳糖衍生物、N-乙酰基半乳糖胺、甘露糖、甘露糖衍生物等)、维生素(例如叶酸、生物素等)、抗生物素蛋白、链霉亲和素、中和亲和素、DNA、RNA等。
此外,所述感兴趣的集合体还可运载诊断剂,例如显像剂、放射性核素或多种造影剂中的任一种。由此,可实现化疗、放疗和/或靶向治疗与实时诊断/监测能力的结合(图11和12)。在一些实施方案中,诊断剂是水难溶性或水不溶性的,因此,不需要例如感兴趣的PAA诱导集合体。
因此,诊断剂可为含金属的材料或顺磁材料(例如磁共振成像材料),其可沉积于感兴趣的纳米复合物的表面或被其捕获从而使纳米颗粒既可用作诊断剂又可用作治疗剂。在本公开内容的另一方面,所述含显像材料的纳米颗粒还可包括靶向部分/基团,所述靶向部分/基团使所述纳米颗粒靶向需要治疗处理的特定部位(例如肿瘤位点)。
因此,具有结合另外分子的能力的分子——例如生物聚合物(例如多肽、或多糖、酶、受体等),其可结合维生素、凝集素、金属等——可用在感兴趣的复合物中。可被感兴趣的聚合物运载的金属和金属离子可以包括但不限于过渡金属,例如Sc、Y、Ti、Zr、Hf、V、Nb、Ta、Cr、Mo、W、Mn、Tc、Re、Fe、Ru、Os、Co、Rh、Ir、Ni、Pd、Pt、Cu、Ag、Au、Zn、CdHg、Ga、In或Tl;碱金属;碱土金属;镧系元素,例如Ce、Pr、Nd、Pm、Sm、Eu、Gd、Tb、Dy、Ho、Er、Tm、Yb和Lu;锕系元素,例如Th、Pa、U、Np、Pu、Am、Cm、Bk、Cf、Es、Fm、Md、No和Lr等。
这些金属和金属离子可被,例如,一种或多种螯合基团运载,所述螯合基团包括但不限于乙二胺四乙酸(EDTA)、二乙三氨五乙酸(DTPA)、二乙三氨五乙酸(DTPA)、1,4,7,10-四氮杂环十二烷四乙酸(DOTA)、1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸(DO3A)、1-氧杂-4,7,10-三氮杂环十二烷-三乙酸(DOXA)、1,4,7-三氮杂壬烷三乙酸(NOTA)、1,4,8,11-四氮杂环十四烷四乙酸(TETA)、DOTAN(2-氨基乙基)酰胺和DOTA-N-(2-氨基苯乙基)酰胺。
为了这样的诊断目的,感兴趣的结合体包括报告分子(reportermolecule),其可通过外部装置(例如γ射线照相机)检测。因此,可配置结合物以使其包括例如,会发射可检测到的辐射的放射性同位素。将所述结合物设置成适于在体内消耗或放置的式样,采用本领域已知的适用于此的试剂。所述结合物组合物以本领域已知的方式给药,例如口服、直肠、静脉内给药等。
在本公开内容的另一方面,所述纳米颗粒可运载不同类型的PAA从而可实现组合治疗或鸡尾酒治疗。这样的PAA可以包括但不限于,各种小分子药物、无机药物和基于生物分子的药物,例如肽、蛋白质、抗体、酶、疫苗等。第二或更多PAA不需要难溶于水或不溶于水,因为第二或更多PAA可位于集合体的空隙中并且不需要位于表面。因此,在本文中指出的或本领域已知的任何PAA可包括第二或更多PAA。
药物制剂和纳米颗粒制剂
PAA和改性的均聚物可以合适的浓度(例如那些为体内应用所建立的浓度,通常为毫克或纳克级)单独地悬浮于合适的缓冲溶液和/或溶剂中,例如,缓冲液、丙酮、乙醇等。然后,将两种溶液在合适的温度(例如室温)下或在其他已知对维持PAA和均聚物的完整性可接受的温度下混合一段合适的时间,例如一小时、两小时等。其他培养时间可随着感兴趣的集合体一旦形成即稳定而在数分钟至数小时之间变化。可通过本领域已知的方法浓缩或收集集合体,例如,通过过滤、离心、蒸发、冻干、渗析等。可干燥集合体以延长保存期。
例如,以多种最高达40mg/mL的量将紫杉醇溶于乙醇中。根据本文中所教导的来制备烃(CH3(CH2)17)改性的无规支化PEOX并且以多种最高达100mg/mL的浓度将其溶于盐水中。
然后将两种溶液以多种体积混合以使最终混合物中均聚物与紫杉醇的摩尔比为3:1至10:1。随后将混合物在-80℃下冷冻3小时,然后根据体积将其冻干20至48小时以获得干燥粉末。
通过光散射测定的集合体或纳米颗粒的尺寸可为直径范围约120nm(例如,当在3mg紫杉醇/mL时)至约165nm(例如,当在5mg紫杉醇/mL时),这取决于药物浓度和均聚物浓度。
或者,PAA和均聚物可溶解于常规溶剂中,该常规溶剂通常不必是亲水的但需要与水混溶,然后再将其加入水溶液中。然后,可将紫杉醇和PEOX溶于丙酮中然后再在搅动下(例如同时搅拌或超声)将其滴入水中,随后用1000MW截留膜透析。然后可冻干终产品。
可将感兴趣的结合物纳入适于给药的药物组合物中,例如,用以诊断显像、生活方式管理或获得治疗性突破。这些组合物通常包括感兴趣的集合体和与药物给药相容的可药用载体、赋形剂或稀释剂(意欲包括任意及所有溶剂)、分散介质、包衣、抗细菌和抗真菌剂、等渗剂和吸收延迟剂等,即除PAA外的可药用组合物的成分,其被纳入药用组合物中用以特定目的,例如,用以膨胀、防腐、延迟释放、结合等,如本领域已知的。这些介质和试剂用于药物活性物质的用途是本领域已知的。除了任何常规介质或试剂与活性化合物不相容的范围,其在组合物中的用途是可预计的。补充的活性化合物也可纳入组合物中。
