CN113226376A - 作为新型药物递送平台的基于大分子前药的热敏性可注射凝胶 - Google Patents
作为新型药物递送平台的基于大分子前药的热敏性可注射凝胶 Download PDFInfo
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- CN113226376A CN113226376A CN201980085886.5A CN201980085886A CN113226376A CN 113226376 A CN113226376 A CN 113226376A CN 201980085886 A CN201980085886 A CN 201980085886A CN 113226376 A CN113226376 A CN 113226376A
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Abstract
本申请公开了基于前药的热敏性凝胶(“ProGel”),其由药物分子与水溶性聚合物载体的缀合物构成,所述热敏性凝胶能够将所述药物分子受控释放到受试者的组织中。还公开了所述ProGel‑药物缀合物用于治疗各种疾病或障碍的用途以及其制备方法。
Description
相关申请的交叉引用
本申请根据35U.S.C.§119(e)要求2018年10月26日提交的美国临时专利申请号62/751,119的优先权,将其公开内容通过引用以其整体并入本文。
技术领域
本发明涉及热响应性聚合物-药物缀合物,其作为可溶于水的前药并且可以在升高的温度下形成水凝胶,使得药物物质可以以受控的方式被局部释放。
关于联邦资助的研究或开发的声明
本发明是根据由美国国立卫生研究院授予的授权号R01 AI119090下在政府支持下完成的。美国政府对本发明拥有一定的权利。
背景技术
关节炎是一种关节病理病症,其包括多于100种不同形式的关节炎和相关疾病。炎性关节炎和骨关节炎是两种最常见形式的关节炎。类风湿性关节炎(RA)是原型形式的炎性关节炎,其影响世界人口的1%-2%。尽管RA疗法取得了重大进展,但患者仍继续经历显著的疼痛、功能受限和残疾。骨关节炎(OA)是最常见形式的关节炎,其在美国影响超过2500万个体,并且大约27%的患有OA的成人具有严重的关节疼痛(Barbour,K.E.等人,Morbidityand Mortality Weekly Report,2017.66(9):第246页)。在关节炎患者中,与关节炎相关的疼痛和活动受限是导致工作障碍、睡眠紊乱、抑郁和焦虑的关键因素(Sharma,A.等人,OpenAccess Rheumatology:research and reviews,2016.8:第103页)。疼痛可能是慢性的或也可能是由机械负荷或运动引起的(Glyn-Jones,S.等人,The Lancet,2015.386(9991):第376-387页;Malfait,A.-M.和Schnitzer,T.J.,Nature Reviews Rheumatology,2013.9(11):第654页)。在膝部,疼痛可能源自多种来源,包括滑膜和脂肪垫炎症、半月板挤压和变性以及韧带和囊病变,其中存在大量伤害感受器将信号传递到脊髓的背根神经节(McDougall,J.J.等人The Anatomical Record:An Official Publication of theAmerican Association of Anatomists,1997.248(1):第29-39页)。新的证据表明软骨下神经支配也可能促成关节炎疼痛(Goldring,S.R.和Goldring,M.B.,Nature ReviewsRheumatology,2016.12(11):第632页;Zhu,S.等人,The Journal of clinicalinvestigation,2019.129(3))。炎性细胞因子和趋化因子(Richter,F.等人,Arthritis&Rheumatism,2010.62(12):第3806-3814页;Brenn,D.,F.Richter和H.G.Schaible,Arthritis&Rheumatism,2007.56(1):第351-359页;Richter,F.等人,Arthritis&Rheumatism,2012.64(12):第4125-4134页)、神经肽(Woolf,C.J.等人,Neuroscience,1994.62(2):第327-331页)和前列腺素是介导关节炎疼痛的生化环境的组分(Miller,R.J.等人,2009,417-449)。关节炎是美国成人中残疾的主要原因(Barbour,K.E.等人,Morbidity and Mortality Weekly Report,2017.66(9):第246页)。据估计,每年因关节炎损失1.809亿个工作日。在2014年,诊断为关节炎和关节疼痛的人的总医疗费用估计为6268亿美元。目前,没有已获批准的显示治愈多样形式的关节炎中的任一种的疗法,但对靶向受影响的关节的新疗法或药物输送系统仍然存在主要未满足的需求,所述疗法或药物输送系统可以减轻导致功能丧失和残疾的疼痛和炎症。
关于OA,目前推荐的对关节疼痛和炎症的治疗包括口服非甾体抗炎药(NSAID)、关节内(IA)注射糖皮质激素(GC)、辣椒素或度洛西汀。NSAID发挥其抗炎和镇痛作用的机制可归因于对前列腺素生成酶环氧合酶(COX)的抑制。尽管仍然没有对GC如何减轻关节炎关节疼痛的全面解释,但有强有力的证据表明GC的IA施用提供了缓解疼痛和炎症的有效短期策略。目前可用的GC的作用的持续时间相对短、需要重复注射、以及GC相关的不良副作用代表对其临床效用和功效的主要限制(Fraioli,A.等人,BioMed Research International,2018)。
大分子前药,尤其是基于N-(2-羟丙基)-甲基丙烯酰胺(HPMA)共聚物的那些已被广泛用于递送用于治疗癌症的化疗剂(Duncan,R.,Nature Reviews Drug Discovery,2003,2(5),347)。开发的许多前药已经过评估,其中若干中被批准用于临床用途(Ekladious,I.等人,Nature Reviews Drug Discovery,2019,18(4),273-294)。这些前药中的大多数是合成的水溶性大分子,将其全身施用以受益于被动肿瘤靶向性的高通透性和滞留(EPR)效应(Fang,J.等人,Advanced Drug Delivery Reviews,2011,63(3),136-151;Maeda,H.,Advances in Enzyme Regulation,2001,41(1),189-207)。在炎性疾病的情况下,我们已经显示,我们先前开发的大分子前药通过我们称为“通过渗漏脉管系统的外渗和炎症细胞介导的隔离(Extravasation through Leaky Vasculature and Inflammatorycell-mediated Sequestration)”(ELVIS)机制的机制被动地靶向关节炎症位点,导致持续的抗炎和疾病改变作用,并且毒性大大降低(Liu,X.-M.等人,Pharmaceutical Research,2008,25(12),2910-2919;Ren,K.K.,Clinical immunology,160(1),71-81;Quan,L.-D.等人,Arthritis Research&Therapy,2010,12(5),R170;Yuan,F.等人,Advanced DrugDelivery Reviews,2012,64(12),1205-1219;Ren,K.等人,Molecular Pharmaceutics,2011,8(4),1043-1051)。
传统上,水溶性聚合物药物缀合物(或大分子前药)广泛用于静脉输注以治疗癌症和炎性疾病(J.等人,Journal of Controlled Release,2001,74(1-3),147-158;Sirova,M.等人,Pharmaceutical Research,2010,27(1),第200页)。HPMA共聚物用作水溶性药物载体已持续几十年,以全身性地递送疏水性化合物。由于淋巴引流的存在,这些药物缀合物尚未被广泛探索作为药物贮库用于持续局部疗法,淋巴引流将最终使前药返回体循环。分子量的显著增加可能延迟前药从注射位点的排出,但也引人注目地增加其血清半衰期并且阻碍肾脏清除,导致前药的广泛脱靶分布和相关毒性。因此,需要新的递送系统来克服这些问题。
发明内容
本发明提供了一种新的药物递送系统来满足上述需要以及解决目前可用的关节内注射糖皮质激素的局限性,使用新的ProGel技术更有效和安全地管理尤其是关节炎疼痛和炎症。
在一方面,本发明提供了一种热响应性聚合物-药物缀合物,其包含与水溶性聚合物载体共价键合的疏水性药物分子部分,其中所述聚合物-药物缀合物在第一温度下可溶于水并且在高于第一温度的第二温度下可以形成前药水凝胶(ProGel),其中所述聚合物-药物缀合物具有取决于选自所述药物分子部分的含量、所述聚合物载体的构造、所述聚合物载体的分子量、和所述缀合物的浓度及其组合的条件的相变图。
在一些实施方案中,所述热响应性聚合物-药物缀合物中的聚合物载体包含多个重复单元(A)和多个重复单元(B)以形成其上附接有所述重复单元(A)和(B)的侧链的聚合物主链:
其中:
R1和R2独立地是H、甲基、或卤素;
R3是被一个、两个或三个OH基团取代的C1-C8烷基;
X是药物分子或其药学上可接受的盐的部分;
L是将所述药物分子部分X与所述聚合物主链共价连接的接头;
Y是官能团,所述官能团与所述药物分子部分X的一部分或所述部分L的一部分一起形成酸不稳定官能团,所述酸不稳定官能团可以在生理或病理条件下水解以释放所述药物分子;
并且
Z是NH或O。
在另一方面,本发明提供了一种药物组合物,其包含根据本文公开的任何实施方案的热响应性聚合物-药物缀合物和一种或多种药学上可接受的载体和赋形剂。
在另一方面,本发明提供了一种治疗疾病或障碍的方法,其包括向需要治疗的受试者施用治疗有效量的根据本文公开的任何实施方案的热响应性聚合物-药物缀合物或其药物组合物,其中在适用的情况下,所述疾病或障碍是类风湿性关节炎、骨关节炎、软组织(例如,肌腱、韧带、囊)炎症和/或损伤、牙周骨质流失、局部感染和组织脓肿、延迟的骨折愈合、神经系统障碍(例如,创伤性脑损伤、帕金森病等)、恶性肿瘤(例如,肝脏、肺、脑肿瘤或转移等)、区域性疼痛(例如,颞下颌关节疼痛、牙痛、背痛、手术后疼痛等)、听力损失、缺血性心脏病、异位骨化、骨科关节植入物松动、生殖功能障碍、用于高危妊娠的激素施用、或皮肤老化。
在另一方面,本发明提供了一种治疗疾病或障碍的方法,其包括向需要治疗的受试者施用治疗有效量的两种或更多种根据本文公开的任何实施方案的ProGel-药物缀合物或其药物组合物,以便实现协同作用,其中所述两种或更多种ProGel-药物缀合物任选地组合成一种注射配方。
在另一方面,本发明提供了根据本文公开的任何实施方案的热响应性聚合物-药物缀合物在制造用于治疗疾病或障碍的药剂(例如,基于热响应性凝胶的药物递送配制品)的用途。
在另一方面,本发明提供了制备所述热响应性聚合物-药物缀合物的方法。
在众多其他益处中,使用本发明的药物释放得到更精确地控制。从常规热响应性水凝胶递送系统中的药物释放主要是通过表面侵蚀、扩散或两者的结合。在ProGel的情况下,在聚合物前药从ProGel表面释放后,母体药物通过局部病理生理因素(例如,低pH、升高的酶活性)而从聚合物前药中释放。在前药被具有高吞噬潜力的细胞(例如,炎性细胞)内化后,母体药物也可以从聚合物前药中释放。内化后,前药被隔离在细胞内溶酶体区室中,此后通过溶酶体因素(例如,低pH、还原性环境、升高的酶活性)释放母体药物。从ProGel释放并且从局部激活过程中逸出的聚合物前药可以通过淋巴系统快速排出并且返回循环,由所述循环其通过肾脏被迅速清除。
鉴于以下具体实施方式、实施例和权利要求书,本发明的其他方面和优点对于本领域普通技术人员将更加明显。
附图说明
图1展示了在不同温度下ProGel-Dex溶液在水中的DLS特征曲线。一式三份地进行测量。
图2展示了ProGel-Dex相变图。
图3展示了储能模量G’和损耗模量G”随使用0.5%的应变和10rad/s的频率在温度斜坡(4℃-50℃,0.5℃/min)期间记录的温度变化的函数。G’和G”在21.892℃和33.492℃处交叉。
图4是光学图像,其示出了注射后4周在关节炎关节中来自IRDye 800CW标记的ProGel的强NIR信号。
图5展示了在非靶器官组织中IRDye 800CW标记的ProGel-Dex的生物分布。除了仅注射ProGel的关节炎关节外,在肾脏中仅观察到低水平的信号,这与前药的肾脏清除率一致。
图6展示了在佐剂诱导的多关节炎大鼠模型中,关节内注射ProGel-Dex提供了在30天内关节炎的持续改善。
