CN111973754A - 含药物纳米颗粒及其制备方法和应用 - Google Patents
含药物纳米颗粒及其制备方法和应用 Download PDFInfo
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- CN111973754A CN111973754A CN201910426775.8A CN201910426775A CN111973754A CN 111973754 A CN111973754 A CN 111973754A CN 201910426775 A CN201910426775 A CN 201910426775A CN 111973754 A CN111973754 A CN 111973754A
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Abstract
一种含铂类药物纳米颗粒,多酚和铂类药物的活性分子配位络合形成纳米颗粒,酚羟基与铂的摩尔配比为20∶1~1∶20,粒径为10纳米~1000纳米。经验证,本发明提供的含铂纳米颗粒,具有更加优异的抗肿瘤能力,且毒副作用更低。
Description
技术领域
本发明一种铂药物的络合物,具体涉及一种主要以多酚和铂类药物形成的纳米颗粒,以及其制备方法和在制备抗肿瘤药物中的应用。
背景技术
顺铂、奥沙利铂等铂类药物是以DNA为靶点,通过铂离子交联DNA来拮抗其复制和转录,从而诱导细胞凋亡(Cancer Chemotherapy and Pharmacology 2016,77:1103-1124),是临床上广泛使用的有效化疗药物,被应用于乳腺癌、肝癌、睾丸癌、卵巢癌、大肠癌等的治疗。然而,小分子的铂类药物存在着药代动力学较差、毒副作用大的问题。采用纳米载体输送铂类药物是克服上述问题的方法:利用肿瘤的超通透与蓄积作用可使纳米药物在肿瘤内有效蓄积而减少药物在重要器官内的剂量,从而降低毒副作用(高分子学报.doi:10.11777/j.issn1000-3304.2019.19005)。例如,Kataoka等利用聚乙二醇-聚谷氨酸嵌段聚合物络合顺铂,得到约30纳米的负载顺铂的纳米颗粒制剂(NC-6004)。临床结果显示,NC-6004能够显著降低顺铂的毒副作用,但没有显著提升其治疗效果(British Journal OfCancer,2011,104,593~598)。因此,开发疗效更好、毒性更低的铂类药物纳米输送体系具有十分迫切的需求。
发明内容
本发明的一个目的在于提供一种含铂类药物的纳米颗粒,将多酚与铂类药物的铂离子络合形成纳米颗粒型纳米药物,降低铂类药物活性分子的细胞毒作用并提高疗效。
本发明的另一个目的在于提供一种含铂类药物的纳米颗粒,将多酚与铂类药物的铂离子络合形成纳米颗粒型纳米药物,增强铂类药物活性分子的水溶性。
本发明的再一个目的在于提供一种含铂类药物的纳米颗粒,将多酚与铂类药物的铂离子络合形成纳米颗粒型纳米药物,改善铂类药物活性分子的药代动力学。
本发明所称的多酚是一类结构上具有两个或多个酚基的植物来源和合成的化合物,植物的来源如:但不限于多巴胺、单宁酸、没食子酸、儿茶酸、丹参素、原花青素、迷迭香酸、表儿茶素、表儿茶素没食子酸酯、没食子儿茶素没食子酸酯、表没食子儿茶素没食儿酸酯,以及黄芩苷等天然多酚。合成的多酚是指由多个单酚或多酚分子为原料合成的化合物和聚合物,如:对羟基苯甲酸与丙三醇键合可制备含有三个酚基的化合物。
