CN114515270A - 一种凝胶缓释给药系统及其应用 - Google Patents
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Abstract
本发明公开了一种凝胶缓释给药系统及其应用,属于生物医药技术领域。该凝胶缓释给药系统,由不带电的天然多糖和带正电的天然多糖通过二硫键交联后制备得到;还包载有正电性的活性分子和/或生物大分子药物。本发明的凝胶缓释给药系统不仅能吸收肿瘤术后的渗出液,还可以共载化疗药物和/或生物大分子药物实现肿瘤的联合免疫治疗。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种凝胶缓释给药系统及其应用。
背景技术
手术切除是局部治疗恶性肿瘤的首选治疗,但是由手术引起的组织损伤,特别是随后的局部促炎和伤口愈合反应显著增加生长因子的水平,支持局部和远端肿瘤复发,从而提高了残余肿瘤细胞的侵袭能力和运动性。目前临床手术切除后,常配合在创面上进行术后辅助化疗,消除残余的肿瘤细胞,并防止肿瘤的复发和转移,提高患者的治疗有效率和生存期。
水凝胶是以大量水为分散介质,具有吸水、锁水但不溶于水的三维多孔网络结构,由于具有良好的生物相容性和可降解性而被广泛地应用于生物医学材料。水凝胶可吸收大量的渗出液,因此常用作术后或者伤口的敷料,通过利用不同的材料性能,常具有抗炎杀菌、促进伤口愈合等特性,同时还能用作药物的缓释储库。将水凝胶进一步冻干可以得到含水较少、体积较小的干胶,有利于凝胶提高凝胶的稳定性,便于长期贮存;这种干胶再次置于水中或湿润环境中后,可吸水膨胀回复形成水凝胶;不仅如此,将适宜体积的含药水溶液递加至干胶上,药物溶液可被干胶充分吸收,从而是药物均匀分布于凝胶之中。基于这些性质,干胶可作为植入剂在手术后埋置于手术部位,并根据需要负载适宜的治疗药物,发挥术后的原位长效治疗作用。
近年来,随着基于“免疫检查点阻断(Immune checkpoint blockade,ICB)”的免疫疗法在临床癌症治疗中取得巨大成功,ICB在不同的肿瘤治疗中逐渐被广泛应用,通过肿瘤免疫疗法提高抗肿瘤疗效的治疗方式受到了广泛关注。一般来说,在实施ICB疗法之前,率先激活机体免疫反应和产生适应性免疫能够有效提高免疫治疗效果。因此,在肿瘤切除后先实施化疗,杀灭残存的的肿瘤细胞,建立适应性免疫,进而给予免疫检查点抑制剂,预期能够有效提高联合免疫治疗效果。
发明内容
本发明的目的是提供一种适用于肿瘤术后辅助治疗的凝胶缓释给药系统。
为了实现上述目的,本发明采用以下技术方案:
一种凝胶缓释给药系统,由不带电的天然多糖和带正电的天然多糖通过二硫键交联后制备得到;
所述不带电的天然多糖为普鲁兰糖、羟乙基淀粉或右旋糖酐;
所述带正电的天然多糖为壳聚糖、羧甲基壳聚糖、羟丙基壳聚糖或季铵化壳聚糖。
在本发明的一个实施例中,不带电的天然多糖为普鲁兰糖,带正电的天然多糖为壳聚糖。
进一步地,所述凝胶缓释给药系统中还包载有正电性的活性分子和/或生物大分子药物;
所述正电性的活性分子为正电性的抗肿瘤药物或正电性的抗肿瘤微粒制剂;
所述生物大分子药物呈负电性或电中性。
具体地,所述正电性的抗肿瘤药物为顺铂、卡铂、奥沙利铂等;
所述正电性的抗肿瘤微粒制剂为阳离子脂质体、阳离子聚合物胶束等,是通过在脂质体或聚合物胶束等微粒表面修饰正电性基团或分子,如氨基、精氨酸、赖氨酸、三苯基膦、阳离子细胞穿膜肽(如TAT、MAP、多聚赖氨酸、多聚精氨酸等);
