Co-Delivery of Metabolic Modulators Leads to Simultaneous Lactate Metabolism Inhibition and Intracellular Acidification for Synergistic Cancer Therapy.
Adv Mater
; 35(46): e2305512, 2023 Nov.
Article
en En
| MEDLINE
| ID: mdl-37487702
ABSTRACT
Simultaneous lactate metabolism inhibition and intracellular acidification (LIIA) is a promising approach for inducing tumor regression by depleting ATP. However, given the limited efficacy of individual metabolic modulators, a combination of various modulators is required for highly efficient LIIA. Herein, a co-delivery system that combines lactate transporter inhibitor, glucose oxidase, and O2 -evolving nanoparticles is proposed. As a vehicle, a facile room-temperature synthetic method for large-pore mesoporous silica nanoparticles (L-MSNs) is developed. O2 -evolving nanoparticles are then conjugated onto L-MSNs, followed by immobilizing the lactate transporter inhibitor and glucose oxidase inside the pores of L-MSNs. To load the lactate transporter inhibitor, which is too small to be directly loaded into the large pores, it is encapsulated in albumin by controlling the albumin conformation before being loaded into L-MSNs. Notably, inhibiting lactate efflux shifts the glucose consumption mechanism from lactate metabolism to glucose oxidase reaction, which eliminates glucose and produces acid. This leads to synergistic LIIA and subsequent ATP depletion in cancer cells. Consequently, L-MSN-based co-delivery of modulators for LIIA shows high anticancer efficacy in several mouse tumor models without toxicity in normal tissues. This study provides new insights into co-delivery of small-molecule drugs, proteins, and nanoparticles for synergistic metabolic modulation in tumors.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Nanopartículas
/
Neoplasias
Límite:
Animals
Idioma:
En
Revista:
Adv Mater
Asunto de la revista:
BIOFISICA
/
QUIMICA
Año:
2023
Tipo del documento:
Article