许多多酚也是一种有效的化学预防和抗癌药物,通过影响信号分子水平(如清除活性氧)、蛋白信号传递和蛋白的表达,调控细胞周期、生长、转化和转移的关键通路,从而抑制肿瘤生长和发展(Journal of Nutritional Biochemistry 2017,45,1~14)。同时,酚羟基与铁离子、锰离子等具有很强的配位络合作用而形成多酚/金属离子的配位复合物(Journal of Inorganic Biochemistry 2007,101,585~593)。
本发明的多酚还包括由单酚或多酚分子共价连接到聚合物上而形成的多酚聚合物。聚合物如:但不限于聚乙二醇、1~6代的树枝状聚谷氨酸、代数为1~6代的树枝状聚天冬氨酸、代数为1~6代的树枝状聚赖氨酸、线性聚谷氨酸、线性聚天冬氨酸和线性聚赖氨酸等含多个反应性基团的聚合物,这些聚合物单独或组合应用于本发明。
一个或多个所述的酚基与聚乙二醇(PEG)共价连接,如式I所示
其中,X为酯键、酰胺键、醚键、硫醚、缩酮、缩醛或席夫碱键,a为0~4的整数,b为1~5的整数;c为1~8的整数;n为2~500的整数。
本发明的含铂纳米颗粒,聚乙二醇链段的分子量为100Da~20,000Da,优选:2,000Da~10,000Da,最优选是5,000Da。
一个或多个所述的酚基与线性聚谷氨酸、线性聚天冬氨酸或线性聚赖氨酸等聚合物共价连接,如式II所示:
其中,X为酯键、酰胺键、缩酮、缩醛和席夫碱键,a为1~4的整数,b为0~4的整数,c为1~5的整数,m为1~100的整数,n为0~500。
合成的多酚化合物可由化学合成,也可由天然多酚为原料合成,其化学式如下式III所示结构:
所示式III中,端基带羧基的聚乙二醇(PEG-COOH)与含有羟基或胺基的含酚基化合物如:对羟甲基苯酚(BA)、多巴胺(DOPA)反应,或端基为羟基或胺基的聚乙二醇与含有羧基的多酚如茶儿酸(PA)、没食子酸(GA)反应制备而得。
合成的含多个酚基的化合物可由含端基为羟基、胺基或羧基的多酚与含有多个官能团(如羟基、羧基或胺基)的分子或支化型聚合物反应制备得到。如式IV所示为含多个多巴胺(DOPA)的化合物由支化谷氨酸与多巴胺反应制备得到,式V所示含多个没食子酸的化合物由支化聚赖氨酸与没食子酸(GA)反应制备。
含多个多酚分子的化合物可由反应性线性聚合物链与多酚分子反应、将多酚连接到线性聚合物上制备得到。如式VI为聚谷氨酸嵌段聚合物(PGA)与含羟基的对羟甲基苯酚(BA)、5-(2-羟基乙基)邻二酚(DAL)或含胺基的多巴胺(DOPA)反应制备,或聚赖氨酸(PEG-PLL)与含羧基的多酚如没食子酸(GA)、原茶儿酸(PA)和α-(3,4-二羟基苯)基丙烯酸(CA)反应制备得到。
式II~式VI中化合物上还可以连接其他化合物或聚合物链。含有PEG链的多酚与含铂药物形成的纳米药物在血液中的清除速度更慢。因此,作为优选,含酚聚合物链以嵌段或接枝的形式接上聚乙二醇链,如:式III~式VI中,n为>1的整数。
本发明的含铂药物纳米颗粒中的含铂类药物,可为但不限于顺铂(CDDP)和顺式-二氯(1,2-环己二胺)铂(DACH-Pt)和奥沙利铂。
一种含铂类药物纳米颗粒,多酚和铂类药物的铂离子配位络合形成,酚羟基与铂的摩尔配比为20∶1~1∶20,粒径为10纳米~1000纳米。
调节酚羟基与铂的摩尔比能实现对颗粒粒径的调节,为使络合形成的颗粒粒径小于200纳米,本发明优先选择1∶1~1∶5。
一种制备含铂类药物纳米颗粒的制备方法:将多酚化合物溶于水中,然后加入铂类化合物进行配位络合,调节pH至6.0~10.0(如:7.0~10.0或8.0~9.0),25℃~40℃(如:37℃)形成酚/铂络合的纳米颗粒。所述酚羟基与铂的摩尔配比为20∶1~1∶20。通过调节多酚/铂的比例来调控所形成纳米颗粒的粒径。