在正电性的抗肿瘤微粒制剂中包载有抗肿瘤药物,如烷化剂、抗生素类、植物生物碱、铂类化合物等,具体药物如紫杉醇、阿霉素、去氧鬼臼毒素、环巴胺、奥沙利铂等。
生物大分子药物可选呈负电性或电中性的分子靶向药物和免疫检查点抑制剂等,具体药物如anti-HER2抗体、anti-CTLA4抗体、anti-PDL1抗体和anti-CD47抗体等。
在本发明的一个实施例中,正电性的活性分子为包载环巴胺的阳离子脂质体,生物大分子药物以IgG作抗体药物的结构类似物,模拟抗体药物的释放。
上述凝胶缓释给药系统的制备方法,包括以下步骤:
步骤1,制备修饰有巯基的不带电的天然多糖;
步骤2,制备修饰有巯基的带正电的天然多糖;
步骤3,将修饰有巯基的不带电的天然多糖和修饰有巯基的带正电的天然多糖溶解在水中,35-40℃反应12-16h,得到交联产物;
步骤4,将交联后的产物反复冻融,得到凝胶;
步骤5,将步骤4的凝胶进行冷冻干燥,得到凝胶干品,即为所述凝胶缓释给药系统。
进一步地,在步骤5中,还可向凝胶干品滴加正电性的活性分子溶液和/或生物大分子药物溶液。
上述凝胶缓释给药系统在制备肿瘤术后用治疗产品中的应用。
一种肿瘤术后用治疗产品,包括上述凝胶缓释给药系统。
本发明的凝胶缓释给药系统不仅能吸收肿瘤术后的渗出液,还可以共载化疗药物和/或生物大分子药物实现肿瘤的联合免疫治疗。一方面,凝胶中包载的正电性化疗药物与带正电的天然多糖(如壳聚糖)存在静电斥力,可率先快速释放,从而杀灭手术部位的残留肿瘤细胞,激活机体免疫反应;另一方面,凝胶中包载的负电性或电中性生物大分子药物与带正电的带正电的天然多糖(如壳聚糖)存在静电吸引,可于化疗药物激活机体免疫反应之后持续缓慢释放,通过阻断免疫检查点提高免疫治疗效果,从而有效防止肿瘤术后复发与转移。
附图说明
图1为巯基修饰壳聚糖的制备及产物的核磁图谱。
图2为巯基修饰普鲁兰糖的制备及产物的核磁图谱。
图3为水凝胶的制备及水凝胶的扫描电子显微镜成像图。
图4为不同处方组成凝胶的黏弹性测定结果。
图5为水凝胶的还原敏感降解过程图。
图6为水凝胶的还原敏感释放曲线。
具体实施方式
下面结合附图和具体实施例对本发明作进一步详细说明,但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。实施例中未注明具体条件的实验方法及未说明配方的试剂均为按照本领域常规条件。
以下实施例中,所采用的壳聚糖购自Sigma-Aldrich,其分子量分布范围为50-375kDa;所采用的普鲁兰糖购自Aladdin,其分子量分布范围为20-2000kDa。
实施例1
1、巯基修饰壳聚糖的制备
称取壳聚糖约0.5g,在磁力搅拌下分散于50mL水中,加入HoBt(0.3485g,2.58mmol),将溶液搅拌至澄明后加入N-乙酰-L-半胱氨酸(N-Acetyl-L-Cysteine,NAC)(0.8420g,5.16mmol)和EDC·HCl(3.9568g,20.64mmol)溶解,并用稀盐酸(约1mol/L)调pH至5.0,氮气保护下避光反应24h。反应结束后,用1mol/L的NaOH调节pH至7.5-8.0范围内,称量二硫苏糖醇(1.5918g,10.32mmol),溶解于约2mL水后加入上述反应体系。氮气保护下避光搅拌反应30h。将反应溶液在5mmol/L HCl+2μmol/L EDTA在10℃下暗处透析3天(透析袋3500Da),而后于5mmol/L HCl+1%NaCl体系下透析一天,最后在水中透析一天,冻干得终产物,即为巯基修饰壳聚糖(CS-SH)。
