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A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy.
Biomaterials 2011; 32(11):3124-33B

Abstract

One of the key challenges in the development of RNA interference-based cancer therapy is the lack of an efficient delivery system for synthetic small interfering RNAs (siRNAs) that would enable efficient uptake by tumor cells and allow for significant knockdown of a target transcript in vivo. Here, we describe a micelleplex system based on an amphiphilic and cationic triblock copolymer, which can systemically deliver siRNA targeting the acid ceramidase (AC) gene for cancer therapy. This triblock copolymer, consisting of monomethoxy poly(ethylene glycol), poly(ε-caprolactone) and poly(2-aminoethyl ethylene phosphate), self-assembles into micellar nanoparticles (MNPs) in aqueous solution with an average diameter of 60 nm and a zeta potential of approximately 48 mV. The resulting micelleplex, formed by the interaction of MNPs and siRNA, was effectively internalized by BT474 breast cancer cells and siRNA was subsequently released, resulting in significant gene knockdown. This effect was demonstrated by significant down-regulation of luciferase expression in BT474-luciferase cells which stably express luciferase, and suppression of AC expression in BT474 cells at both the transcriptional and protein level, following delivery of specific siRNAs by the micelleplex. Furthermore, a micelleplex carrying siRNA targeting the AC (micelleplex(siAC)) gene was found to induce remarkable apoptosis and reduce the proliferation of cancer cells. Systemic delivery of micelleplex(siAC) significantly inhibited tumor growth in a BT474 xenograft murine model, with depressed expression of AC and no positive activation of the innate immune response, suggesting therapeutic promise for micelleplex siRNA delivery in cancer therapy.

Authors+Show Affiliations

CAS Key Laboratory of Brain Function and Diseases and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, PR China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21277018

Citation

Mao, Cheng-Qiong, et al. "A Biodegradable Amphiphilic and Cationic Triblock Copolymer for the Delivery of siRNA Targeting the Acid Ceramidase Gene for Cancer Therapy." Biomaterials, vol. 32, no. 11, 2011, pp. 3124-33.
Mao CQ, Du JZ, Sun TM, et al. A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy. Biomaterials. 2011;32(11):3124-33.
Mao, C. Q., Du, J. Z., Sun, T. M., Yao, Y. D., Zhang, P. Z., Song, E. W., & Wang, J. (2011). A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy. Biomaterials, 32(11), pp. 3124-33. doi:10.1016/j.biomaterials.2011.01.006.
Mao CQ, et al. A Biodegradable Amphiphilic and Cationic Triblock Copolymer for the Delivery of siRNA Targeting the Acid Ceramidase Gene for Cancer Therapy. Biomaterials. 2011;32(11):3124-33. PubMed PMID: 21277018.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy. AU - Mao,Cheng-Qiong, AU - Du,Jin-Zhi, AU - Sun,Tian-Meng, AU - Yao,Yan-Dan, AU - Zhang,Pei-Zhuo, AU - Song,Er-Wei, AU - Wang,Jun, Y1 - 2011/01/28/ PY - 2010/12/08/received PY - 2011/01/04/accepted PY - 2011/2/1/entrez PY - 2011/2/1/pubmed PY - 2011/6/2/medline SP - 3124 EP - 33 JF - Biomaterials JO - Biomaterials VL - 32 IS - 11 N2 - One of the key challenges in the development of RNA interference-based cancer therapy is the lack of an efficient delivery system for synthetic small interfering RNAs (siRNAs) that would enable efficient uptake by tumor cells and allow for significant knockdown of a target transcript in vivo. Here, we describe a micelleplex system based on an amphiphilic and cationic triblock copolymer, which can systemically deliver siRNA targeting the acid ceramidase (AC) gene for cancer therapy. This triblock copolymer, consisting of monomethoxy poly(ethylene glycol), poly(ε-caprolactone) and poly(2-aminoethyl ethylene phosphate), self-assembles into micellar nanoparticles (MNPs) in aqueous solution with an average diameter of 60 nm and a zeta potential of approximately 48 mV. The resulting micelleplex, formed by the interaction of MNPs and siRNA, was effectively internalized by BT474 breast cancer cells and siRNA was subsequently released, resulting in significant gene knockdown. This effect was demonstrated by significant down-regulation of luciferase expression in BT474-luciferase cells which stably express luciferase, and suppression of AC expression in BT474 cells at both the transcriptional and protein level, following delivery of specific siRNAs by the micelleplex. Furthermore, a micelleplex carrying siRNA targeting the AC (micelleplex(siAC)) gene was found to induce remarkable apoptosis and reduce the proliferation of cancer cells. Systemic delivery of micelleplex(siAC) significantly inhibited tumor growth in a BT474 xenograft murine model, with depressed expression of AC and no positive activation of the innate immune response, suggesting therapeutic promise for micelleplex siRNA delivery in cancer therapy. SN - 1878-5905 UR - https://www.unboundmedicine.com/medline/citation/21277018/A_biodegradable_amphiphilic_and_cationic_triblock_copolymer_for_the_delivery_of_siRNA_targeting_the_acid_ceramidase_gene_for_cancer_therapy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0142-9612(11)00007-X DB - PRIME DP - Unbound Medicine ER -