本发明提供的含铂纳米颗粒具有对人乳腺癌、肝癌、睾丸癌、卵巢癌和大肠癌等肿瘤的治疗作用,用于抗癌药物的制备。
本发明提供的多酚/铂纳米药物中,多酚本身具有很好的生物相容性、清除活性氧自由基和抗肿瘤作用,与铂类药物形成具有更高的抗肿瘤活性、低毒副作用的纳米药物,成分简单、制备过程简便。
附图说明
图1为实施例3中单宁酸/二氯环己二胺合铂(TA/DACH-Pt)说形成的纳米药物的粒径分布图;
图2为实施例3中PEG-没食子酸多酚(PEG-GA,PEG的分子量为5000)/顺铂形成的纳米药物的粒径分布图;
图3为本发明实施例4中PEG-没食子酸多酚(PEG-GA,PEG的分子量为5000)/顺铂(PEG-GA/CDDP)形成的纳米药物的药物释放图;
图4为实施例5中单宁酸/二氯环己二胺合铂(TA/DACH-Pt)形成的纳米药物对Hela细胞的细胞毒性图;
图5为实施例5中的PEG-没食子酸多酚(PEG-GA和PEG-GA2,PEG的分子量为5000)/顺铂(PEG-GA/CDDP和PEG-GA2/CDDP)形成的纳米药物对不同肿瘤细胞的细胞毒性图;
图6为实施例6中单宁酸/二氯环己二胺合铂(TA/DACH-Pt)形成的纳米药物在小鼠血浆中随时间的浓度曲线;二氯环己二胺合铂(DACH-Pt)为对照;
图7为实施例6中PEG-没食子酸多酚(PEG-GA和PEG-GA2,PEG的分子量为5000)/顺铂(PEG-GA/CDDP和PEG-GA2/CDDP)纳米药物在小鼠血浆中随时间的浓度曲线;顺铂CDDP为对照;
图8为实施例7中PEG-没食子酸多酚(PEG-GA和PEG-GA2,PEG的分子量为5000)/顺铂(PEG-GA/CDDP和PEG-GA2/CDDP)纳米药物对小鼠乳腺癌4T1肿瘤的抑瘤能力:(a)肿瘤生长曲线,(b)为22天时各组的平均瘤重,(c)为实验期间各组小鼠的平均体重。PBS组为未治疗组对照,CDDP组为阳性对照。
具体实施方式
以下详细描述本发明的技术方案。本发明实施例仅用以说明本发明的技术方案而非限制。尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的精神和范围,其均应涵盖在本发明的权利要求范围中。
实施例1具有聚乙二醇的多酚分子的合成
(1)PEG-DOPA(或BA)的合成。将5.0g端基为羧基的聚乙二醇(PEG-COOH)、0.31g多巴胺(DOPA)、0.19g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和0.12gN-羟基琥珀酰亚胺(NHS)溶于20mL DMF中,冷却到0℃,搅拌反应2h并在室温下反应48h,结束反应用无水乙醚沉淀,洗涤、过滤、干燥即得连有PEG链的多巴胺PEG-DOPA。PEG-BA可以用相同的方法制备。
(2)PEG-PA(GA或CA)的合成。将5.0g端基为胺基的聚乙二醇、0.31g原茶儿酸(PA)或没食子酸(GA)、0.19g EDC和0.12g NHS溶于20mL DMF中,冷却到0℃反应2h,室温反应48h,结束反应用无水乙醚沉淀,洗涤、过滤、干燥即得连有PEG链的原茶儿酸PEG-PA或没食子酸PEG-GA。
(3)PEG-O-PA(或GA)的合成。将5.0g端基为羟基的PEG(PEG-OH)、0.31g PA或GA或CA、0.19g EDC和0.12g NHS溶于20mL DMF中,冷却到0℃反应2h,室温反应48h,结束反应用无水乙醚沉淀,洗涤、过滤、干燥即得到通过酯键连有PEG链的原茶儿酸PEG-O-PA或没食子酸PEG-O-GA。