该反应的反应式如图1a所示,壳聚糖及巯基修饰壳聚糖的核磁图谱如图1b和图1c所示。
2、巯基修饰普鲁兰糖的制备
称取硫辛酸(LA)约46mg,置于50mL三颈瓶中,氮气保护下加入DMSO 4mL溶解。称取261mg的EDC·HCl和135mg的DMAP,用2mL DMSO溶解后,缓慢滴加入到上述三颈瓶中,氮气保护下磁力搅拌,避光并将羧基活化1h。
另称取普鲁兰糖(Pul)约600mg,向上述体系中加入DMSO 50mL溶解,并在氮气保护下,室温避光搅拌反应24h。反应结束后,加入冰乙醇65mL沉淀离心(3000rpm,5min)得到产物,并将产物用冰乙醇洗涤三次,于40℃下旋蒸7min左右干燥得中间产物,并将其溶解于30mL水中,加入二硫苏糖醇188mg,氮气保护下搅拌24h以还原二硫键。还原结束后将反应溶液在5mmol/L HCl+2μmol/L EDTA在10℃下暗处透析3天(透析袋3500Da),之后在5mmol/LHCl+1%NaCl下透析一天,最后在水中透析一天,冷干得终产物,即为巯基修饰普鲁兰糖(Pul-SH)。
该反应的反应式如图2a所示,采用核磁进行结构验证,普鲁兰糖及巯基修饰普鲁兰糖的核磁谱图如图2b和图2c所示。
3、凝胶干品的制备
分别称取制备得到的巯基修饰的壳聚糖(CS-SH)100mg和普鲁兰糖(Pul-SH)50mg,加入1.5mL水中,搅拌溶解,37℃放置12h使得巯基充分反应并交联,交联反应的方程式如图3a所示,再于-20℃和室温反复冻融三次,即形成凝胶。上述凝胶经冷冻干燥后制备得凝胶干品,保存待用。
凝胶冷冻干燥后在-20℃干燥保存,凝胶的扫描电子显微镜成像如图3b所示,从图中能观察到显著的网状结构,表明凝胶的成功制备。
实施例2
不同处方水凝胶的黏弹性考察
按CS-SH:Pul-SH质量比为4:1、2:1、1:1、1:2、1:4,采用流变仪于25℃,1%形变条件下,测定不同Pul-SH与CS-SH比例下,水凝胶的存储模量(G’)和损耗模量(G”)随振荡频率变化的变化趋势,考察不同处方组成对凝胶性能的影响。
如图4所示,随着壳聚糖比例增加,凝胶的存储模量、损耗模量和黏度均有升高的趋势,但CS-SH:Pul-SH为4:1的存储模量和损耗模量反而下降,这可是由于体系水溶性比例较低,凝胶黏弹性质差。当CS-SH:Pul-SH质量比为2:1具有最佳的机械性能及黏弹性。
实施例3
水凝胶的还原敏感降解
取凝胶干品(CS-SH:Pul-SH为2:1)20mg,加入小分子还原剂二硫苏糖醇DTT(50μM和10mM)用于水凝胶的二硫键还原,于1h、9h、48h、70h、118h、166h、262h拍照,取出后经滤纸吸干,称重并记录质量,考察在不同浓度DTT作用下,水凝胶的体外降解情况。
水凝胶的体外降解过程图及降解后微观结构如图5a,降解过程中凝胶的质量变化如图5b,从结果可以看出DTT 10mM能显著加速水凝胶的降解过程,且含DTT 50μM组的凝胶内部孔洞凝胶说明该凝胶具有还原敏感性。
实施例4
1、载药脂质体的制备
