Rational design of targeted cancer therapeutics through the multiconjugation of folate and cleavable siRNA to RAFT-synthesized (HPMA-s-APMA) copolymers.
Rational design of targeted cancer therapeutics through the multiconjugation of folate and cleavable siRNA to RAFT-synthesized (HPMA-s-APMA) copolymers.
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DOI：
10.1021/bm901249n
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发表时间：
2010-02-08
影响因子：
6.2
通讯作者：
McCormick, Charles L.
中科院分区：
文献类型：
--
作者：
York, Adam W.;Huang, Faqing;McCormick, Charles L.
利用通过可逆加成-断裂链转移（RAFT）聚合合成的定义明确的N-（2-羟丙基）甲基丙烯酰胺-s-N-（3-氨基丙基）甲基丙烯酰胺（HPMA-s-APMA）共聚物来合理设计含有基因治疗剂小干扰RNA（siRNA）和癌细胞靶向部分叶酸的多缀合物。该共聚物含有生物相容性聚（HPMA）部分（91摩尔%）和伯胺APMA部分（9摩尔%）。利用胺-和巯基-反应性分子N-琥珀酰亚胺基3-（2-吡啶基二硫代）-丙酸酯（SPDP）将APMA重复的一部分（20摩尔%）转化为活化的硫醇。然后通过与侧基吡啶基二硫代部分的二硫键交换将5 '-巯基化的有义链RNA偶联至聚合物，得到89 ± 4%的缀合度。随后将未修饰的APMA单元（80摩尔%）以81 ± 1%的效率偶联至胺反应性叶酸。这产生了具有91摩尔% HPMA、2摩尔% RNA和6摩尔%叶酸的多缀合物共聚物。通过将反义链退火至缀合的RNA有义链来实现siRNA形成。随后在细胞内条件下的siRNA切割证明了该载体在基因递送中的潜在效用。通过紫外-可见光谱和聚丙烯酰胺凝胶电泳表征多缀合物共聚物和siRNA释放。
A well-defined N-(2-hydroxypropyl)methacrylamide-s-N-(3-aminopropyl)methacrylamide (HPMA-s-APMA) copolymer, synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, was utilized for the rational design of multi-conjugates containing both a gene therapeutic, small interfering RNA (siRNA), and a cancer cell targeting moiety, folate. The copolymer contains a biocompatible poly(HPMA) portion (91 mol%) and a primary amine, APMA, portion (9 mol%). A fraction (20 mol%) of the APMA repeats were converted to activated thiols utilizing the amine- and sulfhydryl-reactive molecule N-succinimidyl 3-(2-pyridyldithio)-propionate (SPDP). 5’-Thiolated sense strand RNAs were then coupled to the polymer through a disulfide exchange with pendant pyridyldithio moieties giving an 89 ± 4 % degree of conjugation. The unmodified APMA units (80 mol%) were subsequently coupled to amine reactive folates with 81 ± 1 % efficiency. This yielded a multi-conjugate copolymer with 91 mol% HPMA, 2 mol% RNA and 6 mol% folate. siRNA formation was achieved by annealing anti-sense strands to the conjugated RNA sense strands. Subsequent siRNA cleavage under intracellular conditions demonstrated the potential utility of this carrier in gene delivery. The multi-conjugate copolymer and siRNA release were characterized by UV-vis spectroscopy and polyacrylamide gel electrophoresis.
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DOI：
10.1016/j.jconrel.2008.10.004
发表时间：
2009-02-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Convertine AJ;Benoit DS;Duvall CL;Hoffman AS;Stayton PS
通讯作者：
Stayton PS
影响因子：
2.9
作者：
Braasch, DA;Jensen, S;Corey, DR
通讯作者：
Corey, DR
影响因子：
5.3
作者：
Davidson, TJ;Harel, S;Troy, CM
通讯作者：
Troy, CM
影响因子：
15
作者：
De, Priyadarsi;Li, Ming;Sumerlin, Brent S.
通讯作者：
Sumerlin, Brent S.
影响因子：
--
作者：
Alidedeoglu, Alp H.;York, Adam W.;Morgan, Sarah E.
通讯作者：
Morgan, Sarah E.