实施例2含有多个多酚分子的化合物的合成
(1)支化聚谷氨酸键合多个多巴胺(PEG-DOPAx)或对羟甲基苯酚(PEG-BAx)(X大于等于2的整数,如:但不限于2、3、4、5、6、7、8、9和10)的合成。
按文献中聚谷氨酸树枝状大分子的合成方法,用PEG-COOH、谷氨酸二叔丁酯Glu制备支化的聚枝状聚谷氨酸,包括连有一个谷氨酸、含两个羧基的PEG-Glu2,连有三个谷氨酸、含4个羧基的PEG5K-Glu4及含有8个羧基的PEG-Glu8。
将5.3g PEG-Glu2、0.62g DOPA、0.38g EDC和0.24g NHS溶于20mL DMF中,冷却到0℃反应2h后,室温反应24h,用无水乙醚沉淀,再用无水乙醚重沉淀三次、过滤、干燥即得端基含有两个DOPA分子的PEG(PEG-DOPA2)。类似地,用端基含有四个羧基的PEG-Glu4与DOPA反应的到端基含有4分子DOPA的PEG-DOPA4,用端基含有8个羧基的PEG-Glu8与DOPA反应的到端基含有8个DOPA分子的PEG-DOPA8。
(2)支化聚赖氨酸键合多个含羧基多酚PEG-PAy(或GA或CA)的合成(y大于等于2)的合成。按文献中聚赖氨酸树枝状大分子的合成方法,用PEG-NH2和N-Boc-Lys-OPFP制备PEG链的一端基连有一个赖氨酸、含2个胺基的PEG-Lys,以及含4胺基的PEG-Lys4和8个胺基的PEG-Lys8。
将5.3g PEG-Lys、0.62g PA、0.38g EDC和0.24g NHS溶于20mL DMF中,冷却到0℃反应2h,然后室温反应24h,用无水乙醚沉淀并重沉淀三次、过滤、干燥即得端基连有2个PA的聚乙二醇(PEG-PA2)。采用相同方法,用PEG-Lys4或PEG-Lys8与过量的PA反应并纯化即可得到PEG-PA4和PEG-PA8。上述聚合物与GA或CA反应制备得到PEG-GA2、PEG-GA4、PEG-GA8、PEG-CA2、PEG-CA4和PEG-CA8。
(3)线性聚谷氨酸键合DOPA或BA(PEG-PGlu-DOPAn,或BA)的合成。5.5g PEG-聚谷氨酸的嵌段聚合物(PEG-PGlu5,聚谷氨酸的聚合度为5)、1.53g DOPA、0.96g EDC和0.58gNHS溶于20mL DMF中,在0℃反应2h,然后室温反应24h,用无水乙醚沉淀并重沉淀三次、过滤、干燥即得聚谷氨酸羧基连接DOPA的聚合物PEG-PGlu5-DOPA5。采用相同方法,用PEG-PGlu10(聚谷氨酸的聚合度为10)即制备PEG-PGlu10-DOPA10和PEG-PGlu5-BA5和mPEG-PGlu10-BA10。
(4)线性聚赖氨酸键合GA、PA或CA(PEG-PLL-GAm,PA或CA)的合成。将5.65g PEG-聚赖氨酸的嵌段聚合物(PEG-PLL5,5为赖氨酸的聚合度)或PEG-PLL10、1.7g GA、0.96g EDC和0.58g NHS溶于20mL DMF中,在0℃反应2h然后在室温反应24h,结束反应用无水乙醚沉淀,再用无水乙醚重沉淀三次、过滤、干燥即得赖氨酸的胺基键合GA、PA或CA反应的聚合物PEG-PLL5-GA5、PEG-PLL5-PA5、PEG-PLL5-CA5、PEG-PLL10-GA10、PEG-PLL10-PA10和PEG-PLL10-CA10。
实施例3多酚/铂络合稳定常数的测定、纳米药物的制备与粒径的测定
称取二氯环己二胺合铂50.0mg,硝酸银44.7mg,加入去离子水10mL,避光反应,用0.45微米滤器过滤得到脱氯铂的水合环己二胺合铂(DACH-Pt)溶液。用相同的方法可得到脱氯的水合顺铂.