图7展示了在单关节佐剂诱导的关节炎(MAA)大鼠模型中的膝关节直径变化。
图8展示了在单关节佐剂诱导的关节炎(MAA)大鼠模型中来自PAM测试的机械缩回阈值比。
图9展示了在单关节佐剂诱导的关节炎(MAA)大鼠模型中来自无能(incapacitance)测试的负重得分。
图10展示了来自不同处理组的大鼠的右股骨的次级松质骨(红色标记)的骨形态参数的显微CT分析(**,P≤0.01;***,P≤0.001;****,P≤0.0001)。
图11展示了来自各组的MAA膝关节的代表性显微CT图像。
图12展示了在单碘乙酸盐诱导的骨关节炎(MIA)小鼠模型中的膝关节直径变化。
图13展示了在单碘乙酸盐诱导的骨关节炎(MIA)小鼠模型中来自无能测试的负重得分。
图14展示了来自MIA小鼠的各处理组的代表性3D重建膝关节。与健康组相比,ProGel-Dex处理的小鼠表现出相似的结构特征,而盐水组则表现出广泛的骨侵蚀。在Dex处理的动物中也发现了骨损害。
图15展示了腰椎体的显微CT分析,其示出了与剂量等效的游离Dex处理和盐水对照相比显著更高的BV/TV。(*,P≤0.05)。
图16展示了在施用后的不同时间点来自不同处理组的MAA大鼠的肝脏和肾脏功能概况(*,P≤0.05;**,P≤0.01;***,P≤0.001;****,P≤0.0001)。
图17展示了在施用后的不同时间点来自不同处理组的MAA大鼠的血液学概况。(*,P≤0.05;**,P≤0.01;***,P≤0.001;****,P≤0.0001)。
图18展示了来自不同处理组的在安乐死时测量的MAA大鼠的器官重量。(*,P≤0.05;**,P≤0.01;***,P≤0.001;****,P≤0.0001)。ProGel-Dex处理组表现出减少的肾上腺重量。
图19展示了来自不同处理组的MIA小鼠的血液学概况。(*,P≤0.05)。
图20展示了来自不同处理组的MIA小鼠的肝脏和肾脏功能概况。(*,P≤0.05;**,P≤0.01;***,P≤0.001;****,P≤0.0001)。
图21展示了来自不同处理组的在安乐死时测量的MIA小鼠的肾上腺重量。(*,P≤0.05;**,P≤0.01;***,P≤0.001;****,P≤0.0001)。
图22展示了对于20%ProGel-Tan(左)和25%ProGel-Tan(右)的水凝胶的形成。
图23展示了从ProGel-Tan中Tan的体外释放。
图24展示了在骨痂内注射后在骨折位点处ProGel-Tan的持续存在。
图25展示了在不同器官中ProGel-Tan水凝胶的离体可视化。
图26展示了来自不同处理组的骨折骨痂组织的X射线图像。
图27展示了骨痂面积的定量X射线图像分析。
具体实施方式
本发明基于具有高Dex含量的N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物-地塞米松(Dex)缀合物的热响应特性的令人惊讶的发现而完成的。
具体地,当HPMA共聚物-Dex缀合物中的地塞米松(Dex)含量增加到异常高的水平(≥19wt%)并且聚合物前药浓度维持在等于或大于12.5w/v%,水溶性聚合物前药表现出热响应性相变行为。它们在低于12℃时是自由流动的水溶液,但当温度升高到高于28℃时会形成水凝胶。虽然先前已经描述了多种具有热响应性特性的聚合物,但这是具有热响应性并且在升高的温度下形成水凝胶的水溶性聚合物前药设计的第一个例子(参见Ruel-Gariépy,E.和J.-C.Leroux,European Journal of Pharmaceutics andBiopharmaceutics,2004.58(2):第409-426页;Jeong,B.等人,Journal of ControlledRelease,2000.63(1):第155-163页;Jeong,B.,S等人,Advanced Drug Delivery Reviews,2012.64:第154-162页)。为了区分于先前用于描述用于全身施用的HPMA共聚物-Dex缀合物的P-Dex(Dex含量为≤10wt%)的命名法,用于局部施用的新的具有异常高的Dex含量(≥19wt%)的HPMA共聚物-Dex缀合物在此命名为“对于Dex的基于前药的水凝胶”或“ProGel-Dex”。相应地命名其他ProGel-药物缀合物。
在一方面,本发明提供了一种热响应性聚合物-药物缀合物,其包含与水溶性聚合物载体共价键合的疏水性药物分子部分,其中所述聚合物-药物缀合物在第一温度下可溶于水并且在高于第一温度的第二温度下可以形成前药水凝胶(ProGel),其中所述聚合物-药物缀合物具有取决于选自所述药物分子部分的含量、所述聚合物载体的构造、所述聚合物载体的分子量、和所述缀合物的浓度及其组合的条件的相变图。
在一些实施方案中,热响应性聚合物-药物缀合物中的聚合物载体是合成的不可降解聚合物,所述合成的不可降解聚合物选自N-(2-羟丙基)-甲基丙烯酰胺(HPMA)共聚物、聚乙二醇、聚噁唑啉、和包含一种或多种单体的水溶性共聚物,所述一种或多种单体选自N-(2-羟丙基)甲基丙烯酰胺、N-异丙基丙烯酰胺、丙烯酰胺、N,N-二甲基丙烯酰胺、N-乙烯基吡咯烷酮、乙酸乙烯酯、2-甲基丙烯酰氧基乙基葡糖苷、丙烯酸、甲基丙烯酸、乙烯基膦酸、苯乙烯磺酸、马来酸、2-甲基丙烯酰氧基乙基三甲基氯化铵、甲基丙烯酰胺基丙基三甲基氯化铵、甲基丙烯酰胆碱硫酸甲酯、N-羟甲基丙烯酰胺、2-羟基-3-甲基丙烯酰氧基丙基三甲基氯化铵、2-甲基丙烯酰氧基乙基三甲基溴化铵、2-乙烯基-1-甲基溴化吡啶鎓、4-乙烯基-1-甲基溴化吡啶鎓、乙烯亚胺、(N-乙酰基)乙烯亚胺、(N-羟乙基)乙烯亚胺、烯丙胺及其组合。
在一些实施方案中,热响应性聚合物-药物缀合物中的聚合物载体是可生物降解聚合物,所述可生物降解聚合物选自壳聚糖、透明质酸、聚谷氨酸、聚天冬氨酸、葡聚糖、淀粉、藻酸盐、明胶、黄原胶、果胶、角叉菜胶、瓜尔豆胶、纤维素醚(例如,羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、羟乙基纤维素(HEC)、和羧甲基纤维素钠(Na-CMC))。
在一些实施方案中,热响应性聚合物-药物缀合物中的聚合物载体(有时是优选的)是包含N-(2-羟丙基)甲基丙烯酰胺单体单元的共聚物。
在一些实施方案中,所述热响应性聚合物-药物缀合物中的聚合物载体包含多个重复单元(A)和多个重复单元(B)以形成其上附接有所述重复单元(A)和(B)的侧链的聚合物主链:
其中:
R1和R2独立地是H、甲基、或卤素;
R3是被一个、两个或三个OH基团取代的C1-C8烷基;
X是药物分子或其药学上可接受的盐的部分;
L是将所述药物分子部分X与所述聚合物主链共价连接的接头;
Y是官能团,所述官能团与所述药物分子部分X的一部分或所述部分L的一部分一起形成酸不稳定官能团,所述酸不稳定官能团可以在生理条件下水解以释放所述药物分子;
并且
Z是NH或O。
在一些实施方案中,在热响应性聚合物-药物缀合物中的聚合物载体的重复单元(A)和重复单元(B)中:
R1和R2各自是H或甲基;
R3是被一个或两个OH基团取代的C2-C5烷基;
L是-[NH(CH2)iC(O)]j-、-NH(CH2)k-、-NH(CH2)k-T-(CH2)p-、-NH(CH2)kNHC(O)-、-NH(CH2)kNH-(CH2)p-T-(CH2)q-C(O)-、或-NH(CH2)kNHC(O)-(CH2)p-T-(CH2)q-C(O)-,其中T是C6-C10亚芳基、C3-C8亚环烷基、5至10元亚杂芳基、或5至10元亚杂环烷基,其中i是选自1至6的整数;j是选自1至4的整数;k是选自1至10的整数;p是0、1、2或3;并且q是0、1、2或3;
Y是O、NH、或NH-N=(其中“=”是双键);并且
Z是NH。
在一些实施方案中,在聚合物载体中的重复单元(B)的接头L中:
i是1或2;
i是1、2或3;
k是选自1至6的整数;
p是0、1或2;
q是0、1或2。
在一些实施方案中,在热响应性聚合物-药物缀合物中的聚合物载体重复单元(B)中:
L是-[NHCH2C(O)]j-、-NH(CH2)k、-NH(CH2)k-T-CH2-、或-NH(CH2)kNHC(O)-T-C(O)-,其中T在每次出现时独立地是C6-C10亚芳基或5至10元亚杂芳基;j是2或3;并且k是2、3或4。
在一些实施方案中,有时优选,在热响应性聚合物-药物缀合物中的聚合物载体的重复单元(A)和重复单元(B)中:
R1和R2各自是甲基;
R3是-CH2CH(OH)CH3;
Y是O、NH、或NH-N=;并且
Z是NH。
在一些实施方案中,在热响应性聚合物-药物缀合物中,所述药物分子选自:糖皮质激素(例如,皮质醇或氢化可的松、可的松、泼尼松、泼尼松龙、甲基泼尼松龙、倍他米松、去炎松、醋酸氟氢可的松等)、非甾体抗炎药(NSAID)(例如,阿司匹林、布洛芬、吲哚美辛、吡罗昔康、甲芬那酸、罗美昔布、利克飞龙、青藤碱等)、镇痛药(例如,氢化吗啡酮、羟考酮、青藤碱、辣椒素、树酯毒素等)、骨合成代谢剂(例如,GSK抑制剂、丹参酮IIA、他汀类、前列腺素E1、E2和前列腺素EP受体激动剂等)、抗氧化剂(例如,丹参酮IIA、姜黄素、维生素E、芹黄素等)、抗癌剂(例如,紫杉醇、喜树碱、多西他赛、阿霉素、激酶通路抑制剂(例如,细胞质酪氨酸激酶)、甲氨蝶呤等)、激素(例如,睾酮、雌二醇、黄体酮等)、和抗生素(例如,氟喹诺酮、大环内酯类、头孢菌素、和芹黄素,它们共有抗氧化和抗细菌活性等)。
在一些实施方案中,有时优选,在热响应性聚合物-药物缀合物中,所述药物分子选自地塞米松、丹参酮IIA、黄体酮、雌二醇、姜黄素、氢化吗啡酮、青藤碱、和芹黄素。
在一些实施方案中,有时优选,在热响应性聚合物-药物缀合物中的聚合物载体的重复单元(A)和重复单元(B)中:
所述重复单元(B)具有选自以下的结构:
在一些实施方案中,有时优选,在热响应性聚合物-药物缀合物中,所述多个重复单元(A)是n,并且所述多个重复单元(B)是m;并且聚合物-药物缀合物具有选自以下的式:
其中n和m分别指示所述聚合物-药物缀合物中所述重复单元(A)和(B)的总数量;并且其中所述重复单元(A)和所述重复单元(B)以使得所述聚合物-药物缀合物维持所述热响应特性的任何顺序排列。
在一些实施方案中,有时优选,热响应性聚合物-药物缀合物是聚合物-地塞米松缀合物(ProGel-Dex),其中Dex的含量在约15-40wt%的范围内,所述ProGel-Dex的浓度在约10-50w/v%的范围内,并且所述ProGel-Dex的分子量在约1-45kDa的范围内。
在一些实施方案中,有时优选,热响应性聚合物-药物缀合物是聚合物-丹参酮IIA缀合物(ProGel-Tan),其中所述ProGel-Tan包含在约12-40wt%的范围内的丹参酮IIA;其中ProGel-Tan的浓度在约10-50w/v%的范围内;并且所述ProGel-Tan的分子量在约1-45kDa的范围内。
在另一方面,本发明提供了一种药物组合物,其包含根据本文公开的任何实施方案的热响应性聚合物-药物缀合物和一种或多种药学上可接受的载体和赋形剂。
在另一方面,本发明提供了一种治疗疾病或障碍的方法,其包括向需要治疗的受试者施用治疗有效量的根据本文公开的任何实施方案的热响应性聚合物-药物缀合物或其药物组合物,其中在适用的情况下,所述疾病或障碍是类风湿性关节炎、骨关节炎、软组织(例如,肌腱、韧带、囊)炎症和/或损伤、牙周骨质流失、局部感染和组织脓肿、延迟的骨折愈合、神经系统障碍(例如,创伤性脑损伤、帕金森病等)、恶性肿瘤(例如,肝脏、肺、脑肿瘤或转移等)、区域性疼痛(例如,颞下颌关节疼痛、牙痛、背痛、手术后疼痛等)、听力损失、缺血性心脏病、异位骨化、骨科关节植入物松动、生殖功能障碍、用于高危妊娠的激素施用、或皮肤老化。
在另一方面,本发明提供了一种治疗疾病或障碍的方法,其包括向需要治疗的受试者施用治疗有效量的两种或更多种根据本文公开的任何实施方案的ProGel-药物缀合物或其药物组合物,以便实现协同作用,其中所述两种或更多种ProGel-药物缀合物任选地组合成一种注射配方。
在一个实施方案中,所述ProGel-药物缀合物选自ProGel-抗生素、ProGel-抗炎药和ProGel-骨合成代谢剂,并且它们一起组合成用于治疗牙周炎和相关骨质流失的单一ProGel配制品。
在另一个实施方案中,所述ProGel-药物缀合物是ProGel-阿片类药物和ProGel-抗炎药,所述ProGel-阿片类药物和ProGel-抗炎药组合成一种用于治疗诸如背痛等疼痛的单一ProGel配制品。
在另一个实施方案中,所述一种或多种ProGel-药物缀合物通过关节内、皮内、腹膜内、肌肉内、玻璃体内、阴道内、颅内、硬膜外、心内或肌肉骨骼软组织(例如,肌腱、韧带、囊)施用,其中所述ProGel的能力保留在组织位点,例如皮下组织,从而缓慢释放活性药物。
在另一个实施方案中,将所述一种或多种ProGel-药物缀合物配制成喷雾剂,所述喷雾剂可以应用于开放性伤口或手术野或者应用于发炎皮肤于例如湿疹、银屑病等炎症的位点处。