精密称取处方量的多聚精氨酸修饰的磷脂DSPE-PEG-R6(12mg)、大豆卵磷脂(52.8mg)、胆固醇(12mg)、环巴胺(Cyclopamine,Cyc,2mg),溶解于4mL氯仿和1mL甲醇的混合溶剂中,将混合体系加入茄形瓶中,39℃条件下旋转蒸发4h形成薄膜,向其中加入4mL纯水水化得到初级脂质体。为进一步获得粒度更小且均一的脂质体,于冰浴下探头超声,设置超声功率300W,超声模式超2s停3s,共超声时间3min。超声结束后,分别依次过0.45μm滤膜三次,0.22μm滤膜三次,得到具淡蓝色乳光的环巴胺脂质体,置于4℃冰箱中保存待用。
取环巴胺脂质体适量,采用动态光散射法测定脂质体的粒径和电位。环巴胺脂质体的平均粒径为95.6nm,电位为16.54mV。
2、水凝胶的还原敏感释放
取凝胶干品(CS-SH:Pul-SH为2:1)20mg,预先将100μL IgG的浓溶液(含1mg)和100μL环巴胺脂质体(含100μg环巴胺)滴加于凝胶干品上,静置10min待完全吸收,随后将载药凝胶置于离心管中进行体外释药实验,待药物溶液完全吸收后,将载药海绵凝胶分别置于加入了4mL体积的生理盐水、含50μM DTT生理盐水的离心管中,置于37℃摇床,设置转速50rpm进行药物的释放实验,分别于不同时间点(2、8、24、72、96、144、192、216h)取出2mL介质并补加新鲜同温介质继续释放,将取出的溶液存储于-20℃,待统一检测。将各时间点的释放结果采用DD-solver软件进行拟合,考察凝胶的释放动力学。
凝胶的释药曲线如图6所示(图6a为IgG的释放曲线,图6b为环巴胺的释放曲线),可以看出该凝胶在8天内具有缓释的效果,同时DTT的作用下能加速药物的释放,论证了该凝胶的还原敏感性。更一步地对该凝胶在生理盐水及DTT存在下的两种药物释放曲线进行拟合,如表1和表2所示。
表1 IgG和Cyc在生理盐水中的释放动力学拟合参数
表2 IgG和Cyc在含DTT50μM的生理盐水中的释放动力学拟合参数
两种药物均符合Rigter-Peppas释放模型,且环巴胺具有更大的k值,说明环巴胺具有更快的释放速率。
Claims (6)
1.一种凝胶缓释给药系统,其特征在于:由不带电的天然多糖和带正电的天然多糖通过二硫键交联后制备得到;
所述不带电的天然多糖为普鲁兰糖、羟乙基淀粉或右旋糖酐;
所述带正电的天然多糖为壳聚糖、羧甲基壳聚糖、羟丙基壳聚糖或季铵化壳聚糖。
2.根据权利要求1所述的凝胶缓释给药系统,其特征在于:所述凝胶缓释给药系统中还包载有正电性的活性分子和/或生物大分子药物;
所述正电性的活性分子为正电性的抗肿瘤药物或正电性的抗肿瘤微粒制剂;
所述生物大分子药物呈负电性或电中性。
3.权利要求1所述凝胶缓释给药系统的制备方法,其特征在于:包括以下步骤:
步骤1,制备修饰有巯基的不带电的天然多糖;
步骤2,制备修饰有巯基的带正电的天然多糖;
步骤3,将修饰有巯基的不带电的天然多糖和修饰有巯基的带正电的天然多糖溶解在水中,35-40℃反应12-16h,得到交联产物;
步骤4,将交联后的产物反复冻融,得到凝胶;
步骤5,将步骤4的凝胶进行冷冻干燥,得到凝胶干品,即为所述凝胶缓释给药系统。
4.根据权利要求3所述的制备方法,其特征在于:在步骤5中,向凝胶干品滴加正电性的活性分子溶液和/或生物大分子药物溶液后,得到所述凝胶缓释给药系统。
5.权利要求1或2所述的凝胶缓释给药系统在制备肿瘤术后用治疗产品中的应用。
6.一种肿瘤术后用治疗产品,其特征在于:包括权利要求1或2所述的凝胶缓释给药系统。
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