RESUMEN
Microcarrier is a promising drug delivery system demonstrating significant value in treating cancers. One of the main goals is to devise microcarriers with ingenious structures and functions to achieve better therapeutic efficacy in tumors. Here, inspired by the nucleus-cytoplasm structure of cells and the material exchange reaction between them, we develop a type of biorthogonal compartmental microparticles (BCMs) from microfluidics that can separately load and sequentially release cyclooctene-modified doxorubicin prodrug (TCO-DOX) and tetrazine-modified indocyanine green (Tz-ICG) for tumor therapy. The Tz-ICG works not only as an activator for TCO-DOX but also as a photothermal agent, allowing for the combination of bioorthogonal chemotherapy and photothermal therapy (PTT). Besides, the modification of DOX with cyclooctene significantly decreases the systemic toxicity of DOX. As a result, the developed BCMs demonstrate efficient in vitro tumor cell eradication and exhibit notable tumor growth inhibition with favorable safety. These findings illustrate that the formulated BCMs establish a platform for bioorthogonal prodrug activation and localized delivery, holding significant potential for cancer therapy and related applications.
Asunto(s)
Doxorrubicina , Sistemas de Liberación de Medicamentos , Verde de Indocianina , Terapia Fototérmica , Profármacos , Doxorrubicina/farmacología , Doxorrubicina/química , Terapia Fototérmica/métodos , Humanos , Profármacos/farmacología , Profármacos/química , Animales , Verde de Indocianina/química , Verde de Indocianina/farmacología , Ratones , Sistemas de Liberación de Medicamentos/métodos , Línea Celular Tumoral , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Ciclooctanos/química , Ciclooctanos/farmacología , Ratones Endogámicos BALB C , Antineoplásicos/farmacología , Antineoplásicos/química , FemeninoRESUMEN
Nucleos(t)ide analogs (NAs) are widely used in the treatment of hepatitis B virus (HBV) and human immunodeficiency virus (HIV). The mutation L210W of HIV1 reverse transcriptase (RT) is one of the six principal mutations which confer in vivo resistance to zidovudine. Due to the similar 3Dstructure and high conservation between HIVRT and HBVRT, the present study aimed to clarify whether corresponding mutations in HBV may decrease its susceptibility to relevant NAs. Mutations including rtL228C/W, rtL229W and rtL228W/L229W were introduced into a HBV replication competent plasmid by fusion polymerase chain reaction. Replication capacity, HBs/e antigen (Ag) levels and susceptibility to NAs were subsequently analyzed in vitro. Single or combination mutations of rtL228 and rtL229 impaired HBV replication. Decreased HBsAg secretion in the supernatant and production in the cell lysate wasobserved with single rtL229W or in combination with rtL228W, while there was no significant difference between wildtype and mutant HBV with regard to the level of HBeAg in the supernatant and susceptibility to commonlyused NAs. Substitution mutations of rtL228 and/or L229 in HBV did not alter the susceptibility of the virus to NAs, although replication and HBsAg secretion were affected.