在另一方面,本发明提供了根据本文公开的任何实施方案的热响应性聚合物-药物缀合物在制造用于治疗疾病或障碍的药剂(例如,基于热响应性凝胶的药物递送配制品)中的用途,所述疾病或障碍选自类风湿性关节炎、骨关节炎、软组织(例如,肌腱、韧带、囊)炎症和/或损伤、牙周骨质流失、局部感染和组织脓肿、延迟的骨折愈合、神经系统障碍(例如,创伤性脑损伤、帕金森病等)、恶性肿瘤(例如,肝脏、肺、脑肿瘤或转移等)、区域性疼痛(例如,颞下颌关节疼痛、牙痛、背痛、手术后疼痛等)、听力损失、缺血性心脏病、异位骨化、骨科关节植入物松动、生殖功能障碍、用于高危妊娠的激素施用、和皮肤老化等。
在另一方面,本发明提供了一种合成热响应性聚合物-药物缀合物的方法,其包括以下步骤:(a)通过接头将单体与药物分子共价偶联;以及(b)将步骤(a)的单体与包含极性官能团的第二单体共聚以形成所述聚合物-药物缀合物。
在另一方面,本发明提供了一种合成热响应性聚合物-药物缀合物的方法,其包括以下步骤:(a’)将包含极性官能团的单体与包含接头部分的第二单体共聚以形成共聚物;以及(b’)通过所述接头使所述共聚物与药物分子反应以形成聚合物-药物缀合物。
在一些实施方案中,所述制备聚合物-药物缀合物ProGel-Dex的方法包括以下步骤:(a)使OH-保护的地塞米松衍生物与肼反应以形成地塞米松腙衍生物;(b)使步骤(a)的地塞米松衍生物与N-甲基丙烯酰基-二甘氨酸反应以形成具有式MA-Gly-Gly-NHN=Dex的单体-Dex缀合物;以及(c)将所述单体-Dex缀合物与包含一个或多个极性官能团的第二单体共聚,使得所述共聚物-Dex缀合物具有热响应特性。
在一些实施方案中,本发明提供了制备如基本所述和所示的根据任何实施方案的热响应性聚合物-药物缀合物的方法。
除非明确定义,否则本申请中的任何术语将具有本领域普通技术人员所理解的普通含义。
如本文所用,单数形式“一个/种(a/an)”和“所述(the)”包括复数指代物,并且反之亦然,除非上下文另外明确规定。
除非另有说明,否则说明书和权利要求书中所用的术语具有以下所述的含义。
“烷基”是指饱和脂族烃基,包括C1-C12直链和支链基团。优选地,烷基是具有1至8个、有时更优选1至6个、有时甚至更优选1至4个碳原子的烷基。代表性例子包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、正戊基等。
“亚烷基”是指二价烷基。例子包括亚甲基(-CH2-)、亚乙基(-CH2CH2-)等。
“芳基”是指具有完全共轭π电子体系的全碳单环或多环稠环。优选地,芳基含有6至10个碳,诸如苯基和萘基并且更优选苯基。
“亚芳基”是指二价芳基,例如1,4-亚苯基、1,2-亚苯基。
“环烷基”是指具有3至8个碳原子,优选3至6个碳原子的饱和单环烃基。单环环烷基的代表性例子包括但不限于环丙基、环丁基、环戊基和环己基等。
“亚环烷基”是指二价环烷基,例如1,4-亚环己基、1,2-亚环丙基等。
“卤素”是指氟、氯、溴或碘原子,有时优选氯或氟,并且有时更优选氯。
“杂环基”是指具有一个或多个杂原子的3至10元饱和和/或部分不饱和单环或多环烃基,所述一个或多个杂原子选自N、O和S(O)m(其中m是0、1或2)作为环原子,但在环中不包括-O-O-、-O-S-或-S-S-,其余环原子是C。优选地,杂环基是具有1至3个杂原子的5至10元的;更优选具有1至2个杂原子的5至6元的。单环杂环基的代表性例子包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基等。
“亚杂环基”是指二价杂环基,其具有与分子中其他基团共价键合的两个不同环碳原子。
“杂芳基”是指具有1至3个选自O、S和N的杂原子作为环原子并且具有5至10个环原子(优选5或6元的)的芳基体系,例如噻二唑基、吡唑基、噁唑基、噁二唑基、咪唑基、三唑基、噻唑基、呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。
“亚杂芳基”是指二价杂芳基,其具有与分子中的其他基团共价键合的两个不同环碳原子。
“药物组合物”是指本发明中所述的一种或多种化合物与其他化学组分诸如生理学/药学上可接受的载体和赋形剂的混合物。药物组合物的目的是促进化合物向生物体的施用,这有利于活性成分的吸收并且从而展现出生物活性。
在热响应性ProGel-药物缀合物中,药物部分可以以游离酸、游离碱或“药学上可接受的盐”形式存在。
“药学上可接受的盐”是指本发明化合物的盐,此类盐当用于哺乳动物时是安全且有效的并且具有相应的生物活性。通常用于形成药学上可接受的盐的酸包括无机酸,诸如盐酸、氢溴酸、氢碘酸、硫酸、磷酸、二硫化氢;以及有机酸,诸如对甲苯磺酸、水杨酸、酒石酸、二氢酒石酸、抗坏血酸、马来酸、苯磺酸(besylic acid)、富马酸、葡萄糖酸、葡萄糖醛酸、甲酸、谷氨酸、甲磺酸、乙磺酸、苯磺酸(benzenesulfonic acid)、乳酸、乙二酸、对溴苯磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸、乙酸以及相关的无机和有机酸。
药学上可接受的盐的阳离子包括但不限于锂、钠、钾、钙、镁和铝;以及无毒的季胺阳离子,诸如铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶和N-甲基吗啉。
如本文所用,术语“治疗有效量”是指足以显示出有意义的患者益处的每种活性成分的总量。当应用于单独施用的单独的活性成分时,所述术语是指单独的成分。当应用于组合时,所述术语是指导致治疗效果的活性成分(无论是组合、连续或同时施用)的组合量。
如本文所用,术语“药学上可接受的”是指在合理的医学判断的范围内,适用于与患者的组织接触而不产生过度的毒性、刺激、过敏反应或其他问题或并发症,与合理的益处/风险比相称并且对其预期用途有效的那些化合物、材料、组合物和/或剂型。
术语“受试者”或“患者”包括人和其他哺乳动物,尤其是家养动物,例如狗、猫、马等。
术语“治疗”是指(i)抑制疾病、障碍、或病症,即阻止其发展;以及(ii)减轻疾病、障碍、或病症,即导致疾病、障碍、和/或病症消退。另外,本发明的化合物可以用于其在预防可能易患疾病、障碍和/或病症但尚未被诊断为患有所述疾病、障碍和/或病症的受试者免于发生疾病、障碍或病症方面的预防作用。
本领域技术人员众所周知,药物的剂量取决于多种因素,包括但不限于以下因素:特定化合物的活性,患者的年龄、体重、一般健康状况、行为、饮食,施用时间,施用途径,排泄率,药物组合等。
如本文所用,术语“约”通常包括指示数字的最多正或负10%。例如,“约10%”可以指示9%至11%的范围,并且“约20”可以意指18至22。有时优选地,术语“约”包括指示值的最多正或负5%。
如本文所公开的,提供了多个数值范围。应当理解还具体公开了在所述范围的上限与下限之间的每个中间值(除非上下文清楚地另外规定,否则至下限的十分之一个单位)。
ProGel技术是可以递送多种类别的药物的平台技术。除了Dex,我们还合成了热响应性HPMA共聚物-抗氧化剂(即,姜黄素和丹参酮)缀合物(ProGel-姜黄素、ProGel-Tan)、HPMA共聚物-激素(即,黄体酮和雌激素)缀合物(ProGel-Pro、ProGel-雌激素)、HPMA共聚物-抗微生物剂/抗氧化剂(即,芹黄素)缀合物(ProGel-芹黄素)和HPMA共聚物阿片类药物(即,氢化吗啡酮)(ProGel-HMP)。这些聚合物前药均显示出在升高的温度下形成水凝胶的热响应性功能。除了使用中性HPMA共聚物作为药物载体外,带正电荷的壳聚糖和带负电荷的透明质酸也可以在不同药物组成的ProGel的制备中用作亲水性聚合物载体。
与其他热敏性水凝胶相比,ProGel提供了多种另外的优点。ProGel平台最佳地适于修饰药物负载能力。根据下面示出的ProGel-Dex的相变图,ProGel可以在宽范围的药物负载量和聚合物前药浓度下形成。尤其是,由于ProGel的热响应性功能基于疏水性药物分子的共价引入,因此ProGel药物负载能力高。例如,ProGel-Dex配制品可以具有约50mg/mL的Dex含量。这种能力拓宽了在注射空间有限的情况下水凝胶用于局部注射的效用。如下所示,临床前数据显示60μL ProGel-Dex保留在关节炎大鼠的滑膜腔中超过1个月。
与常规水溶性聚合物前药相比,ProGel技术在其靶向特异性方面也具有优势。对于全身施用的聚合物前药,其向实体瘤和炎症位点的被动靶向分别由充分确立的EPR和ELVIS机制控制。高分子量是获得高血清半衰期和向病理位点的更显著被动靶向性所必需的。这种所需的高分子量的结果是前药向单核吞噬细胞系统(MPS)的脱靶分布。在ProGel的情况下,前药的分布唯一地由注射位置决定,并且前药的持续局部存在是由于ProGel形成凝胶的能力,所述凝胶物理地保留在注射位点。由于热响应性凝胶的形成,即使具有非常低分子量的聚合物前药也可以在注射位点停留延长的时间。如光学成像数据所示,一旦从ProGel中释放,低分子量聚合物前药(约5kDa)在没有MPS隔离的情况下通过肾脏快速清除。
基于水溶性聚合物(例如,HPMA共聚物、PEG、壳聚糖、透明质酸等)的大分子前药已被广泛用作纳米药物,以改善对许多不同疾病(包括癌症和炎性病理)的治疗。它们提供了改善母体药物水溶性、向肿瘤和/或炎症的被动靶向性、在循环中的稳定性和延长的半衰期、以及位点特异性和病理生理因素驱动的药物激活的优点。
这些前药的所有先前效用都呈有待作为静脉内、皮下、腹膜内或肌肉内注射施用的常规液体配制品的形式。它们被设计为全身施用。因此,这些聚合物前药必须是高度水溶性的。胶束化和聚集的存在可能干扰前药激活。在注射位点处的沉淀或胶凝对于它们预期的全身应用是不希望的。据我们所知,还没有关于这些聚合物前药在升高的温度下凝胶的任何报道。这是因为这些前药的疏水性药物含量一直维持在相对较低的水平,从而实现良好的水溶性。例如,对于作为治疗炎性关节炎的全身疗法而开发的原始HPMA共聚物-地塞米松缀合物(P-Dex),Dex含量一直保持小于12mol%,以提供良好的水溶性以及避免分子内/分子间胶束化或聚集。
对于新发明的基于大分子前药的热敏性可注射凝胶或ProGel,其预期应用是用于局部治疗性干预。这些前药的通用化学结构类似于由相同的共聚单体组成的常规水溶性聚合物前药。但必须增加热敏性凝胶前药的疏水性药物含量以产生适当的两亲性特性,这将导致前药在较低温度下的良好水溶性以及其在升高的温度下相转变为水凝胶。如以下实施例图2所示,对于HPMA共聚物-地塞米松缀合物,我们发现当Dex含量在17-22mol%之间并且在水中大分子前药的浓度>15wt%时,它们在较低温度下形成澄清的自由流动溶液,但当温度升高为高于室温时,可以形成凝胶。
由于在较高浓度下具有较高疏水性药物含量的聚合物前药的相变特性,它们可以在已知的疾病病理位点处体内直接施用。施用后,胶凝化过程物理地将前药局部捕获在组织内,从而产生前药贮库。然后,前药通过被间质液稀释/活化/溶解的过程从凝胶表面缓慢释放。如果需要调节前药释放速率,则可以系统地修改药物含量和前药浓度。也可以局部应用冰垫应用以降低组织温度,从而降低凝胶粘度并且增加前药释放。
不同于其中低分子量药物被物理地捕获在凝胶内的常规的基于热敏性凝胶的药物递送系统,在新的基于前药的热敏性凝胶(我们将其称为“ProGel”)中,药物分子被化学缀合至水溶性聚合物载体。这不仅提供了对药物释放的更好控制,而且还将药物的细胞进入模式从扩散转变为吞噬作用/巨胞饮作用,这使前药细胞进入是细胞选择性的。只有具有高吞噬/微胞饮能力的那些细胞(例如,炎性细胞)将能够内化从凝胶表面释放的聚合物前药。
重要地,由于热响应性凝胶特性,前药的局部保留不需要前药具有高分子量。因此,我们能够设计具有低分子量(即,约5kDa)的聚合物前药,一旦药物溶解并且迁移到循环中,所述聚合物前药将允许前药通过肾脏迅速清除。这种新型策略将避免单核吞噬细胞系统(MPS,包括肝脏和脾脏)的细胞对聚合物前药的潜在隔离,从而降低意料之外的脱靶毒性的风险。
本发明所述的基于大分子前药的热敏性可注射凝胶是新型平台技术,其对于基本上所有基于水溶性聚合物的前药缀合物具有广泛的应用。对于合成的不可降解聚合物载体系统,其包括但不限于HPMA共聚物、聚乙二醇、聚噁唑啉或其他水溶性共聚物,其中所述聚合物包含一种或多种单体,所述一种或多种单体选自N-(2-羟丙基)甲基丙烯酰胺、N-异丙基丙烯酰胺、丙烯酰胺、N,N-二甲基丙烯酰胺、N-乙烯基吡咯烷酮、乙酸乙烯酯、2-甲基丙烯酰氧基乙基葡糖苷、丙烯酸、甲基丙烯酸、乙烯基膦酸、苯乙烯磺酸、马来酸、2-甲基丙烯酰氧基乙基三甲基氯化铵、甲基丙烯酰胺基丙基三甲基氯化铵、甲基丙烯酰胆碱硫酸甲酯、N-羟甲基丙烯酰胺、2-羟基-3-甲基丙烯酰氧基丙基三甲基氯化铵、2-甲基丙烯酰氧基乙基三甲基溴化铵、2-乙烯基-1-甲基溴化吡啶鎓、4-乙烯基-1-甲基溴化吡啶鎓、乙烯亚胺、(N-乙酰基)乙烯亚胺、(N-羟乙基)乙烯亚胺、烯丙胺及其组合。对于可生物降解聚合物载体系统,其可以包括但不限于壳聚糖、透明质酸、聚谷氨酸、聚天冬氨酸、葡聚糖、淀粉、藻酸盐、明胶、黄原胶、果胶、角叉菜胶、瓜尔豆胶、纤维素醚(例如,羟丙基甲基纤维素或HPMC、羟丙基纤维素或HPC、羟乙基纤维素或HEC、羧甲基纤维素钠或Na-CMC)。
