Rational Design of Targeted Cancer Therapeutics through the Multiconjugation of Folate and Cleavable siRNA to RAFT-Synthesized (HPMA-s-APMA) Copolymers
| Autor: | Faqing Huang, Adam W. York, Charles L. McCormick |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Polymers and Plastics
Stereochemistry Acrylic Resins Antineoplastic Agents Bioengineering Article Biomaterials chemistry.chemical_compound Drug Delivery Systems Folic Acid Neoplasms Organometallic Compounds Materials Chemistry Copolymer Humans Methacrylamide Moiety Reversible addition−fragmentation chain-transfer polymerization RNA Small Interfering Acrylamides Chemistry Rational design Chain transfer Raft Combinatorial chemistry Drug Design Amine gas treating |
| Zdroj: | Biomacromolecules. 11:505-514 |
| ISSN: | 1526-4602 1525-7797 |
| Popis: | 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 multiconjugates 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 multiconjugate copolymer with 91 mol % HPMA, 2 mol % RNA, and 6 mol % folate. siRNA formation was achieved by annealing antisense strands to the conjugated RNA sense strands. Subsequent siRNA cleavage under intracellular conditions demonstrated the potential utility of this carrier in gene delivery. The multiconjugate copolymer and siRNA release were characterized by UV-vis spectroscopy and polyacrylamide gel electrophoresis. |
| Databáze: | OpenAIRE |
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