TY - JOUR

T1 - Amphiphilic Polypeptides Obtained by Post-Polymerization Modification of Poly-L-Lysine as Systems for Combined Delivery of Paclitaxel and siRNA

AU - Джужа, Аполлинария Юрьевна

AU - Гандалипов, Эрик

AU - Коржиков-Влах, Виктор Александрович

AU - Катернюк, Елена Владиславовна

AU - Захарова, Наталья Владимировна

AU - Силонов, Сергей Александрович

AU - Тенникова, Татьяна Борисовна

AU - Коржикова-Влах, Евгения Георгиевна

PY - 2023/4/21

Y1 - 2023/4/21

N2 - The development of effective anti-cancer therapeutics remains one of the current pharmaceutical challenges. The joint delivery of chemotherapeutic agents and biopharmaceuticals is a cutting-edge approach to creating therapeutic agents of enhanced efficacy. In this study, amphiphilic polypeptide delivery systems capable of loading both hydrophobic drug and small interfering RNA (siRNA) were developed. The synthesis of amphiphilic polypeptides included two steps: (i) synthesis of poly-αl-lysine by ring-opening polymerization and (ii) its post-polymerization modification with hydrophobic l-amino acid and l-arginine/l-histidine. The obtained polymers were used for the preparation of single and dual delivery systems of PTX and short double-stranded nucleic acid. The obtained double component systems were quite compact and had a hydrodynamic diameter in the range of 90-200 nm depending on the polypeptide. The release of PTX from the formulations was studied, and the release profiles were approximated using a number of mathematical dissolution models to establish the most probable release mechanism. A determination of the cytotoxicity in normal (HEK 293T) and cancer (HeLa and A549) cells revealed the higher toxicity of the polypeptide particles to cancer cells. The separate evaluation of the biological activity of PTX and anti-GFP siRNA formulations testified the inhibitory efficiency of PTX formulations based on all polypeptides (IC 50 4.5-6.2 ng/mL), while gene silencing was effective only for the Tyr-Arg-containing polypeptide (56-70% GFP knockdown).

AB - The development of effective anti-cancer therapeutics remains one of the current pharmaceutical challenges. The joint delivery of chemotherapeutic agents and biopharmaceuticals is a cutting-edge approach to creating therapeutic agents of enhanced efficacy. In this study, amphiphilic polypeptide delivery systems capable of loading both hydrophobic drug and small interfering RNA (siRNA) were developed. The synthesis of amphiphilic polypeptides included two steps: (i) synthesis of poly-αl-lysine by ring-opening polymerization and (ii) its post-polymerization modification with hydrophobic l-amino acid and l-arginine/l-histidine. The obtained polymers were used for the preparation of single and dual delivery systems of PTX and short double-stranded nucleic acid. The obtained double component systems were quite compact and had a hydrodynamic diameter in the range of 90-200 nm depending on the polypeptide. The release of PTX from the formulations was studied, and the release profiles were approximated using a number of mathematical dissolution models to establish the most probable release mechanism. A determination of the cytotoxicity in normal (HEK 293T) and cancer (HeLa and A549) cells revealed the higher toxicity of the polypeptide particles to cancer cells. The separate evaluation of the biological activity of PTX and anti-GFP siRNA formulations testified the inhibitory efficiency of PTX formulations based on all polypeptides (IC 50 4.5-6.2 ng/mL), while gene silencing was effective only for the Tyr-Arg-containing polypeptide (56-70% GFP knockdown).

KW - амфифильные сополимеры

KW - полипептиды

KW - полимерные частицы

KW - СИСТЕМЫ ДОСТАВКИ ЛЕКАРСТВ

KW - доставка двух лекарств

KW - паклитаксел

KW - миРНК

KW - amphiphilic copolymers

KW - drug delivery systems

KW - dual-drug delivery

KW - paclitaxel

KW - polymer particles

KW - polypeptides

KW - siRNA

UR - https://www.mendeley.com/catalogue/e2cb7e6f-267b-39c2-82ba-dcacd7c4b3b1/

U2 - 10.3390/pharmaceutics15041308

DO - 10.3390/pharmaceutics15041308

M3 - Article

C2 - 37111793

VL - 15

JO - Pharmaceutics

JF - Pharmaceutics

SN - 1999-4923

IS - 4

M1 - 1308

ER -