如以下例子中所示,地塞米松(Dex)是我们合作过的第一个模型有效负载药物。热响应性HPMA共聚物-地塞米松缀合物已指定为“ProGel-Dex”。有广泛的另外的药物有效负载候选物,其包括但不限于糖皮质激素(例如,皮质醇或氢化可的松、可的松、泼尼松、泼尼松龙、甲基泼尼松龙、倍他米松、去炎松、醋酸氟氢可的松等)、非甾体抗炎药(NSAID)(例如,阿司匹林、布洛芬、吲哚美辛、吡罗昔康、甲芬那酸、罗美昔布、利克飞龙、青藤碱等)、镇痛药(例如,氢化吗啡酮、羟考酮、青藤碱、辣椒素、树酯毒素等)、骨合成代谢剂(例如,GSK抑制剂、丹参酮IIA、他汀类、前列腺素E1、E2和前列腺素EP受体激动剂等)、抗氧化剂(例如,丹参酮IIA、姜黄素、维生素E、芹黄素等)、抗癌药(例如,紫杉醇、喜树碱、多西他赛、阿霉素、激酶通路抑制剂(例如,细胞质酪氨酸激酶)、甲氨蝶呤等)、激素(例如,睾酮、雌二醇、黄体酮等)、和抗生素(例如,氟喹诺酮、大环内酯类、头孢菌素、和芹黄素,它们共有抗氧化和抗细菌活性等)。这些药物中的一些正在开发中,如基于前药的热敏性凝胶在以下作为实施例示出。除了类风湿性关节炎和骨关节炎,其他类别的疾病也可以受益于这种独特的基于前药热响应性凝胶的药物递送配制品。这包括但不限于软组织(例如,肌腱、韧带、囊)炎症和/或损伤、牙周骨质流失、局部感染和组织脓肿、延迟的骨折愈合、神经系统障碍(例如,创伤性脑损伤、帕金森病等)、恶性肿瘤(例如,肝脏、肺、脑肿瘤或转移等)、区域性疼痛(例如,颞下颌关节疼痛、牙痛、背痛、手术后疼痛等)、听力损失、缺血性心脏病、异位骨化、骨科关节植入物松动、生殖功能障碍、用于高危妊娠的激素施用、皮肤老化等。
我们相信这种新型ProGel平台药物递送技术将改变当前的递送范式并且有很大希望显著改善局部递送的治疗剂的持续性、功效和安全性。以下非限制性实施例进一步说明了本发明的某些方面。
实施例
实施例1
1.Dex单体(MA-Gly-Gly-NHN=Dex)的合成
方案1.MA-Gly-Gly-NHN=Dex的合成
将Gly-Gly-OH(13.2g,100mmol)溶解在水(50mL)中,并且然后将溶液冷却至0℃。将甲基丙烯酰氯(10.4g,100mmol)和NaOH(50mL,2M)逐滴添加到溶液中。添加后,将反应混合物在室温下搅拌1h,然后用浓盐酸酸化至pH 2,并且形成浓稠的白色沉淀。收集固体并且通过热水洗涤直到滤液呈中性。将粗固体产物在真空下干燥并且通过重复结晶(乙醇/水=50/50)进一步纯化以得到白色晶体(4.9g,25%)。
1H NMR:(500MHz,DMSO-d6)δ12.55(br,1H),8.16(t,J=5.8Hz,1H),8.10(t,J=5.8Hz,1H),5.74(s,1H),5.37(s,1H),3.76(s,2H),3.75(s,2H),1.87(s,3H);
13C NMR(125MHz,DMSO-d6)δ171.6,169.8,168.1,139.9,120.2,42.6,41.1,18.9。
将地塞米松(11.76g,30mmol)和咪唑(4.08g,60mmol)溶解在无水DMF(90mL)中,并且通过冰浴将溶液冷却至0℃。添加TBSCl(4.95g,33mmol)。将溶液在0℃下搅拌1h,并且然后允许在室温下3h。添加乙酸乙酯(200mL),并且然后将溶液用饱和盐水(200mL,并且然后150mL×4)洗涤。然后将有机相经Na2SO4干燥,并且然后除去溶剂以获得粗产物(15.1g)。
1H NMR(500MHz,DMSO-d6):δ(ppm)=7.28(d,J=10.2Hz,1H),6.22(d,J=10.2Hz,1H),6.00(s,1H),5.29(s,1H),4.97(s,1H),4.78(d,J=19.1Hz,1H),4.29(d,J=19.1Hz,1H),4.14(d,J=9.4Hz,1H),2.91(m,1H),2.61(td,J=13.6Hz,5.8Hz,1H),2.36(m,2H),2.11(m,2H),1.76(m,1H),1.62(q,J=11.8Hz,1H),1.48(s,3H),1.41(d,J=13.5Hz,1H),1.33(m,1H),1.06(m,1H),0.88(s,9H),0.87(s,3H),0.74(d,J=7.3Hz,1H),0.04(s,3H),0.03(s,3H)。
13C NMR(125MHz,DMSO-d6):δ(ppm)=209.19,185.45,167.20,152.94,129.17,124.29,101.38(d,JC-F=174Hz),90.52,70.84(d,JC-F=36.9Hz),68.14,48.13(d,JC-F=22.5Hz),47.65,36.03,35.33,33.82(d,JC-F=19.3Hz),32.09,30.46,27.42,25.97,23.08(d,JC-F=5.5Hz),18.34,16.86,15.38,-4.89,-5.04。
MS(ESI):m/z=507.2(M+H+),计算值506.3。
然后将粗产物溶解在一水合肼(6.0g,120mmol)在甲醇(120mL)中的溶液中,并且然后添加乙酸(0.9g,15mmol)。将溶液在室温搅拌4h。添加乙酸乙酯(200mL),并且然后将溶液用饱和盐水(150mL×3)洗涤。将有机相经Na2SO4干燥,并且然后除去溶剂以获得残余物。快速柱色谱法(乙酸乙酯:己烷=1:1至2:1)以得到产物(7.78g)。产率:49.9%。回收一些化合物2(5.53g)。
1H NMR(500MHz,DMSO-d6):δ(ppm)=6.72(d,J=10.4Hz,0.37H),6.43(s,0.63H),6.30(s,1.94H),6.28(d,J=10.4Hz,0.37H),6.04(d,J=10.1Hz,0.63H),5.99(d,J=10.1Hz,0.63H),5.04(d,J=13.2Hz,1H),4.93(s,1H),4.78(d,J=19.1Hz,1H),4.28(d,J=19.1Hz,1H),4.10(br,1H),2.90(m,1H),2.56(td,J=13.1Hz,,4.7Hz,0.63H),2.45(td,J=13.1Hz,,4.7Hz,0.37H),2.24(m,1H),2.12(m,3H),1.66(m,0.63H),1.61(m,0.37H),1.59(m,1H),1.38(s,3H),1.36(d,J=13.5Hz,1H),1.29(m,1H),1.05(m,1H),0.88(s,9H),0.85(s,3H),0.77((d,J=7.1Hz,3H),0.04(s,3H),0.03(s,3H)。
13C NMR(125MHz,DMSO-d6):δ(ppm)=209.27,170.49,150.62,143.85,139.98,139.89,138.18,132.13,127.68,121.60,116.04,110.69,100.36(d,JC-F=171.6Hz),100.16(d,JC-F=172.2Hz),90.63,90.57,69.74(J=37.5Hz),69.67(d,JC-F=37.1Hz),68.15,59.91,47.62,47.60,47.00,46.85,46.82,46.65,43.76,36.16,36.08,35.31,34.19(d,JC-F=19.6Hz),34.13(d,JC-F=19.6Hz),32.06,30.94,29.88,27.47,25.97,25.07(d,JC-F=4.6Hz),24.63(d,JC-F=4.6Hz),20.93,18.35,16.90,15.40,14.25,-4.89,-5.03。
MS(ESI):m/z=521.2(M+H+),计算值520.3。
在0℃下将MA-Gly-Gly-OH(60mg,0.3mmol)、DCC(82.4mg,0.4mmol)和Et3N(60mg,0.6mmol)溶解在无水DMF(3mL)中。将溶液搅拌15min,并且然后添加化合物3(130mg,0.25mmol)。允许溶液达到室温并且搅拌过夜。添加乙酸乙酯(50mL),并且然后将溶液用饱和盐水(50mL×4)洗涤。将有机相经Na2SO4干燥,并且然后除去溶剂。将残余物通过柱色谱法(乙酸乙酯:MeOH=15:1)纯化以得到产物4(106mg)。产率60.4%。
1H NMR(500MHz,DMSO-d6):δ(ppm)=10.93(s,0.23H),10.85(s,0.30H),10.50(s,0.12H),10.49(s,0.23H),8.21(t,J=4.2Hz,0.35H),8.19(t,J=5.7Hz,0.65H),8.10(t,J=4.9Hz,0.37H),7.89(t,J=5.4Hz,0.57H),7.02(d,J=10.6Hz,0.24H),6.93(d,J=10.2Hz,0.13H),6.79(s,0.32H),6.68(s,0.31H),6.62(t,J=10.5Hz,0.25H),6.46(d,J=11.1Hz,0.23H),6.43(d,J=11.2Hz,0.36H),6.28(t,J=10.2Hz,0.23H),6.22(d,J=10.1Hz,0.32H),6.00(s,0.15H),5.96(s,0.25H),5.74(s,1H),5.38(s,1H),5.16(m,1H),4.95(s,1H),4.77(d,J=19.0Hz,1H),4.13(m,2.29H),3.86(m,0.78H),3.78(dd,J=14.7Hz,5.8Hz,2H),2.90(m,1H),2.60(m,0.62H),2.25(m,1.78H),2.11(m,2.47H),1.87(s,3.2H),1.71(m,1.08H),1.58(m,1.09H),1.41(m,4.20H),1.31(m,1.14H),1.06(m,1.10H),0.88(s,9H),0.84(s,3H),0.78(d,J=7.1Hz,3.26H)。
13C NMR(125MHz,DMSO-d6):δ(ppm)=209.27,170.60,170.57,170.50,169.63,169.43,167.93,167.82,165.62,165.53,157.41,157.02,152.24,151.46,146.77,146.31,144.12,143.95,143.17,139.69,139.62,126.60,120.58,120.00,119.90,117.07,116.63,111.61,111.44,101.47(d,JC-F=173Hz),101.42(d,JC-F=173Hz),100.08(d,JC-F=173Hz),100.03(d,JC-F=173Hz),90.63,90.56,79.37,70.08(d,JC-F=36.9Hz),68.19,59.95,47.43(d,JC-F=22.8Hz),47.27(d,JC-F=22.8Hz),43.68,42.64,42.50,41.56,40.70,36.15,36.08,35.36,34.10(d,JC-F=21.4Hz),34.03(d,JC-F=19.4Hz),32.10,31.06,31.01,30.13,29.97,27.50,27.44,24.42(d,JC-F=4.9Hz),24.06(d,JC-F=4.5Hz),23.98(d,JC-F=4.7Hz),20.94,18.76,18.73,18.36,16.90,15.42,15.40,14.28,-4.86,-5.01。
MS(ESI):m/z=703.3(M+H+),计算值702.38。
将化合物4(70mg,0.1mmol)溶解在THF(5ml)中,并且然后添加TBAF(0.2mL,1M),将溶液在室温下搅拌15min。添加乙酸乙酯(50mL),并且然后将溶液用饱和盐水(50mL×4)洗涤。将有机相经Na2SO4干燥,并且除去溶剂。将残余物通过柱色谱法(乙酸乙酯:MeOH=10:1)纯化以得到48mg产物5(MA-Dex),产率:81.6%。