配制用于本文中公开的用途的本公开内容的药物组合物以与预期的给药途径相容。给药途径的实例包括肠胃外给药,例如,静脉内、皮内、皮下、口服(例如吸入)、经皮(局部)、经粘膜和直肠给药。用于肠胃外、皮内或皮下应用的溶液或悬浮剂可包括无菌稀释液,例如注射用水、盐水、油、聚乙二醇、甘油、丙二醇或其他合成溶剂;抗细菌剂,例如苄醇或尼泊金甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如EDTA;缓冲溶液,例如乙酸盐、柠檬酸盐或磷酸盐;渗透压调节剂,例如氯化钠或葡萄糖。可使用酸或碱(例如HCl或NaOH)调节pH。所述肠胃外制剂可封装于安瓿、一次性注射器或多剂量小瓶中,它们为由玻璃或塑料制成的制品。通常,体内诊断剂通过口服、直肠、静脉内、腹膜内等给药。
适合注射用途的药物组合物包括无菌水溶液或分散液以及用于无菌注射用溶液或分散液临时配制的无菌粉末。对于静脉内给药,合适的载体包括生理盐水、抑菌水或磷酸盐-缓冲盐水(PBS)。所述组合物通常是无菌的并且是流动的以达到易于注射的程度。所述组合物在制造和储存条件下必须是稳定的并且必须在抵抗微生物(例如细菌和真菌)污染作用下保存。载体可为含以下成分的溶剂或分散介质:例如,水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等)及其合适的混合物。合适的流动性可通过例如使用包衣(如卵磷脂)、在分散液的情况下通过维持所需的颗粒尺寸,以及通过使用表面活性剂来维持。防止微生物的作用可通过多种抗细菌剂和抗真菌剂实现,例如尼泊金、氯丁醇、苯酚、抗坏血酸、硫柳汞等。等渗剂——例如糖、多元醇(例如甘露醇、山梨糖醇)或氯化钠——可包括在所述组合物中。注射用组合物的延长吸收可通过在组合物中纳入延迟吸收剂来实现,所述延迟吸收剂为例如单硬脂酸铝或明胶。
无菌注射用溶液可通过将在所需量的合适溶剂中的活性化合物与所需的上述列举的一种成分或数种成分的结合物相结合,再通过过滤除菌来制备。通常,分散液通过将活性化合物纳入无菌赋形剂中来制备,所述无菌赋形剂含有基础分散介质和所需的其他成分,例如上文列举的及本领域已知的成分。对于用于配制无菌注射溶液的无菌粉末,可通过例如冻干、真空干燥或冷冻干燥来制备所述制剂,这生成活性成分的粉末加上来自其之前无菌过滤的溶液的任意其他所需成分。感兴趣的制剂可被储存并用合适用途的液体将其复原。
口服组合物通常包括惰性稀释剂、矫味剂、芳香剂或可食用载体。组合物可封装于明胶胶囊中或被压成片剂。为了口服治疗给药的目的,活性化合物可与赋形剂一起纳入并以片剂、锭剂或胶囊剂的形式使用。也可使用液体载体制备口服组合物以得到糖浆剂或液体制剂,或者用作漱口剂,其中流体载体中的化合物被口服施用,然后冲洗及吐出或吞下。
可包括药物相容性粘合剂和/或辅助材料作为组合物的一部分。片剂、丸剂、胶囊剂、锭剂等可含有粘合剂,例如微晶纤维素、黄蓍树胶或明胶;赋形剂,例如淀粉或乳糖;崩解剂,例如海藻酸、Primogel或玉米淀粉;润滑剂,例如硬脂酸镁或Sterote;助流剂,例如胶体二氧化硅;甜味剂,例如蔗糖或糖精;或者矫味剂,例如薄荷、水杨酸甲酯或橙味调味剂。
为了吸入给药,所述化合物以例如湿的或干的气溶胶喷雾的形式从含有合适推进剂的加压容器或分配器中释放出,所述推进剂为例如气体,如二氧化碳,或喷雾剂或雾。
全身给药也可通过经粘膜或经皮方式进行。为了经粘膜或经皮给药,在制剂中使用适合用于待渗透的屏障的渗透剂。此类渗透剂通常在本领域是已知的并且包括例如,用于经粘膜给药的清洁剂、胆汁盐和梭链孢酸衍生物。经粘膜给药可通过使用鼻喷雾剂或栓剂来完成。为了经皮给药,如本领域通常已知的,将所述活性化合物配制成软膏、油膏、凝胶或乳膏。合适的载体包括二甲基亚砜。
化合物也可以栓剂(例如具有常规栓剂基料,例如可可脂和其他甘油酯)或用于直肠递送的滞留灌肠剂的形式制备。
在一个实施方案中,所述活性化合物与会阻止该化合物从身体快速排出的载体一起制备,例如作为控释制剂,包括植入物、微胶囊化的给药系统。可使用可生物降解的生物相容性聚合物,例如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。
制备这些制剂的方法对于本领域的技术人员来说是显而易见的。所述材料也可从例如AlzaCorporation和NovaPharmaceuticals,Inc.商购获得。
本发明的集合体可以局部形式使用,例如乳膏、油膏、乳液、软膏、其他化妆品等。可运载PAA和其他生物活性或惰性化合物,包括润肤剂、漂白剂、止汗剂、药品、保湿剂、香味剂、着色剂、颜料、染料、抗氧化剂、油、脂肪酸、脂质、无机盐、有机分子、遮光剂、维生素、药品、角质软化剂、UV阻断剂、晒黑促进剂、脱色剂、除臭剂、香水、驱虫剂等。
可有利的是以便于给药和剂量均匀性的剂量单位形式配制口服或肠胃外组合物。本文使用的剂量单位形式是指适合作为单元剂量用于待治疗的受试者的物理离散单位;每个单位含有经计算以产生所需的治疗终点的预计量的活性化合物。