通过25℃下等温滴定量热实验测定DACH-Pt与多酚单宁酸的稳定常数。DACH-Pt溶液(0.3mM)以每滴7.0μL,分38次注射到样品室,每滴样品注射持续20s,滴定间隔200s。样品池中的TA溶液(0.2μM)以300转/分钟的速度搅拌以保证样品快速混合。采用相同的方法和参数,将DACH-Pt溶液滴定至纯水中,以测定每次滴定的稀释热,用于校正滴定曲线。通过软件单点拟合,计算得到DACH-Pt与TA反应的热力学参数,包括焓变(H),熵变(S),结合位点数(N)以及稳定常数(K)。由表1可见,DACH-Pt与单宁酸的络合常数达到105M-1,表明多酚能够有效络合铂离子,但络合强度低于与铁离子的络合。
表1 DACH-Pt与单宁酸络合参数
取上述铂水化物200微升,加入去离子水800微升,加入当量的多酚搅拌并调节pH至6~8.5,置于37℃摇床反应4h~72h,超滤除去多余小分子即得到多酚/铂纳米药物。取制备好的溶液200μL置于马尔文ZEN0040样品池中使用动态光散射仪(DLS)在25℃条件下对其尺寸及分布进行测定。散射光条件为:后向散射角为173°,自动位置测量和自动激光衰减。25℃下的纯净水的折射率和粘度指数作为参数进行数据分析,实验数据经DispersionTechnology Software version6.1处理所得,每组实验重复3次后取平均值。结果如图1、图2和表2所示。不同多酚及比例制备所得纳米颗粒粒径不同,在40纳米~500纳米之间。
表2多酚/铂药物络合形成的纳米药物的粒径
实施例4多酚/铂纳米药物的体外释放研究
取1mL制备好的单宁酸/环己二胺二胺合(TA/DACH-Pt)络合形成的纳米药物(Pt浓度为200μg/mL),置于截留分子量为3500Da的透析袋中,然后放入50mL pH6.5或pH7.4的PBS缓冲液(10mM)中透析。在不同时间点,取出200μL透析袋外的缓冲溶液,利用原子吸收光谱仪检测其中的Pt含量,绘制出药物释放曲线。实验结果如图3所示,TA/DACH-Pt纳米药物呈现出持续且快速的酸响应性释放。在pH6.5的酸性条件中,药物快速释放,8h就有86%的Pt被释放出来;而pH7.4时,Pt的释放相对较慢,8h时只要30%的药物得到释放。
实施例5细胞毒性实验
采用3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)法来检测纳米药物在Hela细胞上的体外细胞毒性。Hela细胞以5K细胞/孔接种于96孔板中,每孔100μL含10%血清的培养基,于37℃恒温培养箱中培养24h。随后每孔加入一系列不同浓度的TA/DACH-Pt纳米药物100μL,空白对照组加入100μL培养基,继续培养48h。然后于1,100rpm离心6min,并弃尽每孔内的培养基,置换成100μL新鲜配制的含有0.75mg/mL MTT的培养基,在培养箱中继续培养3h。最后于2,800rpm离心7min并弃尽每孔内的培养基,加入100μL DMSO,涡旋震荡使DMSO充分溶解结晶,并利用酶标仪测量每孔样品在562nm和620nm处的吸光度值。细胞存活率(百分比)是以实验组的吸光度值去除以空白组的吸光度值来表示。每一组数据均为同组试样三个孔的平均值。每组数据均为同一样品三次独立实验的平均值。实验结果如图4所示,TA/DACH-Pt纳米药物的IC50值分别为1.77和13.9。图5所示实施例1和2中制备的PEG-没食子酸多酚(PEG-GA和PEG-GA2,PEG的分子量为5000)与顺铂形成的PEG-GA/CDDP和PEG-GA2/CDDP纳米药物对不同肿瘤细胞的细胞毒性。由此可见,这些纳米药物对肿瘤细胞具有细胞毒性。
实施例6纳米药物的血浆清除实验
体重约20g的雌性ICR小鼠被随机分成两组,每组3只,分别通过尾静脉给药DACH-Pt或TA/DACH-Pt纳米药物(Pt的当量剂量为4mg/kg)。在每个设定的时间点,小鼠眼眶取血100μL置于肝素钠浸润的离心管中。用10K转/分钟的转速离心5分钟,吸取50μL上层血清用王水硝化并定容成5mL,然后采用原子吸收光谱仪检测样品中的铂含量。