1H NMR(500MHz,DMSO-d6):δ(ppm)=10.92(s,0.21H),10.84(s,0.32H),10.50(s,0.13H),10.50(s,0.23H),8.21(t,J=4.2Hz,0.31H),8.18(t,J=5.7Hz,0.67H),8.10(t,J=4.9Hz,0.40H),7.88(t,J=5.4Hz,0.57H),7.02(d,J=10.6Hz,0.22H),6.93(d,J=10.2Hz,0.12H),6.78(s,0.34H),6.68(s,0.38H),6.62(d,J=10.4Hz,0.23H),6.47(d,J=11.1Hz,0.25H),6.43(d,J=11.2Hz,0.36H),6.27(t,J=10.2Hz,0.25H),6.22(d,J=10.1Hz,0.35H),6.00(s,0.12H),5.96(s,0.22H),5.74(s,1H),5.37(s,1H),5.14(m,1H),4.93(s,1H),4.67(br,1H),4.49(d,J=19.2Hz,1H),4.14(m,2.05H),4.07(d,J=19.2Hz,1H),3.87(m,0.90H),3.79(dd,J=14.9Hz,5.7Hz,2H),2.93(m,1H),2.60(m,0.60H),2.50(m,1.12H),2.25(m,1.80H),2.13(m,2.25H),1.87(s,3.2H),1.71(m,1.04H),1.59(m,1.11H),1.42(m,4.37H),1.31(m,1.79H),1.06(m,1.15H),0.88(s,9H),0.84(s,3.61H),0.787(d,J=7.0Hz,3.34H)。
13C NMR(125MHz,DMSO-d6):δ(ppm)=211.47,170.63,170.60,169.71,169.52,168.02,167.91,165.74,165.66,162.62,157.56,157.15,152.37,151.56,146.89,146.44,144.26,144.06,143.25,139.77,139.72,139.66,139.12,117.11,116.67,111.69,111.49,100.93(d,JC-F=172.9Hz),100.88(d,JC-F=172.9Hz),100.75(d,JC-F=174.7Hz),100.72(d,JC-F=173.9Hz),90.48,90.42,70.18(d,JC-F=35.9Hz),66.55,60.02,53.07,47,6947.47(d,JC-F=22.8Hz),47.33(d,JC-F=22.8Hz),43.70,42.71,42.56,41.64,40.76,36.16,36.09,35.16,34.12(d,JC-F=20.5Hz),34.08(d,JC-F=20.5Hz),32.24,31.08(br),30.18,30.03,28.18,27.55,24.45(d,JC-F=5.0Hz),24.09(d,JC-F=5.9Hz),21.34,20.99,20.14,18.79,18.77,16.91,15.54,15.52,14.32,14.07。
MS(ESI):m/z=589.1(M+H+),计算值588.3。
2.ProGel-Dex的合成
将HPMA(400mg,2.79mmol)、MA-Gly-Gly-NHN=Dex(256.7mg,0.44mmol)溶解在甲醇(5mL)中,然后添加引发剂2,2’-偶氮二异丁腈(AIBN,38.8mg,0.24mmol)和RAFT剂S,S’-双(α,α’-二甲基-α”-乙酸)-三硫代碳酸酯(CTA,37.1mg,0.13mmol),将溶液用氩气吹扫并且在50℃下聚合2天。将所得聚合物首先在LH-20柱上纯化以除去未反应的低分子量化合物,并且然后透析。将聚合物溶液冻干以获得最终ProGel-Dex。
方案2.ProGel-Dex的合成
实施例2
3.ProGel-丹参酮的合成
方案3.ProGel-丹参酮(ProGel-Tan)的合成
将HPMA(500mg,3.49mmol)和MA-Gly-Gly-NHNH2(134mg,0.63mmol)溶解在玻璃安瓿中的甲醇(5mL)中,并且向此溶液中添加引发剂2,2’-偶氮双(异丁腈)(AIBN,37.5mg,0.23mmol)和RAFT剂S,S’-双(α,α’-二甲基-α”-乙酸)-三硫代碳酸酯(CTA,35.8mg,0.13mmol)。将溶液用氩气吹扫,将其火焰密封并且在50℃下聚合48h。将所得聚合物首先在LH-20柱上纯化以除去未反应的低分子量化合物并且获得所希望的产物。然后将所得共聚物(530mg)和丹参酮(184mg,0.63mmol)溶解在甲醇(6mL)中。将三氟乙酸(0.2mL)作为催化剂添加到反应溶液中。将溶液再次用氩气吹扫,并且在70℃下避光回流12h。反应溶剂蒸发后,将ProGel-Tan产物通过LH-20柱纯化。
实施例3
4.ProGel-姜黄素的合成
方案4.N-(3-叠氮基丙基)甲基丙烯酰胺的合成
将3-氯丙基-1-胺盐酸盐(1.0g,7.75mmol)溶解在10.0mL H2O中,并且向此溶液中添加叠氮化钠(3.8g,58.5mmol),将溶液在80℃下搅拌过夜。然后将反应冷却至0℃,并且添加KOH以将pH值调节至11,分离有机层,并且将水相用EA(30mL×2)萃取。将合并的有机溶液经无水MgSO4干燥。过滤并且除去溶剂后,获得呈无色油状物的3-叠氮基丙-1-胺(465mg),可以将其不经进一步纯化而用于下一步。
方案5.可点击姜黄素衍生物的合成
向在0℃下3-叠氮基丙-1-胺(500mg,5mmol)在干DCM中的溶液中添加三乙胺(1.01g,10mmol),并且将溶液搅拌10分钟。逐滴添加甲基丙烯酰氯(572mg,5.5mmol),并且通过TLC监测反应并且进行过夜直到3-叠氮基丙-1-胺完全消失。将反应通过水淬灭,并且将产物用DCM(20mL×3)萃取。将合并的有机相用5%HCl(水溶液)和盐水洗涤,并且然后经Na2SO4干燥。过滤后,除去溶剂。将残余物通过快速柱色谱法(MeOH/DCM=1:10)纯化以得到相应的产物。1H NMR(500MHz,CDCl3)δ(ppm)=6.08(s,1H),5.68(s,1H),5.34(s,1H),3.42-3.37(m,4H),1.95(s,3H),1.86-1.82(m,2H)。2-(3,5-双((E)-4-羟基-3-甲氧基苯乙烯基)-1H-吡唑-1-基)乙酸乙酯的合成。
将姜黄素(500mg,1.36mmol)、2-肼基乙酸乙酯盐酸盐(420mg,2.72mmol)、三乙胺(0.375mL,2.72mmol)和TFA(0.05mL,0.68mmol)溶解在无水甲苯(10mL)中。将溶液在回流下搅拌3h并且通过TLC监测直到起始材料完全消失。然后将反应混合物冷却至室温,添加水并且用DCM(20mL×3)萃取,将合并的有机溶液用5%HCl(水溶液)洗涤并且经Na2SO4干燥。过滤后,除去溶剂并且将残余物通过快速柱色谱法(MeOH/DCM=1:40)纯化以得到呈黄色固体的相应产物(380mg,产率:62%)。1H NMR(500MHz,DMSO-d6)δ(ppm)=7.22(d,J=1.35Hz,1H),7.16(d,J=1.35Hz,1H),7.10-7.07(m,1H),7.05-7.04(m,1H),7.02-7.01(m,2H),6.98-6.95(m,1H),6.93-6.92(m,1H),6.93(s,1H),6.77(dd,J=10.1,7.75Hz,2H),5.20(s,2H),4.16(q,J=7.05Hz,2H),3.83(s,3H),3.82(s,3H),1.21(t,J=7.15Hz,3H)。13C NMR(125MHz,DMSO-d6)δ168.7,150.5,148.3,147.7,147.2,143.8,132.7,130.2,128.9,128.5,121.2,120.5,118.2,116.0,112.1,110.8,110.1,99.1,61.5,56.2,56.1,50.8,14.5。
2-(3,5-双((E)-4-羟基-3-甲氧基苯乙烯基)-1H-吡唑-1-基)乙酸的合成
将酯(180mg,0.4mmol)溶解在混合溶液(甲醇/H2O=4mL/4mL)中。添加KOH(112mg,2.0mmol)并且将溶液在室温下搅拌过夜。通过TLC监测反应。将溶液浓缩至2mL并且用HCl溶液酸化至pH=2,并且然后用DCM(20mL×3)萃取。将合并的有机相经Na2SO4干燥,过滤,浓缩,并且通过快速柱色谱法(MeOH/DCM/HOAc=1:5:0.05)纯化以得到相应产物(150mg,产率:89%)。1H NMR(500MHz,DMSO-d6)δ(ppm)=7.22(d,J=1.1Hz 1H),7.15(d,J=1.1Hz,1H),7.06-6.89(m,6H),6.79-6.76(m,3H),4.97(s,2H),3.82(s,6H);13C NMR(125MHz,DMSO-d6)δ168.2,149.8,148.3,147.7,147.1,143.4,132.1,129.7,129.1,128.6,121.1,120.3,118.5,116.1,112.6,110.6,110.1,98.9,56.2,56.1,51.9。
2-(3,5-双((E)-4-羟基-3-甲氧基苯乙烯基)-1H-吡唑-1-基)-N-(丙-2-炔-1-基)的合成。
将酸(60mg,0.142mmol)溶解在无水DMF(2mL)中,然后添加DIPEA(36.7mg,0.284mmol)和HATU(81g,0.213mmol)。将反应混合物在室温下在黑暗中搅拌5min,并且然后添加丙-2-炔-1-胺(15.6mg,0.284mmol)。将反应保持在室温下在黑暗中过夜直到起始材料完全消失。然后向溶液中添加水,并且然后用EA(20mL×3)萃取。将合并的有机溶液用盐水洗涤并且经Na2SO4干燥、过滤、浓缩并且通过快速柱色谱法(MeOH/DCM=1:10)纯化以得到呈黄色固体的相应产物(43mg,66%)。δ1H NMR(500MHz,DMSO-d6)δ(ppm)=8.63(t,J=7.25Hz,1H),7.21(d,J=1.1Hz 1H),7.16(d,J=1.1Hz,1H),7.08-6.81(m,6H),6.79-6.76(m,3H),4.94(s,2H),3.92(s,2H),3.83(s,3H),3.82(s,3H),3.16(s,1H);13C NMR(125MHz,DMSO)δ167.2,150.2,148.3,147.7,147.1,143.9,132.3,129.9,129.0,128.6,121.2,120.4,118.4,116.0,112.6,110.6,110.1,98.9,81.2,73.8,73.3,56.2,56.1,51.8,28.6。
方案6.ProGel-姜黄素的合成
将HPMA(200mg,1.39mmol)和AzMA(73.5mg,0.437mmol)溶解在玻璃安瓿中的甲醇(2mL)中,并且然后添加引发剂2,2’-偶氮双(异丁腈)(AIBN,16.2mg,0.098mmol)和RAFT剂S,S’-双(α,α’-二甲基-α”-乙酸)-三硫代碳酸酯(CTA,15.4mg,0.055mmol)。将溶液用氩气吹扫,火焰密封并且在55℃下搅拌48h。将溶液首先在LH-20柱上纯化以除去未反应的低分子量化合物以得到所希望的产物。将所得共聚物(100mg)、炔烃(161mg,0.44mmol)和五水硫酸铜(55mg,0.22mmol)添加到t-BuOH(4mL)和水(4mL)的混合溶液中。将溶液用氩气鼓泡5min后,添加L-抗坏血酸钠盐(87mg,0.44mmol)。在氩气下将溶液在室温下搅拌48h。添加EDTA二钠和NaHCO3,并且将溶液透析24小时,并且然后冻干。将粗化合物溶解在甲醇中并且通过LH-20柱纯化以得到最终产物。
实施例4
5.ProGel-芹黄素的合成
方案7.可点击芹黄素的合成
将芹黄素(200mg,0.74mmol)溶解在DMF(3mL)中,并且然后添加K2CO3(102mg,0.74mmol)和溴乙酸乙酯(124mg,0.74mmol)。将混合物在室温下搅拌过夜。然后将反应用水淬灭并且将溶液用EA(20mL×3)萃取。将有机相经Na2SO4干燥,过滤,浓缩,并且通过快速柱色谱法(MeOH/DCM=1:50)纯化以得到相应产物(130mg,产率:50%)。1H NMR(400MHz,DMSO-d6):δ(ppm)=12.96(s,1H),10.39(s,1H),7.95(d,J=8.75Hz,2H),7.09(d,J=8.75Hz,2H),6.93(s,1H),6.80(d,J=2.05Hz,1H),6.40(d,J=2.05Hz,1H),4.92(s,2H),4.18(q,2H),1.23(t,J=7.1Hz,3H)。
将酯(100mg,0.28mmol)溶解在混合溶液(甲醇/H2O=4mL/4mL)中。添加K2CO3(193mg,1.4mmol),并且将溶液在70℃下搅拌3h。通过TLC监测反应并且进行直到起始材料完全消失。然后将溶液浓缩至2mL并且用HCl溶液酸化至pH=2,将混合物用DCM(10mL×3)萃取。将有机相经Na2SO4干燥,过滤,浓缩,并且通过快速柱色谱法(MeOH/DCM/HOAc=1:5:0.05)纯化以得到相应产物(83mg,产率:90%)。1H NMR(400MHz,DMSO-d6):δ12.95(s,1H),10.50(s,1H),7.97(d,J=8.7Hz,2H),6.93(d,J=8.7Hz,2H),6.85(s,1H),6.75(d,J=1.75Hz,1H),6.37(d,J=1.75Hz,1H),4.80(s,2H)。