可利用本领域已知的方法,基于从临床前和临床研究获得的经验数据得到所述剂量,例如优选的给药途径和用量。所述剂量和给药形式可决定于并可取决于PAA的特性、聚合物、待实现的具体治疗效果、受体的特征和病症等。为了在数天或更长时间内重复给药,取决于病症,可维持所述治疗直到达到所期望的治疗终点。示例性的剂量方案公开于WO94/04188。
通过常规技术和试验以及患者情况(patientinput)可监测治疗的进展。
所述药物组合物可与给药说明书一起纳入容器、包装物或分配器中。
另一种给药方法包括将感兴趣的化合物加入食物或饮料中或者与食物或饮料混合作为食物补充物或添加剂、或者作为与维生素类似的基于预防的剂型。感兴趣的集合体可被包封成可以经过胃环境后仍存在的剂型。此类剂型通常称为肠溶包衣制剂。或者,如本领域已知的,可以将感兴趣的集合体进行改性,例如化学改性或与已知引起延迟释放、缓慢释放或控制释放的试剂结合,以增加半衰期。
本公开内容现将在下列非限定性的实施例中示例性的说明。
实施例
材料
对称支化的PPI树枝形分子购自Sigma-Aldrich。对称支化的PEI树枝形分子和树枝形接枝分子根据美国专利4,631,337、5,773,527、5,631,329和5,919,442提供的方法制备。所有抗体购自Sigma-Aldrich、Biodesign或Fitzgerald。不同代的PAMAM树枝形分子购自Dendritech,Inc。
具有氨基官能团的改性对称支化的PPI(m-SB-PPI-NH
2
-1.0)的合成
使用包括以下化合物的试剂:对称支化的PPI(SB-PPI-4、8、16、32、64,MW316、773、1,687、3,514和7,168)、丙烯酸甲酯(MA,FW=86.09)、乙二胺(EDA,FW=60.10)和甲醇。
向圆底烧瓶中加入1.0gPPI-61树枝形分子(MW7168)和20mL甲醇(溶液A)。向单独的圆底烧瓶中加入2.4g丙烯酸甲酯(MA)和10mL甲醇(溶液B)。然后在室温下在搅拌下将溶液A缓慢滴入溶液B中。使得到的溶液在40℃下反应2小时。一旦反应结束,就通过旋转蒸发除去溶剂和未反应的MA单体,随后将产物——2.5g经MA官能化的PPI重新溶解于20mL甲醇中。
向圆底烧瓶中加入160gEDA和50mL甲醇,随后在0℃下缓慢加入经MA官能化的PPI。然后使该溶液在4℃下反应48小时。通过旋转蒸发除去溶剂和过量的EDA。然后将粗产物从乙醚溶液中沉淀出并通过透析将其进一步纯化以得到约2.8g经伯胺官能化的对称支化的PPI(m-SB-PPI-NH2-1.0),其分子量为约21,760。产品通过1H和13C核磁共振(NMR)及体积排阻色谱(SEC)表征。
以相似的方法制备具有不同分子量的其他MA或经伯胺改性的对称支化的PPI树枝形分子和对称支化的PEI树枝形接枝分子。
具有混合的羟基和氨基官能团的改性对称支化的PPI
(mix-m-SB-PPI-64-NH
2
/OH-2)的合成
使用经氨基官能化的对称支化的PPI(m-SB-PPI-64-NH2-1.0)、MA、EDA、单乙醇胺(MEA,FW=61.08)和甲醇。
向圆底烧瓶中加入1.0g经氨基改性的PPI或由前述方法制备的m-SB-PPI-NH2-1.0和20mL甲醇(溶液A)。向单独的圆底烧瓶中加入2.4gMA和10mL甲醇(溶液B)。然后在室温下在搅拌下将溶液A缓慢滴入溶液B中。使得到的溶液在40℃下反应2小时。一旦反应结束,就通过旋转蒸发除去溶剂和未反应的MA单体,随后将产物——2.5g经MA官能化的m-SB-PPI-64-MA-1.5重新溶解于20mL甲醇中。
向圆底烧瓶中加入32gEDA、130gMEA和100mL甲醇(EDA:MEA的摩尔比为20:80),随后在0℃下缓慢加入m-SB-PPI-64-MA-1.5。然后使该溶液在4℃下反应48小时。通过旋转蒸发除去溶剂和过量的EDA。然后将粗产品从乙醚溶液中沉淀出并通过透析将其进一步纯化以得到约2.8g混合的羟基和氨基官能化的(混合表面的)SBP(mix-m-SB-PPI-64-NH2/OH-2.0,其具有平均20%NH2和80%OH表面基团且分子量为约21,862)。
以相似的方法制备具有不同分子量以及具有不同羟基和氨基基团比的其他改性无规AB-PEI和规则ABPLL分子。
无规不对称支化PEI购自Aldrich和Polysciences。规则ABP根据美国专利4,289,872提供的方法制备。所有抗体均购自Sigma-Aldrich、Biodesign或Fitzgerald。
具有氨基官能团的改性无规不对称支化PEI(m-ran-AB-PEI-NH
2
-1.0)
的合成
使用无规不对称支化PEI(ran-AB-PEI,MW2,000、25,000和75,000)、MA、EDA和甲醇。
向圆底烧瓶中加入1.0gPEI(MW2,000)和20mL甲醇(溶液A)。向单独的圆底烧瓶中加入3.0gMA和10mL甲醇(溶液B)。然后在室温下在搅拌下将溶液A缓慢滴入溶液B中。使得到的溶液在40℃下反应2小时。一旦反应结束,就通过旋转蒸发除去溶剂和未反应的MA,随后将产物——经MA官能化的PEI重新溶解于20mL甲醇中。
