Polymeric RNAi Constructs Tailored with Appreciable Transcellular Trafficking Functions for Potential Suppression of Parathyroid Hormone Production.
Bioconjug Chem
; 32(5): 909-915, 2021 05 19.
Article
en En
| MEDLINE
| ID: mdl-33890782
ABSTRACT
Polymeric small interfering RNA (siRNA) conjugate was elaborated to sequentially circumvent the predefined biological barriers encountered in the journey of transcellular delivery of siRNA into cytosol. Herein, classic ring-opening polymerization was employed for synthesis of well-defined poly(amino acid) derivatives possessing an array of carboxyl groups in an attempt to resemble the structural characteristics of hyaluronan. Furthermore, the hyaluronan-like synthetic was conjugated with a multiple of siRNA through a glutathione (GSH)-responsive disulfide linkage. The siRNA conjugate appeared to utilize the hyaluronan-specific receptors of CD44 for cell internalization, indicating similar functionalities to our hyaluronan-mimicking synthetic. Furthermore, the carboxyl groups of hyaluronan-like synthetics were designed to be selectively detached in subcellular acidic endosomes/lysosomes and transform into the cytomembrane-disruptive flanking ethylenediamine moieties, which appeared to be crucial in facilitating translocation of siRNA payloads from entrapment and degradation in lysosomes toward the cytosol. Eventually, active siRNA could be smoothly released from the synthetic due to the GSH cleavage disulfide linkage (disulfide), consequently accounting for potent RNA knockdown activities (>90%) toward cancerous cells. In addition, appreciable knockdown of parathyroid hormone was also achieved from our proposed siRNA conjugates in parathyroid cells. Hence, the elaborated siRNA conjugate showed tremendous potential in treatment of hyperparathyroidism, and could be developed further for systemic RNA interference (RNAi) therapeutics. Moreover, this study could also be the first example of a synthetic mimic to hyaluronan acquiring its functionalities, which could have important implications for further development of biomimic materials in pursuit of biomedical applications.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Hormona Paratiroidea
/
Polímeros
/
Portadores de Fármacos
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Interferencia de ARN
Idioma:
En
Revista:
Bioconjug Chem
Asunto de la revista:
BIOQUIMICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
China