将酸(150mg,0.46mmol)溶解在无水DMF(4mL)中,并且然后添加DIPEA(119mg,0.92mmol)和HATU(350g,0.92mmol)。将溶液搅拌5min,添加丙-2-炔-1-胺(50.6mg,0.92mmol)并且将溶液搅拌过夜直到起始材料完全消失。添加水,并且将溶液用EA(20mL×3)萃取,并且将合并的有机溶液用盐水洗涤。将有机相经Na2SO4干燥,过滤,浓缩,并且通过快速柱色谱法(MeOH/DCM=1:10)纯化以得到呈黄色固体的相应产物(117mg,70%)。1H NMR(400MHz,DMSO-d6):δ(ppm)=12.96(s,1H),10.39(s,1H),8.65(t,J=5.55Hz,1H)7.95(d,J=8.75Hz,2H),6.93(d,J=8.7Hz,2H),6.85(s,1H),6.78(d,J=2.1Hz,1H,),6.41(d,J=2.1Hz,1H),4.65(s,2H),3.94(s,2H),3.17(s,2H)。
方案8.ProGel-芹黄素的合成
6.ProGel-芹黄素的合成
将HPMA(200mg,1.39mmol)和AzMA(73.5mg,0.437mmol)溶解在玻璃安瓿中的甲醇(2mL)中,然后添加引发剂2,2’-偶氮双(异丁腈)(AIBN,16.2mg,0.098mmol)和RAFT剂S,S’-双(α,α’-二甲基-α”-乙酸)-三硫代碳酸酯(CTA,15.4mg,0.055mmol)。将溶液用氩气吹扫,火焰密封并且在55℃下搅拌48h。将溶液首先通过LH-20柱纯化以除去未反应的低分子量化合物。将所得共聚物(100mg)、炔烃(202mg,0.44mmol)和五水硫酸铜(55mg,0.22mmol)添加到t-BuOH(4mL)和水(4mL)的混合溶液中。将溶液用氩气鼓泡5min后,添加L-抗坏血酸钠盐(87mg,0.44mmol)。在氩气下将溶液在室温下搅拌48h。添加EDTA二钠和NaHCO3,并且将溶液透析24小时,并且然后冻干。将粗化合物溶解在甲醇中并且通过LH-20柱纯化以得到纯化的ProGel-芹黄素。
实施例5
7.ProGel-雌二醇的合成
方案9.ProGel-雌二醇的合成
将MA-Gly-Gly-OH(200mg,1mmol)和雌二醇(272mg,1mmol)溶解在无水DMF(5mL)中。将溶液冷却至0℃并且然后添加DCC(309mg,1.5mmol)和DMAP(24mg,0.2mmol)。将溶液在0℃下搅拌5小时。添加乙酸乙酯(100mL)并且将溶液用盐水(50ml x 4)洗涤。然后将有机相经硫酸钠干燥,并且然后除去溶剂。将残余物通过柱色谱法纯化以得到产物(350mg)。
1H NMR:(500MHz,DMSO-d6)δ(ppm)=8.37(t,J=5.8Hz,1H),8.21(t,J=5.9Hz,1H),7.30(d,J=8.5Hz,1H),6.83(d,J=8.5Hz,1H),5.75(s,1H),5.38(s,1H),4.52(d,J=4.8Hz,1H),4.08(d,J=5.8Hz,2H),3.79(d,J=5.9Hz,2H),3.54(m,1H),2.79(m,2H),2.29(d,J=11.9Hz,1H),2.17(t,J=10.6Hz,1H),1.88(s,3H),1.86(m,3H),1.71(m,1H),1.60(m,1H),1.0-1.40(m,7H),0.67(s,3H)。
将HPMA(120mg,0.84mmol)、MA-Gly-Gly-雌二醇(53mg,0.12mmol)、AIBN(0.81mg,0.0050mmol)和CTA(1.38mg,0.0050mmol)溶解在安瓿中的无水DMF(1.24mL)中。通过氩气吹扫1min后,将安瓿密封并且置于63℃油浴中48h。然后将溶液通过LH-20纯化以得到产物。在0℃下用4mL水溶解产物。冻干后,获得42mg最终产物。
实施例6
8.ProGel-黄体酮的合成
方案10.ProGel-黄体酮的合成
将APMA-TERE-OMe(化合物1,912mg,3mmol)溶解在甲醇(10mL)中,添加KOH(0.5mL,10M)和水(2mL)。将溶液在室温下搅拌过夜。然后除去溶剂,并且然后将残余物溶解在甲醇(10mL)中并且用浓氯化氢溶液中和至pH=1。然后再次除去溶剂,并且将残余物通过柱色谱法纯化以得到产物2(840mg,96%)。
将黄体酮(化合物2,628mg,2mmol)溶解在甲醇(10mL)中,并且将溶液冷却至0℃。添加NaBH4(152mg,4mmol)。将溶液在0℃下搅拌2h。添加乙酸乙酯(100mL)并且用盐水(80mL×3)洗涤。将有机相经Na2SO4干燥,并且除去溶剂以获得产物3(620mg)。
1H NMR:(500MHz,DMSO-d6)δ(ppm)=5.17(s,1H),4.53(d,J=5.6Hz,1H),4.07(d,J=5.6Hz,1H),3.90(m,1H),3.46(m,1H),2.14(m,2H),1.92(m,1H),1.74(m,1H),1.66(m,1H),1.61(m,1H),1.53(m,2H),1.0-1.4(m,9H),0.98(s,3H),0.93(s,3H),0.90(m,1H),0.81(m,1H),0.69(s,3H),0.67(m,1H)
13C NMR:(125MHz,DMSO-d6)δ(ppm)=144.5,125.5,68.48,66.19,57.87,55.52,54.50,42.22,36.96,35.59,35.55,33.11,31.84,29.28,25.47,24.37,23.95,20.64,18.72,12.20
然后将粗产物溶解在无水二氯甲烷(20mL)中。添加MnO2(2.6g,30mmol)并且将溶液搅拌过夜。过滤后,然后将溶液浓缩,并且通过柱色谱法纯化以得到产物4(570mg,产率:两个步骤90.7%)。
1H NMR:(500MHz,DMSO-d6)δ(ppm)=5.65(s,1H),3.65(m,1H),2.35(m,2H),2.21(m,1H),2.06(dt,J=12.8Hz,3.3Hz),1.95(dt,J=13.2Hz,3.3Hz),1.77(m,1H),1.35-1.65(m,6H),1.27(q,J=9.0Hz,1H),1.16(d,J=5.5Hz,1H),1.12(s,3H),1.10(m,1H),1.07(d,J=6.1Hz,1H),0.96(m,2H),1.13(td,J=11.4Hz,3.9Hz,1H),0.73(s,3H),
13C NMR:(125MHz,DMSO-d6)δ(ppm)=199.54,171.48,123.65,70.24,58.21,55.25,53.73,42.25,39.51,38.53,35.58,35.35,33.85,32.79,31.97,25.49,24.34,23.64,20.80,17.28,12.29
将化合物4(1.58g,5mmol)和一水合肼(1.5g)溶解在甲醇(20mL)中。将溶液在室温搅拌1h。添加乙酸乙酯(100mL),并且将溶液用盐水(50mL×4)洗涤。然后将有机相经Na2SO4干燥,并且然后除去溶剂。将残余物通过柱色谱法纯化以得到产物5(1.08g)。
将化合物5(330mg,1mmol)、DCC(309mg,1.5mmol)、HOBt水合物(306,2mmol)和Et3N(202mg,2mmol)溶解在DMF(10mL)中,并且然后将溶液冷却至0℃。添加化合物1,并且将溶液在0℃下搅拌4小时。添加乙酸乙酯(100mL),并且将溶液用盐水(60mL×4)洗涤。然后将有机相经Na2SO4干燥,并且除去溶剂。将残余物通过柱色谱法纯化以得到产物5(282mg)。
将化合物6(280mg,0.47mmol)和Et3N(237mg,5mmol)溶解在二氯甲烷和DMSO(6mL,5:1)的溶液中。添加SO3吡啶(224mg,1.41mmol)。将溶液搅拌2h并且通过Na2S2O3溶液淬灭。添加乙酸乙酯(50mL),并且将溶液用盐水(40mL×4)洗涤。然后将有机相经Na2SO4干燥,并且除去溶剂。将残余物通过柱色谱法纯化以得到产物7(162mg)。
将HPMA(80mg,0.56mmol)和化合物7(48mg,0.079mmol)、AIBN(1.40mg,0.0086mmol)和CTA(2.39mg,0.0086mmol)溶解在安瓿中的甲醇(1.1mL)中。通过氩气吹扫1min后,将安瓿密封并且置于63℃油浴中48h。然后将溶液通过LH-20纯化以得到最终产物(86mg)。
实施例7
9.ProGel-青藤碱的合成
方案11.ProGel-青藤碱的合成
将HPMA(600mg,4.19mmol)、APMA-Terephlate-OMe(219mg,0.72mmol)、CTA(46.3mg,0.16mmol)和AIBN(48.4mg,0.30mmol)溶解在甲醇(6mL)中。然后将溶液转移到安瓿中并且通过氩气鼓泡1min。然后将安瓿密封并且置于加热的油浴(55℃)中。将溶液搅拌48h。通过LH-20分离和冻干后,获得聚合物(640mg)。
将聚合物(320mg)和一水合肼(300mg)溶解在甲醇(10mL)中并且搅拌过夜。除去溶剂,并且将残余物通过LH-20纯化。将产物冻干以获得酰肼聚合物(260mg)。
将含有酰肼的HPMA共聚物(100mg)、HOAc(4mg)和青藤碱(200mg)溶解在甲醇(2mL)中并且搅拌40h。然后将溶液过滤,并且将滤液通过LH-20纯化以除去小分子。冻干后,获得110mg产物。
实施例8
10.ProGel-氢化吗啡酮的合成
方案12.ProGel-氢化吗啡酮的合成
将含有酰肼的HPMA共聚物(100mg)、HOAc(3mg)和氢化吗啡酮(100mg)溶解在甲醇(2mL)中并且搅拌40h。然后将溶液过滤,并且将滤液通过LH-20纯化以除去小分子。冻干后,获得105mg产物。
ProGel-Dex的表征
用配备有多角度激光散射(MALS,Wyatt)和Optilab T-rEX折光率检测器(Wyatt)的纯快速蛋白液相色谱法(FPLC)系统使用尺寸排阻色谱法(SEC,Superdex 75 10/300GL,流动相在1×PBS中的30%乙腈)来确定共聚物的重均分子量(Mw)和多分散性指数(PDI)。为了定量ProGel-Dex中的Dex含量,将共聚物(2mg/mL)在50%甲醇中的0.2N HCl中水解过夜。将所得溶液使用在50%甲醇中的0.2N NaOH中和并且在具有反相分析型C18柱(InfinityLab Poroshell 120EC-C18,4.6x 250mm,2.7μm,流动相,乙腈/水4:6;检测,UV240nm;流速,1mL/min;注射体积,10μL)的Agilent1260Infinity II HPLC系统上基于Dex标准曲线进行分析。一式三份地进行分析。使用Excel获得平均值和标准偏差。
使用动态光散射来表征流体动力学直径(Dh),并且使用Malvern ZetasizerNano-ZS表征电位变化。将ProGel-Dex以200mg/mL溶解在ddH2O中。在4℃、8℃和12℃下以角度一式三份地确定聚合物组装物(例如,胶束)的直径。在测量前,以15-min平衡时间设定温度。通过Zetasizer软件7.12版分析数据。
ProGel-Dex溶胶-凝胶相变温度的确定
使用小瓶标题(titling)方法测量具有不同参数(Dex含量和ProGel-Dex浓度)的ProGel-Dex的相变温度(Kashyap,N.等人,Design and evaluation of biodegradable,biosensitive in situ gelling system for pulsatile delivery ofinsulin.Biomaterials,2007.28(11):第2051-2060页)。将含有ProGel-Dex的玻璃小瓶放置在装配有水循环泵的冷水浴中,以使温度均匀升高。将精度为0.1℃的温度计浸入玻璃小瓶中,并且确定每种ProGel-Dex的相变温度。
流变特性表征
使用流变仪(具有20mm平行板的DHR-2,TA Instrument,美国)评估ProGel-Dex的流变行为。在10rad/s的固定频率和0.5%的应变下进行振荡温度斜坡(4℃-40℃),加热速率为0.5℃/min。流变参数在线性粘弹性范围(LVR)内。在30℃和10rad/s下进行振荡应变扫描(0.01%-100%)。在30℃下进行流动剪切速率扫描(0.006-1000 1/s)。所有样品厚度均为500μm。胶凝化温度(T凝胶)是指在温度斜坡实验期间在第一温度下储能模量(G’)等于损耗模量(G”)的温度。剪切屈服应力被定义为在振荡应变扫描实验中G’等于G”时的应力。在剪切速率扫描实验中确定粘度。
ProGel-Tan的表征