向圆底烧瓶中加入80gEDA和50mL甲醇,随后在0℃下缓慢加入经MA官能化的PEI(1gMA溶于20mL甲醇中)。然后使该溶液在4℃下反应48小时。通过旋转蒸发除去溶剂和过量的EDA。然后将粗产品从乙醚溶液中沉淀出并通过透析将其进一步纯化以得到约3.0g经伯胺官能化的无规不对称支化PEI(m-ran-AB-PEI-NH2-1.0),其分子量为约7,300。产品通过1H和13CNMR及SEC表征。
以相似的方法制备具有不同分子量的其他MA或经伯胺改性的无规不对称支化PEI和规则不对称支化PLL聚合物。
具有烃链的支化聚合物的改性
具有10%烃链的无规支化PEI是改性用作实例。将1克支化PEI(FW=25000)溶解于10mL甲醇中。向该溶液中加入0.23g1,2-环氧己烷(FW=100.16)并将混合物在40℃加热2小时。然后旋转蒸除溶剂并将残留物重新溶解于水中。透析后(3,500截留分子量)得到改性的PEI。以相似的方法制备其他MBP,例如PAMAM、PEI和PPI树枝形分子和树枝形接枝分子,以及具有不同烃链百分比和长度(例如C4、C12、C18和C22)的不对称PLL。
具有混合的羟基和氨基官能团的改性无规不对称支化PEI
(m-ran-AB-PEI-NH
2
/OH-2)的合成
使用氨基官能化的无规不对称支化PEI(m-ran-AB-PEI-NH2-1.0)、MA、EDA、单乙醇胺(MEA,FW=61.08)和甲醇。
向圆底烧瓶中加入1.0g氨基改性PEI或由前述方法制备的m-ran-AB-PEI-NH2-1.0和20mL甲醇(溶液A)。向单独的圆底烧瓶中加入3.0gMA和10mL甲醇(溶液B)。然后在室温下在搅拌下将溶液A缓慢滴入溶液B中。使得到的溶液在40℃下反应2小时。一旦反应结束,就通过旋转蒸发除去溶剂和未反应的MA,随后将产物——经MA官能化的m-ran-AB-PEI-MA-1.5重新溶解于20mL甲醇中。
向圆底烧瓶中加入60gEDA、244gMEA和100mL甲醇(EDA:MEA的摩尔比为20:80),随后在0℃下缓慢加入m-ran-AB-PEI-MA-1.5(1gMA溶于20mL甲醇中)。然后使该溶液在4℃下反应48小时。通过旋转蒸发除去溶剂和过量的EDA。然后将粗产品从乙醚溶液中沉淀出并通过透析将其进一步纯化以得到约2.4g混合的羟基和氨基官能化的无规ABP(m-ran-AB-PEI-NH2/OH-2,其具有平均20%NH2和80%OH表面基团且分子量为约18,000)。
以相似的方法制备具有不同分子量以及不同的羟基与氨基比的其他改性无规AB-PEI和规则AB聚赖氨酸聚合物。
具有伯胺链末端基团的经烷基改性的无规不对称支化聚(2-乙基噁唑啉
(PEOX)的合成
提供CH3-(CH2)11-PEOX-ABP100(ABP100是表示在初始反应中单体与引发剂比例的任意名称)的合成作为制备核壳结构的一般步骤。在N2下用蒸馏头将在500mL甲苯中的CH3(CH2)11-Br(2.52g)混合物共沸蒸馏约15分钟以除去水。通过加料漏斗滴加2-乙基噁唑啉(100g)并使混合物回流24至48小时。一旦聚合反应结束,就向反应聚合物溶液(A)中加入12.12gEDA以引入胺官能团。聚噁唑啉链端与EDA的摩尔比为1:20。
可加入N-叔丁氧羰基哌嗪(N-Boc-哌嗪)或水(例如用1NNa2CO3)来终止反应。还可向反应聚合物溶液(A)中加入吗啉或PEI来终止反应。将粗产品重新溶于甲醇中,然后从大过量的乙醚中沉淀出。将底层重新溶于甲醇中并通过旋转蒸发和真空将其干燥,得到呈白色固体的不对称无规支化PEOX聚合物或PEOX-PEI共聚物(101g)。以类似方法制备其他不对称无规支化聚合物,例如C6-PEOXABP20、50、100、200、300、500;C18-PEOXABP20、50、200、300、500;C22-PEOXABP20、50、100、200、300、500和聚苯乙烯-PEOX等,以及未改性和改性的聚(2-取代噁唑啉),例如聚(2-甲基噁唑啉)。所有产品通过SEC和NMR进行分析。
混合的表面改性的对称支化聚合物-IgG结合物的制备
提供混合的表面(OH/NH2混合)改性的对称支化PPI-IgG结合物(mix-m-SB-PPI-64-NH2/OH-2-IgG结合物)的制备作为制备聚合物抗体和聚合物链霉亲和素结合物的一般步骤。