将2min时间点的血浆铂浓度设为100%,后续各时间点的铂浓度均以此为参照,分别计算出百分比含量,做出药物的血浆清除曲线,并利用DAS软件计算出药物清除半衰期(t1/2)及药时曲线下面积(AUC)。实验结果如图6所示,DACH-Pt在血流中很快被清除,而TA/DACH-Pt纳米药物在血液中具有显著增长的保留能力,注射24h后,在血浆中的浓度仍然有初始总注射量的8%左右,而DACH-Pt仅有约2%的药物残留。与DACH-Pt相比,单宁酸/铂纳米药物具有明显更优的药代动力学特性,其血浆清除半衰期(T1/2β)和曲线下面积(AUC)分别是DACH-Pt的67倍和2.8倍(P<0.05)。图7为实施例1和2中PEG-没食子酸多酚(PEG-GA和PEG-GA2,PEG的分子量为5000)与水合顺铂形成的PEG-GA/CDDP和PEG-GA2/CDDP纳米药物在小鼠血浆中随时间的浓度曲线。可以看到,该纳米药物在血液中的清除速率远远低于顺铂对照。
实施例7抑瘤实验
6-8周的雌性BALB/c小鼠右腋皮下接种4T1小鼠乳腺癌细胞(1.5×106细胞),待肿瘤体积达到50mm3左右后,将其随机分成4组,每组7只,分别尾静脉注射PBS,CDDP,PEG-GA/CDDP和PEG-GA2/CDDP(等效CDDP剂量5mg/kg),每两天给一次药,共给药4次,每两天记录裸鼠体重及肿瘤体积(V=[Length×(Width)2]/2),绘制肿瘤体积-时间曲线。实验第22天,按照动物伦理要求处死裸鼠,剥离肿瘤并称重。实验结果如图8所示,相对于PBS对照组,CDDP,PEG-GA/CDDP和PEG-GA2/CDDP都明显抑制了肿瘤生长,CDDP组在给药期间裸鼠肿瘤的生长受到一定程度的抑制,但停药后开始快速反弹,与PEG-GA/CDDP和PEG-GA2/CDDP组具有显著性差异(p<0.05)。PEG-GA/CDDP和PEG-GA2/CDDP组在停止给药后,肿瘤反弹缓慢,两者没有显著性差异。此外,CDDP具有明显的系统毒性,小鼠体重明显下降,其余各组的小鼠在实验过程中体重并没有明显下降。由此可见,该纳米药物具有更加优异的抗肿瘤能力,且毒副作用更低。
Claims (14)
1.一种含铂类药物纳米颗粒,其特征在于多酚和铂类药物通过酚基与铂离子配位络合形成,酚羟基与铂的摩尔配比为20∶1~1∶20,粒径为10纳米~1000纳米。
2.根据权利要求1中所述的含铂类药物纳米颗粒,其特征在于所述的多酚分子是含有至少一个酚基的化合物。
3.根据权利要求1中所述的含铂类药物纳米颗粒,其特征在于所述的多酚,可选自于多巴胺、单宁酸、没食子酸、儿茶酸、丹参素、原花青素、迷迭香酸、表儿茶酸、表儿茶素没食子酸酯、没食子儿茶素没食子酸酯和表没食子儿茶素没食儿酸酯等之一种或几种。
4.根据权利要求1所述的含铂类药物纳米颗粒,其特征在于所述的多酚还包括由含酚基分子共价连接而成的含有多个酚基的化合物和聚合物。
6.根据权利要求5所述的含铂纳米颗粒,其特征在于所述的PEG分子量为100Da~20,000Da。
7.根据权利要求4所述的含铂类药物纳米颗粒,其特征在于所述的含有多个酚基的聚合物,还包括由一个或多个所述的含酚基分子键合到枝状聚合物上来制备,所述的枝状聚合物可选自于代数为1~6代的树枝状聚谷氨酸、代数为1~6代的树枝状聚天冬氨酸或代数为1~6代的树枝状聚赖氨酸等。
9.根据权利要求8所述的含铂类药物纳米颗粒,其特征在于所述的聚合物的分子量为1000Da~100,000Da。
10.根据权利要求1所述的含铂类药物纳米颗粒,其特征在于所述的铂类药物可为顺式-二氯(1,2-环己二胺)铂、顺式-二氯二氨合铂(顺铂)和奥沙利铂之一种或几种。
11.一种制取权利要求1~10之一所述的含铂类药物纳米颗粒的方法,其特征在于,将多酚化合物溶于水中,然后加入铂类化合物进行配位络合,调节pH至6.0~10.0,使多酚和铂类药物的铂离子络合形成纳米颗粒。
12.根据权利要求11中所述的制取含铂类药物纳米颗粒的方法,其特征在于所述的酚羟基与所述铂的摩尔配比为20∶1~1∶20。
13.根据权利要求1~10之一所述的含铂类药物纳米颗粒在制备抗肿瘤药物中的应用。
14.根据权利要求13所述的用途,其特征在于所述的肿瘤为人乳腺癌、肝癌、睾丸癌、卵巢癌和大肠癌。
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