Reversible covalent nanoassemblies for augmented nuclear drug translocation in drug resistance tumor.
J Control Release
; 353: 186-195, 2023 01.
Article
en En
| MEDLINE
| ID: mdl-36403684
ABSTRACT
The drug efflux by P-glycoprotein (P-gp) is the primary contributor of multidrug resistance (MDR), which eventually generates insufficient nuclear drug accumulation and chemotherapy failure. In this paper, reversible covalent nanoassemblies on the basis of catechol-functionalized methoxy poly (ethylene glycol) (mPEG-dop) and phenylboronic acid-modified cholesterol (Chol-PBA) are successfully synthesized for delivery of both doxorubicin (DOX, anti-cancer drug) and tariquidar (TQR, P-glycoprotein inhibitor), which shows efficient nuclear DOX accumulation for overcoming tumor MDR. Through naturally forming phenylboronate linkage in physiological circumstances, Chol-PBA is able to bond with mPEG-dop. The resulting conjugates (PC) could self-assemble into reversible covalent nanoassemblies by dialysis method, and transmission electron microscopy analysis reveals the PC distributes in nano-scaled spherical particles before and after drug encapsulation. Under the assistance of Chol, PC can enter into lysosome of tumor cells via low-density lipoprotein (LDL) receptor-mediated endocytosis. Then the loaded TQR and DOX are released in acidic lysosomal compartments, which inhibit P-gp mediated efflux and elevate nuclear accumulation of DOX, respectively. At last, this drug loaded PC nanoassemblies show significant tumor suppression efficacy in multidrug-resistant tumor models, which suggests great potential for addressing MDR in cancer therapy.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Nanopartículas
/
Neoplasias
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
J Control Release
Asunto de la revista:
FARMACOLOGIA
Año:
2023
Tipo del documento:
Article