其他结合物,例如m-SB-PPI-4-NH2-1-IgG、m-SB-PPI-8-NH2-1-IgG、m-SB-PPI-16-NH2-1-IgG、m-SB-PPI-32-NH2-1-IgG、m-SB-PPI-4-NH2-2-IgG、m-SB-PPI-8-NH2-2-IgG、m-SB-PPI-16-NH2-2-IgG、m-SB-PPI-32-NH2-2-IgG、m-SB-PPI-4-NH2-3-IgG、m-SB-PPI-8-NH2-3-IgG、m-SB-PPI-16-NH2-3-IgG、m-SB-PPI-32-NH2-3-IgG、mix-m-SB-PPI-4-NH2/OH-1(OH/NH2mix)-IgG、mix-m-SB-PPI-8-NH2/OH-1(OH/NH2mix)-IgG、mix-m-SB-PPI-16-NH2/OH-1(OH/NH2mix)-IgG、mix-m-SB-PPI-32-NH2/OH-1(OH/NH2mix)-IgG、mix-m-SB-PPI-4-NH2/OH-2(OH/NH2mix)-IgG、mix-m-SB-PPI-8-NH2/OH-2(OH/NH2mix)-IgG、mix-m-SB-PPI-16-NH2/OH-2(OH/NH2mix)-IgG、mix-m-SB-PPI-32-NH2/OH-2(OH/NH2mix)-IgG、mix-m-SB-PPI-4-NH2/OH-3(OH/NH2mix)-IgG、mix-m-SB-PPI-8-NH2/OH-3(OH/NH2mix)-IgG、mix-m-SB-PPI-16-NH2/OH-3(OH/NH2mix)-IgG、mix-m-SB-PPI-32-NH2/OH-3(OH/NH2mix)-IgG以及伯胺和混合OH/NH2改性的梳爆PEI树枝形接枝分子(0-5代)也以相似的方法获得。还以类似的方法获得与感兴趣的改性SBP连接的其他蛋白的合成。按照BioconjugateTechniques(G.Hermanson,AcademicPress,1996)提供的方法合成生物素化-IgG结合物。
LC-SPDP-混合的表面m-SB-PPI-64-NH
2
/OH-2
向在400μL磷酸盐缓冲溶液(20mM磷酸盐和0.1MNaCl,pH7.5)中的混合表面无规支化mix-m-SB-PPI-64-NH2/OH-2(4x10-7mol)中加入在400μL水中的4.0x10-6mol磺基-LC-SPDP(PIERCE,1L)。将混合物涡漩并在30℃培养30分钟。通过凝胶过滤色谱纯化LC-SPDP-mix-m-SB-PPI-64-NH2/OH-2并用缓冲溶液A(0.1M磷酸盐、0.1MNaCl和5mMEDTA,pH6.8)将其平衡。进一步浓缩得到465μL溶液,浓度为约0.77nmol。
由LC-SPDPmix-m-SB-PPI-64-NH
2
/OH-2制备硫醇化的混合的
m-SB-PPI-64-NH
2
/OH-2
将LC-SPDPmix-m-SB-PPI-64-NH2/OH-2(50nmol在65μL缓冲溶液A中)与100μL二硫苏糖醇(DTT)(在缓冲溶液A中,50mM)混合,并在室温培养15分钟。用缓冲溶液A通过凝胶过滤除去过量DTT和副产物。将产物在10KCentriconConcentrator中浓缩,得到390μL硫醇化的mix-m-SB-PPI-64-NH2/OH-2,其用于与活化抗体结合。
马来酰亚胺R(MAL-R)活化的抗体
向在PBS中的抗体(310μL,5.1mg或34nmol)加入20.4μLMAL-R-NHS(N-羟基琥珀酰亚胺)溶液(10mM,在水中)。将混合物涡漩并在30℃培养15分钟。用缓冲溶液A通过凝胶过滤将产物纯化。该马来酰亚胺-R活化的抗体被用于与硫醇化的mix-m-SB-PPI-64-NH2/OH-2结合。
mix-m-SB-PPI-64-NH
2
/OH-2-抗体结合物
向硫醇化的mix-m-SB-PPI-64-NH2/OH-2(310μL或35.7nmol)中加入MAL-R-活化的抗体(4.8mL或34nmol)。将反应混合物浓缩至约800μL,然后在4℃下培养过夜,和/或在室温下培养约1小时。一旦完成,就用100μL乙基马来酰亚胺(50毫摩尔浓度的溶液)淬灭反应,然后在羧甲基纤维素柱(5mL)上使用在pH为6的20mM磷酸盐缓冲溶液中的氯化钠不连续梯度将所述结合物进行分级。结合物用氯化钠梯度洗脱,并通过阳离子交换色谱、UV光谱和聚丙烯酰胺凝胶电泳表征。
通过还原偶联来结合
抗体的还原
向在160μL缓冲溶液B(含有0.1M磷酸钠、5mMEDTA和0.1MNaCl,pH6.0)中的2.1mg或14nmol抗体中加入40μLDTT(50mM,在缓冲溶液B中)。将溶液在室温静置30分钟。在用经缓冲溶液B平衡的SephadexG-25柱中通过凝胶过滤将产物纯化。将还原的抗体浓缩至220μL并用于结合。
MAL-R-混合表面改性SBP
向在pH为7.4的400μL(400x10-9mol)混合表面改性SBP中加入400μLMAL-R-NHS(10mM,在水中)。将其混合并在30℃培养15分钟。一旦终止,就将产物在经缓冲溶液B平衡的SephadexG-25柱中纯化。收集MAL-R-混合表面改性SBP并将其在-40℃下、在相同的缓冲溶液中等分储存。
混合表面改性SBP-抗体结合物
在搅拌下向还原的抗体(14nmol,220μL)中加入MAL-R-mix-m-SB-PPI-64-NH2/OH-2(154μL,16.6nmol)。通过加入12.5μL碳酸钠(1.0M溶液)将pH调节至约6.8,在室温下继续反应1小时,通过加入100μL半胱胺溶液(0.4mM溶液)来终止反应。将结合混合物在CM纤维素柱上纯化,用氯化钠梯度洗脱。
