Charge neutralized poly(β-amino ester) polyplex nanoparticles for delivery of self-amplifying RNA

被引:7
|
作者
Dastgerdi, Nazgol Karimi [1 ,2 ]
Gumus, Nurcan [1 ]
Bayraktutan, Hulya [1 ]
Jackson, Darryl [3 ]
Polra, Krunal [4 ]
Mckay, Paul F. [4 ]
Atyabi, Fatemeh [2 ]
Dinarvand, Rassoul [2 ,5 ]
Shattock, Robin J. [4 ]
Martinez-Pomares, Luisa [3 ]
Gurnani, Pratik [6 ]
Alexander, Cameron [1 ]
机构
[1] Univ Nottingham, Sch Pharm, Div Mol Therapeut & Formulat, Nottingham NG7 2RD, England
[2] Univ Tehran Med Sci, Sch Pharm, Dept Pharmaceut Nanotechnol, Tehran, Iran
[3] Univ Nottingham, Fac Med & Hlth Sci, Sch Life Sci, Nottingham NG7 2RD, England
[4] Imperial Coll London, Dept Infect Dis, Sect Immunol Infect, Norfolk Pl, London W2 1PG, England
[5] Univ Tehran Med Sci, Fac Pharm, Nanotechnol Res Ctr, Tehran 1417614315, Iran
[6] UCL, UCL Sch Pharm, 29-39 Brunswick Sq, London WC1N 1AX, England
来源
NANOSCALE ADVANCES | 2024年 / 6卷 / 05期
关键词
GAMMA-GLUTAMYL-TRANSPEPTIDASE; MESSENGER-RNA; ACID; TRANSFECTION; EXPRESSION; COMPLEXES; MECHANISMS; PROTECTION; VACCINES; SKIN;
D O I
10.1039/d3na00794d
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Therapeutic self-amplifying RNA (saRNA) is a promising approach for disease treatment, as it can be administered in lower doses than messenger RNA (mRNA) to achieve comparable protein production levels. However, saRNA requires an appropriate delivery vehicle to protect it during transit and facilitate its transfection. A widely-adopted approach has been to use polycations to condense these large anionic macromolecules into polyplex nanoparticles, however their high charge density often elicits cytotoxic effects. In this study we postulated that we could improve the potency and tolerability of such delivery vehicles by co-formulating poly(beta-amino ester)s saRNA polyplexes with a non-toxic anionic polymer, gamma-polyglutamic acid (gamma-PGA) to neutralize partially this positive charge. Accordingly, we prepared a poly(beta-amino ester) from 1,6-hexanedioldiacrylate (HDDA) and 4-aminobutanol (ABOL) and initially evaluated the physicochemical properties of the binary polyplexes (i.e. formed from polymer and saRNA only). Optimised binary polyplex formulations were then taken forward for preparation of ternary complexes containing pHDDA-ABOL, saRNA and gamma-PGA. Our findings demonstrate that gamma-PGA integration into polyplexes significantly enhanced transfection efficacy in HEK293T and A431 cells without affecting polyplex size. Notably, gamma-PGA incorporation leads to a pronounced reduction in zeta potential, which reduced the toxicity of the ternary complexes in moDC, NIH3T3, and A431 cells. Furthermore, the presence of gamma-PGA contributed to colloidal stability, reducing aggregation of the ternary complexes, as evidenced by insignificant changes in polydispersity index (PDI) after freeze-thaw cycles. Overall, these results suggest that incorporating the appropriate ratio of a polyanion such as gamma-PGA with polycations in RNA delivery formulations is a promising way to improve the in vitro delivery of saRNA. Therapeutic self-amplifying RNA (saRNA) is a promising approach for disease treatment, as it can be administered in lower doses than messenger RNA (mRNA) to achieve comparable protein production levels.
引用
收藏
页码:1409 / 1422
页数:14
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