为了确定聚合物中丹参酮IIA的含量,我们使用UV-Vis光谱法分析含量。我们选择480nm作为波长,因为在此波长处将不会检测到聚合物载体的紫外吸收。基于丹参酮单体的标准曲线确定丹参酮含量。
在不同的pH(4.5、6.0和7.4)下评估ProGel-Tan的体外释放速率。在第1、2、4、7、14和30天确定释放的丹参酮浓度。
多关节佐剂诱导的关节炎(AA)大鼠模型
使用来自Charles River Laboratories(威尔明顿,马萨诸塞州,美国)的雄性Lewis大鼠(175-200g)建立AA大鼠模型。简而言之,大鼠经由在大鼠尾巴的基部皮下(s.c.)注射而接受一种在石蜡油(100μL)中含有热杀死的结核分枝杆菌(mycobacteriumtuberculosis)(H37RA,1mg)和N,N-双十八烷基-N’,N’-双(2-羟乙基)-1,3-丙二胺(LA,5mg)的佐剂混合物。从免疫后第11天起观察发炎的关节。建立的AA大鼠在第14天达到炎症平台,然后随机分为3组:1.盐水处理组(208.3μL/kg);2.ProGel-Dex处理组(在盐水中20w/v%,Dex的剂量当量=10mg/kg,208.3μL/kg);3.游离Dex处理组(在盐水中的地塞米松磷酸钠63.4mg/mL,Dex当量剂量:10mg/kg,208.3μL/kg)。所有处理均在诱导后第14天经由单次关节内注射至右脚踝。将另外一组健康大鼠用作阴性对照。从第11天起每天监测关节炎症和体重变化。
单关节佐剂诱导的关节炎(MAA)大鼠模型
雄性Lewis大鼠(175-200g)购自Charles River Laboratories(威尔明顿,马萨诸塞州)。如先前所述建立单关节佐剂诱导的关节炎(Weber,L.等人,The Development of aMacromolecular Analgesic for Arthritic Pain.Molecular Pharmaceutics,2019)。简而言之,大鼠在它们背上的不同位点处皮下接受两次佐剂免疫,间隔为一周。佐剂混合物含有甲基化牛血清白蛋白(mBSA,2mg/mL,在水中,0.25mL)和热杀死的结核分枝杆菌(H37RA,2mg/mL,在石蜡油中,0.25mL)。第二次免疫后两周,大鼠在右膝关节中接受mBSA(10g/L,在水中,50μL)的加强i.a.(关节内)注射。在加强注射的第二天开始处理,此时通过关节肿胀的存在证实在右膝关节中关节炎的开始。在第0天将患有建立的关节炎的大鼠随机分配到以下处理组中:1.盐水处理组(208.3μL/kg);2.ProGel-Dex处理组(在盐水中20w/v%,Dex的剂量当量=10mg/kg,208.3μL/kg);3.游离Dex处理组(在盐水中的地塞米松磷酸钠63.4mg/mL,Dex当量剂量:10mg/kg,208.3μL/kg)。包括匹配的健康对照大鼠。使用数字游标卡尺测量大鼠膝关节的宽度。测量以下疼痛相关行为:无能测试和压力施加测量(PAM)。每周通过尾动脉收集血液样品并且分析CBC、肝脏和肾脏功能测试。从全血样品中分离出血清样品并且储存在-20℃以供进一步评价。在第21天将大鼠安乐死。收集组织/器官(心脏、肾脏、肝脏、脾脏、肺、肾上腺),称重并且固定在中和的福尔马林中用于未来的毒性评价。还收集后腿并且固定在中和的福尔马林中,用于进一步的显微CT分析和形态分析。
单碘乙酸盐(MIA)诱导的骨关节炎模型诱导
将来自Charles River Laboratories(威尔明顿,马萨诸塞州)的九周龄CD-1小鼠用于MIA模型。在麻醉下,小鼠经由关节内注射到右膝关节而接受单碘乙酸盐(MIA,0.3mg/10μL/小鼠)。为了更好地分散MIA,将膝关节手动伸展和弯曲30秒。在MIA注射后的第二天建立MIA模型。然后将小鼠随机分配到以下处理组中:1.盐水处理组(416.6μL/kg);2.ProGel-Dex处理组(在盐水中20w/v%,Dex的剂量当量=20mg/kg,416.6μL/kg);3.游离Dex处理组(在盐水中的地塞米松磷酸钠63.4mg/mL,Dex当量剂量:20mg/kg,416.6μL/kg)。将另外的小鼠用作健康对照。使用数字游标卡尺测量膝关节宽度。测量以下疼痛相关行为:无能测试和压力施加测量。安乐死后,经由心脏穿刺收集血液样品,以用于CBC、肝脏和肾脏功能测试。从血液样品的其余部分中分离出血清样品并且储存在-20℃以供进一步评价。
ProGel-Dex生物分布
将IRDye 800CW标记的ProGel-Dex(ProGel-Dex-IRDye)和ProGel-Dex混合并且在第0天施用于MAA大鼠(n=5)(IRDye剂量=4.5×10-7mol IRDye/kg,Dex当量剂量=10mg/kg)。然后在指定时间点在麻醉下用Xenogen IVIS光谱体内系统对大鼠进行成像。用以下条件捕获图像:激发:778nm(滤光片:745nm);发射:794nm(滤光片:800nm);曝光时间:2s;视野:24.5cm;分箱因数(binning factor):8;f数:2。然后使用Living Image 4.5软件(PerkinElmer Inc.)分析捕获的图像。
静态重量分布
为了测试处理的镇痛作用,使用无能测试仪测量大鼠和小鼠后肢之间的静态重量分布,所述无能测试仪由两个能够测量放置在每条后肢上的体重的力传感器组成。将动物放置在设备上,它们的后爪居中于两个力传感器上,并且在3s的时间段内计算以克计的平均体重分布。负重得分表示为通过同侧肢体放置的重量与通过对侧和同侧肢体两者放置的重量的总和的比率,其中50%的比率是由于在双后肢中的重量分布相等。在模型建立前、在药物施用前以及在处理后每天测量重量分布。
机械性痛觉过敏
使用压力施加测量(PAM)来测试大鼠的机械性痛觉过敏。PAM设备由安装在装配到操作员拇指上的单元上的力传感器组成。拇指单元连接到含有控制面板和数字读数显示器的记录基础单元。所述设备具有范围为0-1500g的力传感器,并且圆形接触件的直径是5mm。鉴于设备的表面积为19.6mm2,将动物轻轻但牢固地保持,并且将操作员拇指单元放置在小鼠标膝关节的一侧,并且将食指放置在另一侧。以大约300克/秒的速率在关节上施加逐渐增加的挤压力,最大测试持续时间为5s。仪器校准后,施加的力(以克计)显示在数字屏幕上并且将其记录。当动物缩回其肢体或显示出不适或痛苦的行为迹象(诸如胡须运动僵住或扭动)时确定测试终点。记录在肢体缩回之前立即施加的峰值力,并且将此值指定为肢体缩回阈值(LWT),肢体缩回阈值用于评估每组的疼痛水平。
显微CT分析
为了评价在施用后ProGel-Dex的治疗作用和潜在毒性,从实验大鼠和小鼠中分离全腿和腰椎骨并且将其固定,用于显微CT(skyscan 1172,bruker)分析。对于小鼠骨,将扫描参数设定为55kV、181μA、8.88μm、0.5mm铝过滤器、0.4旋转步长、4帧平均和扫描。对于大鼠骨,将扫描参数设定为70kV、141μA、13.47μm、0.5mm铝过滤器、0.4旋转步长、6帧平均和扫描。在用作用于骨矿物质密度(BMD)计算的标准的每种条件下扫描两个标准钙羟基磷灰石棒。使用NRecon软件(skyscan)重建数据集并且使用CTAn软件进行分析。在分析之前,将所有数据集进行重新对齐和3D注册。选择第5腰椎或股骨远端的小梁骨作为感兴趣的区域以评价地塞米松的潜在副作用。分析跟骨或关节软骨下骨以评价治疗功效。分析小梁骨的骨矿物质密度(BMD)、小梁数量(Tb.N)和骨体积百分比(BV/TV)。
ProGel-Tan加速延迟的骨折愈合
将7周龄CD-1小鼠随机分组为健康对照组、盐水处理的延迟的骨折愈合和ProGel-Tan处理的延迟的骨折愈合。在骨折前口服施用泼尼松(12mg/kg,每日)3周以诱导骨质疏松症,用于延迟的骨折愈合模型的第一步。如先前所述建立小鼠股骨闭合性骨折模型。麻醉后,将右腿用碘垫擦洗以准备手术。产生3-mm内侧髌旁切口。将髌骨脱位以暴露股骨髁。使用25号针在髁内切迹处在股骨髓内管中钻孔。将25号针插入髓内管中以稳定即将发生的骨折。重新定位髌骨,并且使用5-0不可吸收缝线将切口闭合。然后用3点弯曲装置在右股骨中产生闭合的骨干骨折。这种方法具有最小的粉碎和髓内针的最小角度。在骨折后立即对动物进行射线照相以验证已经产生骨干中部骨折,并且然后每周进行,直到它们被安乐死。
骨折后三天,将ProGel-Tan-IRDye水凝胶(20%w/v,100uL/小鼠)局部给予ProGel-Tan处理组的骨折位点,而向盐水处理组中的小鼠给予盐水。在药物注射之前和之后立即进行LICOR成像。在第1、2、3、5、7、14、21、28和56天,拍摄图像以评估水凝胶从骨折位点的清除率。
结果
ProGel-Dex的表征
ProGel-Dex具有6.79kDa的重均分子量(Mw),PDI为1.006。ProGel-Dex的地塞米松含量是242.7±1.3mg/g。我们合成了不同地塞米松含量的聚合物ProGel-Dex-低(202.0±4.0mg/g)和ProGel-Dex-高(279.7±0.7),用于溶胶-凝胶相变表征。
ProGel-Dex溶液(在ddH2O中20w/v%)的平均流体动力学直径(Dh)(按数量计的尺寸分布)是在4℃下23.12nm,并且随着温度升高而增加至在8℃下31.58nm、在12℃下53.38nm和在16℃下77.85nm,与胶束的温度依赖性聚集一致(图1)。当温度达到高于16℃时,ProGel-Dex溶液变得混浊,与大组装物的形成一致,其不再适合进一步的光散射分析。然而,当ProGel-Dex溶液浓度制备为10w/v%和30w/v%时,溶液变得不稳定,在所有分析温度下均观察到不均匀的平均流体动力学直径(Dh)。
ProGel-Dex溶胶-凝胶相变图
将ProGel-Dex、ProGel-Dex-低和ProGel-Dex-高溶解在300μL蒸馏水中以制备不同浓度的溶液。将ProGel-Dex样品在4℃水浴中孵育,并且使温度逐渐升高。使用精度为0.1℃的数字温度计来监测温度。通过小瓶倒置法以2℃的步进增加来确定转变温度。将小瓶倒置15秒;并且如果没有可见的溶液流动性,则认为已发生胶凝化。记录胶凝化温度并且相变图绘制在图2中。
流变特性表征
在30℃下在流动剪切速率扫描(0.0001-1000 1/s)实验中确定粘度。在0.0025 1/s剪切速率下的粘度是21845.5Pa.s。在10rad/s的频率下的应变扫描(0.01%-100%)期间获得屈服应力。屈服应力是51.4064Pa。在振荡温度斜坡实验中确定胶凝化温度点。在10rad/s的频率和0.5%的应变下,胶凝化温度为21.892℃(参见图3)。在发生脱水收缩的33.492℃下记录G’和G”的另一个交叉。当向上移动几何形状时,在水凝胶上方观察到透明流体薄层,这与在相变实验中观察到的现象相关。
治疗性评价
AA模型
光学成像证明在注射后4周IRDye 800CW标记的ProGel保留在发炎的膝盖中(图4)。无法检测到在非靶器官/组织中IRDye 800CW标记的ProGel-Dex的分布,除了在肾脏中非常低的水平(图5),这与预期的低的关节外前药暴露量和前药的肾脏清除率一致。
对于治疗作用,ProGel-Dex处理的动物显示出明显的炎症消退,如通过发炎的踝部的直径递减所指示(图6)。
MAA模型
ProGel-Dex在MAA大鼠中显示出持续的抗炎作用,导致关节肿胀的改善(图7)。PAM(图8)和无能测试(图9)与关节疼痛的快速消退(3天)一致,并且这种作用持续到ProGel-Dex施用后最高第28天。右侧股骨的次级松质骨的显微CT分析显示在ProGel-Dex处理的动物中保留了骨的微构造(图10)。图11示出了来自四个组(健康组、Dex处理组、ProGel-Dex处理组和盐水处理组)的MAA膝关节的代表性显微CT图像。
MIA模型
ProGel-Dex处理在施用后3天内改善了单碘乙酸盐诱导的骨关节炎(MIA)小鼠的关节炎症(图12)并且减轻了关节疼痛,并且这种作用持续到最高第28天(图13)。基于膝关节的重建代表性显微CT图像,ProGel-Dex处理导致保留关节周围骨结构(图14)。
ProGel安全性评价
AA模型
在所有模型中都没有检测到响应于ProGel-Dex关节内沉积的急性炎性反应的迹象。基于在AA模型中的显微CT分析(图15),没有证据表明GC诱导的腰椎骨质减少。
MAA模型
进行全面的血液学和肝脏和肾脏分析以评估ProGel-Dex的安全性。ProGel-Dex处理显示对血液学概况或肝脏和肾脏功能概况没有显著的毒性作用(图16和17)。与其他治疗组相比,在用ProGel-Dex处理的MAA大鼠中观察到显著更低的肾上腺重量(图18)。
MIA模型
在安乐死后分析血液学和肝脏和肾脏功能测试。在ProGel-Dex处理组中,血液学和肝脏和肾脏功能概况显示没有显著的毒性证据(图19和20)。
在用ProGel-Dex处理的MIA小鼠的肾上腺重量中没有观察到统计学上显著的差异(图21)。
ProGel-Tan表征