IgG-不对称无规支化聚合物结合物的制备
提供无规支化混合表面(OH/NH2混合)m-ran-AB-PEI-NH2/OH-2-IgG结合物的制备作为制备聚合物-抗体和聚合物-链霉亲和素结合物的一般步骤。其他结合物,例如,PEI-IgG、m-ran-AB-PEI-NH2-1-IgG、m-ran-AB-PEI-NH2-2-IgG、m-ran-AB-PEI-NH2-3-IgG、m-ran-AB-PEI-NH2-4-IgG,以及m-ran-AB-PEI-NH2/OH-1(OH/NH2mix)-IgG、m-ran-AB-PEI-NH2/OH-2(OH/NH2mix)-IgG、m-ran-AB-PEI-NH2/OH-3(OH/NH2mix)-IgG、规则聚赖氨酸聚合物、具有伯胺链端的烷基改性无规支化聚(2-乙基噁唑啉)均以相似的方法合成。具有不对称无规支化PEOX聚合物的各种蛋白质结合物的合成也以相似的方法进行。按照BioconjugateTechniques(G.Hermanson,AcademicPress,1996)提供的方法合成生物素化-IgG结合物。
LC-SPDP-混合表面m-ran-AB-PEI-NH
2
/OH-2
向在400μL磷酸盐缓冲溶液(20mM磷酸盐和0.1MNaCl,pH7.5)中的混合表面无规支化m-ran-AB-PEI-NH2/OH-2(4x10-7mol)中加入在400μL水中的4.0x10-6mol磺基-LC-SPDP(PIERCE,1L)。将其涡漩混合并在30℃培养30分钟。通过凝胶过滤色谱纯化LC-SPDP-m-ran-AB-PEI-NH2/OH-2并将其用缓冲溶液A(0.1M磷酸盐、0.1MNaCl和5mMEDTA,pH6.8)平衡。将产物进一步浓缩以得到465μL溶液,其浓度为约0.77nmol/μmol。
由LC-SPDPm-ran-AB-PEI-NH 2 /OH-2制备硫醇化的m-ran-AB-PEI-NH2/OH-2
将LC-SPDPm-ran-AB-PEI-NH2/OH-2(50nmol,在65mL缓冲溶液A中)与100μL二硫苏糖醇(DTT)(在缓冲溶液A中,50mM)混合,并将其在室温培养15分钟。用缓冲溶液A通过凝胶过滤除去过量的DTT和副产物。将产物在10KCentriconConcentrator中浓缩,得到390μL硫醇化的m-ran-AB-PEI-NH2/OH-2,其用于与活化的抗体结合。
将如上所述制备的马来酰亚胺-R活化的抗体用于与硫醇化的m-ran-AB-PEI-NH2/OH-2结合。
m-ran-AB-PEI-NH
2
/OH-2-抗体结合物
向硫醇化的m-ran-AB-PEI-NH2/OH-2(310μL或35.7nmol)中加入MAL-R-活化的抗体(4.8mL或34nmol)。将反应混合物浓缩至约800μL,然后将其在4℃下培养过夜,和/或在室温下培养约1小时。一旦结束,就用100μL乙基马来酰亚胺(50毫摩尔浓度的溶液)淬灭反应,然后在羧甲基纤维素柱(5mL)上使用在pH为6的20mM磷酸盐缓冲溶液中的氯化钠阶段梯度将结合物进行分级。结合物用氯化钠梯度洗脱,并通过阳离子交换色谱、UV光谱和聚丙烯酰胺凝胶电泳表征。
紫杉醇制剂和纳米颗粒制剂
将紫杉醇在乙醇中溶解至最高达40mg/mL的浓度。
如本文中所教导来制备经C18烃改性的无规支化PEOX。
将聚合物单独在盐水中溶解至最高达100mg/mL的浓度。然后将两种溶液以多种体积混合以使得聚合物与紫杉醇在混合物中的最终摩尔比为3:1至10:1。随后将混合物在-80℃下冷冻3小时,然后根据体积,将其冻干20至48小时。
通过光散射法测定的集合体的尺寸为直径约120nm至约165nm。
或者,可将紫杉醇和PEOX聚合物均溶于常规溶剂(例如丙酮)中,然后在搅拌或超声下将其滴入水中,随后用1000MW截留膜渗透。然后通过冻干得到终产物。通过光散射法来测定集合体的尺寸。
可以相似的方法制备其他PAA诱导的集合体或纳米颗粒,这使用多种疏水表面改性的支化聚合物,例如,C4、C6、C12或C22烃改性的无规支化PEOX、PEI和PPI聚合物;C4、C6、C12,C18和C22烃改性的PAMAM、PEI和PPI树枝形分子和树枝形接枝分子;以及C4、C6、C12、C18和C22烃改性的支化PLL/聚合物。
因此,将C18-PEOx-100-NH2(500mg)溶于5mL乙醇中以获得100mg/mL溶液。还通过将100mg紫杉醇溶于5mL乙醇中来制备20mg/mL的紫杉醇溶液。将两种溶液混合20分钟以得到每mL含有10mg紫杉醇和50mg聚合物的溶液,这提供了药物:聚合物比为1:5的溶液。将混合物置于旋转蒸发仪上,除去乙醇至干燥。将生成的固体在搅拌下重新溶解于33mL盐水溶液中使最终的紫杉醇浓度为3mg/mL。将溶液制剂通过0.8μm过滤器,然后通过0.22μm过滤器。将滤液置于小瓶中于-70℃下冷冻至少2小时,然后冻干72小时。将小瓶塞住并且在室温下储存该即用型白色粉末。
纳米颗粒测量
使用MalvernZetasizerNano-ZSZen3600颗粒尺寸分析仪通过动态光散射法测量各种聚合物、仅含聚合物的集合体以及药物诱导的聚合物集合体的尺寸。
活性测试
活细胞中的代谢产生“还原等价物”,例如,NADH或NADPH。这些还原性化合物传递电子至中间体电子转移剂,所述中间体电子转移剂可将四唑鎓产物——MTS(Promega)还原成水可溶性甲臜(formazan)产物,该产物是有颜色的。在细胞死亡时,细胞迅速失去还原四唑鎓产物的能力。因此,有色甲臜产物的生成与培养的活细胞数目成比例。
CellTiterAqueous产品(Promega)为用于确定培养的活细胞数目的MTS试样。MTS四唑鎓与MTT四唑鎓相似,其优势在于MTS还原的甲臜产物可溶于培养介质中并且不需要使用增溶液。使用以推荐比例为20μL试剂比100μL培养介质向试样孔中直接加入的单一试剂。细胞在37℃下培养1-4小时,然后在490nm下测量吸光度。
因此,将各种含紫杉醇的感兴趣的集合体连同商购的Taxol和Abraxane、包裹有人血清白蛋白的紫杉醇纳米颗粒用于测试不同的癌细胞系(来自ATCC),所述癌细胞系包括肺癌A549、乳癌MDA-MB-231和OV90卵巢癌细胞系,以及用于测试正常人纤维原细胞系。
所述药物诱导的纳米颗粒在杀死癌细胞方面至少是相同的或者更有效,尤其是在0.5μg/mL至0.5ng/mL范围的低药物浓度时。未观察到对正常人纤维原细胞系的毒性。
将所述药物诱导的纳米颗粒的最大耐受剂量(MTD)与Taxol的最大耐受剂量进行对比。7周的过程中,将各种剂量的Taxol与含紫杉醇的感兴趣的纳米颗粒注射进CD-1小鼠的尾静脉。紫杉醇纳米颗粒的MTD比Taxol的MTD高7倍,并且对存活的小鼠没有主要的副作用。并且,与接受感兴趣的紫杉醇纳米颗粒的小鼠体重未下降相比,在接受Taxol的小鼠中观察到体重显著下降。
在异种移植小鼠模型中使用肺癌A548细胞系和乳腺癌MDA-MB-231细胞系的对照研究显示紫杉醇纳米颗粒在体内抑制肿瘤生长明显优于Taxol和Abraxane的抑制作用。与接受Taxol和Abraxane的小鼠相比,在接受感兴趣的紫杉醇纳米颗粒的小鼠中观察到肿瘤显著的减小。
喜树碱制剂和纳米颗粒制剂
将喜树碱(2.1mg)与聚合物(10.5mg)溶于氯仿:乙醇的体积比为4:1的混合物中。在彻底混合后,在旋转蒸发仪上除去溶剂至干燥。将所得的固体混合物重新溶解于2mL盐水溶液中、混合、然后通过0.8μm的注射器式过滤器。将滤液置于冻干小瓶中在-70℃下冷冻至少2小时,然后冻干过夜(~16小时)。塞住小瓶并且在-70℃下储存该即用型白色粉末。在临使用前用2mL水将所述材料复原。
伊立替康,还称为CPT-11,是喜树碱的合成类似物。CPT-11含有,例如,在A环和B环上的联哌啶羧基和乙基基团,以产生具有比母体分子的细胞毒性更强的化合物。
制备了各种浓度的上述CPT-11和喜树碱支化聚合物集合体。
将两种癌细胞系在认可的培养条件下维持在合适的介质中。MCF-7是人乳腺癌细胞系,而H460是人上皮肺癌细胞系。将所述细胞系暴露于各种浓度的CPT-11和各种浓度的喜树碱集合体中,所述浓度基于药物的用量计。如上所述评估细胞的存活能力。
图17总结了用MCF-7乳腺癌细胞系获得的结果。可知细胞对CPT-11的细胞毒性随着药物浓度的增加而增加。另一方面,喜树碱集合体在所有受试的剂量下的细胞毒性均更高。未与药物结合的聚合物没有细胞毒性。因此,虽然喜树碱自身不具有与CPT-11相同水平的细胞毒性,但是当它与支化聚合物结合时,该集合体具有比CPT-11更高的细胞毒性。
用H460肺癌细胞系获得了相似的结果。如图18所示,观察到CPT-11的细胞毒性的剂量响应曲线。然而,在各自的受试浓度下,喜树碱/支化聚合物集合体具有比CPT-11更高的细胞毒性。
本文中引用的所有参考文献的全文在此以引用的方式纳入本说明书。
可以理解的是,根据本说明书的教导,在不背离本公开内容的主旨和范围的前提下可以进行各种改变和修饰。
Claims (20)
1.一种集合体,包括
a)支化均聚物,其中所述均聚物被表面基团改性并且其中所述表面改性的支化均聚物包括对称支化聚合物、不对称支化聚合物或其结合,和
b)水不溶性或水难溶性的药物活性剂(PAA),
其中所述集合体的尺寸不同于仅由所述表面改性的支化均聚物形成的集合体的尺寸;
其中所述PAA被物理捕获在所述支化聚合物的表面基团中。
2.权利要求1的集合体,其中所述表面基团为疏水的。
3.权利要求1的集合体,其中所述均聚物包括聚乙二醇、聚环氧乙烷、聚丙烯酰胺、聚磷酸酯、聚乙基吡咯烷酮、聚乙烯基醇、聚乙烯亚胺、聚丙烯亚胺、聚酰胺胺或其结合。
4.权利要求1的集合体,其中所述表面基团含有1至22个碳的脂族和/或饱和烃或不饱和烃、芳族烃、聚乙烯聚合物、聚苯乙烯聚合物、全氟聚合物、聚二甲基硅氧烷、聚丙烯酸酯、聚甲基丙烯酸甲酯或其结合。
5.权利要求1的集合体,其中所述水不溶性或水难溶性PAA包括抗感染药或抗肿瘤药。