ProGel-Tan的丹参酮含量是160mg/g。当温度升高时,ProGel-Tan形成水凝胶。对于具有20%w/v浓度的ProGel-Tan,其粘度在35℃下急剧增加。然后在37℃下,形成水凝胶。对于具有25%w/v浓度的ProGel-Tan,其粘度在30℃下增加,并且在35℃下形成水凝胶(图22)。
在pH 4.5下,释放速率相对快,平均大约1.4%/天,而在pH 6.0下,释放速率约0.6%/天(图23)。在pH 7.4下,释放缓慢得多,并且一个月仅释放5%的Tan。这证实了pH敏感性腙键作为接头的有效性。
图24和25证明,骨痂内注射的ProGel-Tan在骨痂注射位点处持续至少1个月。除了在肝脏中可检测的存在外,ProGel-Tan信号在所有其他器官/组织检查中都低。
骨痂面积的射线照相分析和定量评估证明,健康的和ProGel-Tan处理的动物两者共有在时间上相似的愈合过程,与盐水处理的小鼠的愈合延迟形成对比(图26和27)。
总而言之,用ProGel-Dex和ProGel-Tan的体内研究令人信服地证明,作为局部位点特异性递送媒介物的ProGel技术平台在一系列病理病症(包括炎性关节炎、OA和骨折愈合)中具有广泛的效用。我们将ProGel前药的功效归因于它们在局部注射位点形成凝胶的独特能力以及凝胶用作在延长的时间段内持续的活性药物释放的贮库。重要地,这种作用机制导致全身药物分布的明显减少,从而避免了潜在的脱位点非靶器官毒性。
出于所有目的,将本文引用的所有参考文献通过引用以其整体并入。虽然在以上实施例中描述了若干个实施方案,但本领域普通技术人员应理解,在不脱离如由以下权利要求所定义的本公开文本的精神和范围的情况下,可以在形式和细节上进行各种改变。
Claims (26)
1.一种热响应性聚合物-药物缀合物,其包含与水溶性聚合物载体共价键合的疏水性药物分子部分,其中所述聚合物-药物缀合物在第一温度下可溶于水并且在高于第一温度的第二温度下可以形成前药水凝胶(ProGel),其中所述聚合物-药物缀合物具有取决于选自所述药物分子部分的含量、所述聚合物载体的构造、所述聚合物载体的分子量、和所述缀合物的浓度及其组合的条件的相变图。
2.根据权利要求1所述的热响应性聚合物-药物缀合物,其中所述聚合物载体是合成的不可降解聚合物,所述合成的不可降解聚合物选自N-(2-羟丙基)-甲基丙烯酰胺(HPMA)共聚物、聚乙二醇、聚噁唑啉、和包含一种或多种单体的水溶性共聚物,所述一种或多种单体选自N-(2-羟丙基)甲基丙烯酰胺、N-异丙基丙烯酰胺、丙烯酰胺、N,N-二甲基丙烯酰胺、N-乙烯基吡咯烷酮、乙酸乙烯酯、2-甲基丙烯酰氧基乙基葡糖苷、丙烯酸、甲基丙烯酸、乙烯基膦酸、苯乙烯磺酸、马来酸、2-甲基丙烯酰氧基乙基三甲基氯化铵、甲基丙烯酰胺基丙基三甲基氯化铵、甲基丙烯酰胆碱硫酸甲酯、N-羟甲基丙烯酰胺、2-羟基-3-甲基丙烯酰氧基丙基三甲基氯化铵、2-甲基丙烯酰氧基乙基三甲基溴化铵、2-乙烯基-1-甲基溴化吡啶鎓、4-乙烯基-1-甲基溴化吡啶鎓、乙烯亚胺、(N-乙酰基)乙烯亚胺、(N-羟乙基)乙烯亚胺、烯丙胺及其组合。
3.根据权利要求1所述的热响应性聚合物-药物缀合物,其中所述聚合物载体是可生物降解聚合物,所述可生物降解聚合物选自壳聚糖、透明质酸、聚谷氨酸、聚天冬氨酸、葡聚糖、淀粉、藻酸盐、明胶、黄原胶、果胶、角叉菜胶、瓜尔豆胶、纤维素醚(例如,羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、羟乙基纤维素(HEC)、和羧甲基纤维素钠(Na-CMC))。
4.根据权利要求1所述的热响应性聚合物-药物缀合物,其中所述聚合物载体是包含N-(2-羟丙基)甲基丙烯酰胺单体单元的共聚物。
6.根据权利要求5所述的热响应性聚合物-药物缀合物,其中
R1和R2各自是H或甲基;
R3是被一个或两个OH基团取代的C2-C5烷基;
L是-[NH(CH2)iC(O)]j-、-NH(CH2)k-、-NH(CH2)k-T-(CH2)p-、-NH(CH2)kNHC(O)-、-NH(CH2)kNH-(CH2)p-T-(CH2)q-C(O)-、或-NH(CH2)kNHC(O)-(CH2)p-T-(CH2)q-C(O)-,其中T是C6-C10亚芳基、C3-C8亚环烷基、5至10元亚杂芳基、或5至10元亚杂环烷基,其中i是选自1至6的整数;j是选自1至4的整数;k是选自1至10的整数;p是0、1、2或3;
并且q是0、1、2或3;
Y是O、NH、或NH-N=(其中“=”是双键);并且
Z是NH。
7.根据权利要求6所述的热响应性聚合物-药物缀合物,其中
i是1或2;
i是1、2或3;
k是选自1至6的整数;
p是0、1或2;
q是0、1或2。
8.根据权利要求5至7中任一项所述的热响应性聚合物-药物缀合物,其中L是-[NHCH2C(O)]j-、-NH(CH2)k、-NH(CH2)k-T-CH2-、或-NH(CH2)kNHC(O)-T-C(O)-,其中T在每次出现时独立地是C6-C10亚芳基或5至10元亚杂芳基;j是2或3;并且k是2、3或4。
10.根据权利要求1至9中任一项所述的热响应性聚合物-药物缀合物,其中所述药物分子选自:糖皮质激素(例如,皮质醇或氢化可的松、可的松、泼尼松、泼尼松龙、甲基泼尼松龙、倍他米松、去炎松、醋酸氟氢可的松等)、非甾体抗炎药(NSAID)(例如,阿司匹林、布洛芬、吲哚美辛、吡罗昔康、甲芬那酸、罗美昔布、利克飞龙、青藤碱等)、镇痛药(例如,氢化吗啡酮、羟考酮、青藤碱、辣椒素、树酯毒素等)、骨合成代谢剂(例如,GSK抑制剂、丹参酮IIA、他汀类、前列腺素E1、E2和前列腺素EP受体激动剂等)、抗氧化剂(例如,丹参酮IIA、姜黄素、维生素E、芹黄素等)、抗癌剂(例如,紫杉醇、喜树碱、多西他赛、阿霉素、激酶通路抑制剂(例如,细胞质酪氨酸激酶)、甲氨蝶呤等)、激素(例如,睾酮、雌二醇、黄体酮等)、和抗生素(例如,氟喹诺酮、大环内酯类、头孢菌素、和芹黄素,它们共有抗氧化和抗细菌活性等)。
11.根据权利要求1至9中任一项所述的热响应性聚合物-药物缀合物,其中所述药物分子选自地塞米松、丹参酮IIA、黄体酮、雌二醇、姜黄素、氢化吗啡酮、青藤碱、和芹黄素。
14.根据权利要求13所述的热响应性聚合物-药物缀合物,其为聚合物-地塞米松缀合物(ProGel-Dex),其中Dex的含量在约15-40wt%的范围内,所述ProGel-Dex的浓度在约10-50w/v%的范围内,并且所述ProGel-Dex的分子量在约1-45kDa的范围内。
15.根据权利要求13所述的热响应性聚合物-药物缀合物,其为聚合物-丹参酮IIA缀合物(ProGel-Tan),其中所述ProGel-Tan包含在约12-40wt%的范围内的丹参酮IIA;其中ProGel-Tan的浓度在约10-50w/v%的范围内;并且所述ProGel-Tan的分子量在约1-45kDa的范围内。
16.一种药物组合物,其包含根据权利要求1至15中任一项所述的热响应性聚合物-药物缀合物和一种或多种药学上可接受的载体和赋形剂。
17.一种治疗疾病或障碍的方法,其包括向需要治疗的受试者施用治疗有效量的根据权利要求1至15中任一项所述的热响应性聚合物-药物缀合物或根据权利要求16所述的药物组合物,其中在适用的情况下,所述疾病或障碍是类风湿性关节炎、骨关节炎、软组织(例如,肌腱、韧带、囊)炎症和/或损伤、牙周骨质流失、局部感染和组织脓肿、延迟的骨折愈合、神经系统障碍(例如,创伤性脑损伤、帕金森病等)、恶性肿瘤(例如,肝脏、肺、脑肿瘤或转移等)、区域性疼痛(例如,颞下颌关节疼痛、牙痛、背痛、手术后疼痛等)、听力损失、缺血性心脏病、异位骨化、骨科关节植入物松动、生殖功能障碍、用于高危妊娠的激素施用、或皮肤老化。
18.一种治疗疾病或障碍的方法,其包括向需要治疗的受试者施用治疗有效量的两种或更多种根据权利要求1至15中任一项所述的ProGel-药物缀合物或根据权利要求16所述的药物组合物,以便实现协同作用,其中所述两种或更多种ProGel-药物缀合物任选地组合成一种注射配方。
19.根据权利要求18所述的方法,其中所述ProGel-药物缀合物选自ProGel-抗生素、ProGel-抗炎药和ProGel-骨合成代谢剂,并且它们一起组合成用于治疗牙周炎和相关骨质流失的单一ProGel配制品。
20.根据权利要求18所述的方法,其中所述ProGel-药物缀合物是ProGel-阿片类药物和ProGel-抗炎药,所述ProGel-阿片类药物和ProGel-抗炎药组合成一种用于治疗诸如背痛等疼痛的单一ProGel配制品。
21.根据权利要求17至20中任一项所述的方法,其中所述一种或多种ProGel-药物缀合物通过关节内、皮内、腹膜内、肌肉内、玻璃体内、阴道内、颅内、硬膜外、心内或肌肉骨骼软组织(例如,肌腱、韧带、囊)施用,其中所述ProGel的能力保留在组织位点,例如皮下组织,从而缓慢释放活性药物。
22.根据权利要求17至20中任一项所述的方法,其中将所述一种或多种ProGel-药物缀合物配制成喷雾剂,所述喷雾剂可以应用于开放性伤口或手术野或者应用于发炎皮肤于例如湿疹、银屑病等炎症的位点处。
23.根据权利要求1至15中任一项所述的热响应性聚合物-药物缀合物在制造用于治疗疾病或障碍的药剂(例如,基于热响应性凝胶的药物递送配制品)的用途,所述疾病或障碍选自类风湿性关节炎、骨关节炎、软组织(例如,肌腱、韧带、囊)炎症和/或损伤、牙周骨质流失、局部感染和组织脓肿、延迟的骨折愈合、神经系统障碍(例如,创伤性脑损伤、帕金森病等)、恶性肿瘤(例如,肝脏、肺、脑肿瘤或转移等)、区域性疼痛(例如,颞下颌关节疼痛、牙痛、背痛、手术后疼痛等)、听力损失、缺血性心脏病、异位骨化、骨科关节植入物松动、生殖功能障碍、用于高危妊娠的激素施用、和皮肤老化等。
24.一种合成聚合物-药物缀合物的方法,其包括以下步骤:(a)通过接头将单体与药物分子共价偶联;以及(b)将步骤(a)的单体与包含极性官能团的第二单体共聚;或者可替代地,(a’)将包含极性官能团的单体与包含接头部分的第二单体共聚以形成共聚物;以及(b’)通过所述接头使所述共聚物与药物分子反应以形成聚合物-药物缀合物。
25.根据权利要求24所述的方法,其中所述聚合物-药物缀合物是ProGel-Dex,所述方法包括以下步骤:(a)使OH-保护的地塞米松衍生物与肼反应以形成地塞米松腙衍生物;(b)使步骤(a)的地塞米松衍生物与N-甲基丙烯酰基-二甘氨酸反应以形成具有式MA-Gly-Gly-NHN=Dex的单体-Dex缀合物;以及(c)将所述单体-Dex缀合物与包含一个或多个极性官能团的第二单体共聚,使得所述共聚物-Dex缀合物具有热响应特性。
26.制备如基本所述和所示的根据权利要求1至15中任一项所述的热响应性聚合物-药物缀合物的方法。
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CN114522219B (zh) * | 2022-02-23 | 2024-03-26 | 宜春学院 | 一种共递送聚合物前药及其制备方法和用途 |
WO2023212124A1 (en) * | 2022-04-26 | 2023-11-02 | University Of Maryland, Baltimore | Nanogel platform technology for long-term biologics therapy |
CN115919748B (zh) * | 2022-11-30 | 2024-05-17 | 复旦大学 | 一种基于前药的刺激响应型纳米凝胶及制备方法 |
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US20070287680A1 (en) * | 2004-05-10 | 2007-12-13 | University Of Utah Research Foundation | Combined Active and Passive Targeting of Biologically Active Agents |
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AU2019364570A1 (en) | 2021-05-20 |
IL282544A (en) | 2021-06-30 |
WO2020087057A8 (en) | 2024-01-04 |
JP2022512804A (ja) | 2022-02-07 |
US20220008543A1 (en) | 2022-01-13 |
EP3870232A4 (en) | 2022-10-12 |
EP3870232A1 (en) | 2021-09-01 |
TW202033222A (zh) | 2020-09-16 |
WO2020087057A1 (en) | 2020-04-30 |
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