6.权利要求1的集合体,其中所述水不溶性或水难溶性PAA包括紫杉醇、多西他赛、泰素帝、长春碱、长春新碱、长春地辛、长春瑞滨、伊立替康、拓扑替康、喜树碱、伊立替康、拓扑替康、多柔比星、顺铂、卡铂、奥沙利铂、沙铂、达拉根、洛哌丁胺、筒箭毒碱、布洛芬、地西泮、萘普生、卡马西平、灰黄霉素、硝苯地平、植物甾醇、奥美拉唑、多潘立酮、齐多夫定、两性霉素B、氮芥、苯丁酸氮芥、白消安、塞替派、环磷酰胺、雌莫司汀、异环磷酰胺、二氯甲基二乙胺、美法仑、尿嘧啶氮芥、lonuistine、链脲佐菌素、达卡巴嗪、丙卡巴肼、替莫唑胺、(SP-4-3)-(顺)-胺二氯-[2-甲基吡啶]-铂(II)、甲氨蝶呤、培美曲塞、雷替曲塞、三甲曲沙、克拉利宾、克拉屈滨、克罗拉滨、氟达拉滨、6-巯基嘌呤、喷司他汀、硫代鸟嘌呤、阿扎胞苷、卡培他滨、阿糖胞苷、依达赛特、氟尿苷、5-氟尿嘧啶、吉西他滨、曲沙他滨、博来霉素、放线菌素D、阿霉素、放线菌素、光神霉素、丝裂霉素、米托蒽醌、泊非霉素、柔红霉素、表阿霉素、依达比星、戊柔比星、苯芥胆甾醇、他莫昔芬、piposulfancamptothesin、安吖啶、依托泊甙、替尼泊甙、氟羟甲睾酮、睾内酯、比卡鲁胺、环丙氯地孕酮、氟他胺、尼鲁米特、氨鲁米特、瑞宁得、依西美坦、福美斯坦、来曲唑、地塞米松、强的松、己烯雌酚、氟维司群、雷洛昔芬、托瑞米芬、布舍瑞林、戈舍瑞林、亮丙瑞林、曲普瑞林、醋酸甲羟孕酮、醋酸甲地孕酮、左甲状腺素、碘塞罗宁、六甲蜜胺、左旋咪唑、米托坦、奥曲肽、丙卡巴肼、苏拉明、沙利度胺、甲氧沙林、卟吩姆钠、硼替佐米、盐酸厄洛替尼、吉非替尼、甲磺酸伊马替尼、semaxanib、阿达帕林、蓓萨罗丁、反式维甲酸、9-顺式视黄酸和N-(4-羟基苯基)维甲酰酚胺或其结合。
7.权利要求1的集合体,还包括共价连接至所述均聚物的靶向部分,其中所述部分包括抗体、其抗原结合部分、抗原、细胞受体、细胞受体配体或凝集素配体。
8.权利要求1的集合体,还包括造影剂。
9.权利要求1的集合体,其中所述包含取代的噁唑啉的支化聚合物包括聚(2-甲基噁唑啉)、聚(2-乙基噁唑啉)、聚(2-丙基噁唑啉)或聚(2-丁基噁唑啉)。
10.权利要求8的集合体,其中所述造影剂包括磁共振显像造影剂。
11.权利要求8的集合体,其中所述造影剂包括放射性核素。
12.一种集合体,包括
a)支化均聚物,其中所述支化均聚物包括噁唑啉单体(POX),并且所述支化均聚物被表面基团改性,和
b)水不溶性或水难溶性的药物活性剂(PAA),
其中所述集合体的尺寸不同于仅由所述改性POX单独形成的集合体的尺寸;
其中所述PAA被物理捕获在所述支化聚合物的表面基团中。
13.权利要求12的集合体,其中所述噁唑啉是被取代的噁唑啉。
14.权利要求12的集合体,其中所述所述噁唑啉包括2-取代的噁唑啉。
15.权利要求12的集合体,其中所述表面基团含有1至22个碳的脂族和/或饱和烃或不饱和烃、芳族烃、聚乙烯聚合物、聚苯乙烯聚合物、全氟聚合物、聚二甲基硅氧烷、聚丙烯酸酯、聚甲基丙烯酸甲酯或其结合。
16.权利要求12的集合体,其中所述水不溶性或水难溶性PAA包括抗感染药或抗肿瘤药。
17.权利要求12的集合体,其中所述水不溶性或水难溶性PAA包括紫杉醇、多西他赛、泰素帝、长春碱、长春新碱、长春地辛、长春瑞滨、伊立替康、拓扑替康、喜树碱、伊立替康、拓扑替康、多柔比星、顺铂、卡铂、奥沙利铂、沙铂、达拉根、洛哌丁胺、筒箭毒碱、布洛芬、地西泮、萘普生、卡马西平、灰黄霉素、硝苯地平、植物甾醇、奥美拉唑、多潘立酮、齐多夫定、两性霉素B、氮芥、苯丁酸氮芥、白消安、塞替派、环磷酰胺、雌莫司汀、异环磷酰胺、二氯甲基二乙胺、美法仑、尿嘧啶氮芥、lonuistine、链脲佐菌素、达卡巴嗪、丙卡巴肼、替莫唑胺、(SP-4-3)-(顺)-胺二氯-[2-甲基吡啶]-铂(II)、甲氨蝶呤、培美曲塞、雷替曲塞、三甲曲沙、克拉利宾、克拉屈滨、克罗拉滨、氟达拉滨、6-巯基嘌呤、喷司他汀、硫代鸟嘌呤、阿扎胞苷、卡培他滨、阿糖胞苷、依达赛特、氟尿苷、5-氟尿嘧啶、吉西他滨、曲沙他滨、博来霉素、放线菌素D、阿霉素、放线菌素、光神霉素、丝裂霉素、米托蒽醌、泊非霉素、柔红霉素、表阿霉素、依达比星、戊柔比星、苯芥胆甾醇、他莫昔芬、piposulfancamptothesin、安吖啶、依托泊甙、替尼泊甙、氟羟甲睾酮、睾内酯、比卡鲁胺、环丙氯地孕酮、氟他胺、尼鲁米特、氨鲁米特、瑞宁得、依西美坦、福美斯坦、来曲唑、地塞米松、强的松、己烯雌酚、氟维司群、雷洛昔芬、托瑞米芬、布舍瑞林、戈舍瑞林、亮丙瑞林、曲普瑞林、醋酸甲羟孕酮、醋酸甲地孕酮、左甲状腺素、碘塞罗宁、六甲蜜胺、左旋咪唑、米托坦、奥曲肽、丙卡巴肼、苏拉明、沙利度胺、甲氧沙林、卟吩姆钠、硼替佐米、盐酸厄洛替尼、吉非替尼、甲磺酸伊马替尼、semaxanib、阿达帕林、蓓萨罗丁、反式维甲酸、9-顺式视黄酸和N-(4-羟基苯基)维甲酰酚胺或其结合。
18.权利要求12的集合体,还包括共价连接至所述均聚物的靶向部分,其中所述部分包括抗体、其抗原结合部分、抗原、细胞受体、细胞受体配体或凝集素配体。
19.权利要求12的集合体,还包括造影剂。
20.权利要求12的集合体,其中所述的支化聚合物被无规支化。
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