RESUMO
Therapeutic goals for metastatic breast cancer, including shrinkage of established metastasis and suppression of movement of tumor cells, are often hard to achieve and remain the main obstacles restricting the antimetastatic efficacy of targeted drug delivery systems (TDDSs). Herein, we proposed an E-selectin-targeting nanoplatform for the systemic treatment of metastatic breast cancer. Versatile functions, including killing the circulating tumor cells, shrinking the established lesions, as well as inhibiting the movement of tumor cells, were integrated into doxorubicin-loaded sialic acid-dextran-octadecanoic acid (SDO) micelles (SDD). The prepared SDD micelles could not only inhibit lung and liver metastasis in the orthotopic 4T1 tumors model, but also decrease the metastatic lesions in the metastatic 4T1 cell model, resulting in 27.33% reduced number of metastatic nodules when compared to those without sialic acid modification. It was found that the good antimetastatic effect of SDD was only partially attributed to its ability on removing metastatic cells and metastases. Most importantly, the blank SDO micelles left in the lesion could further inhibit the cell migration and cell-cell binding. These results suggest that SA-driven TDDS has the potential for specific targeting and effective treatment of cancer metastasis.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Selectina E/metabolismo , Nanoconjugados/química , Animais , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Linhagem Celular Tumoral/transplante , Movimento Celular/efeitos dos fármacos , Dextranos/química , Modelos Animais de Doenças , Doxorrubicina/farmacocinética , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Humanos , Ligantes , Camundongos , Micelas , Ácido N-Acetilneuramínico/química , Células Neoplásicas Circulantes/efeitos dos fármacos , Ácidos Esteáricos/químicaRESUMO
Both targeted and stimuli-sensitive drug-delivery systems (DDSs) have been developed to augment antitumor effects. However, lack of knowledge regarding tumor tissue targeting and different effects of the stimuli-sensitive DDSs in orthotropic and ectopic tumors have impeded further advances in their clinical applications. Herein, we first reported a pH-triggered micelle with sialic acid (SA)-driven targeting ability (SA-poly(ethylene glycol)-hydrazone linker-doxorubicin (DOX), SPD). The SPD micelles encapsulated with DOX (SPDD) showed sustained drug release over 48 h in response to the pH gradient in vivo, slow under physical conditions and accelerated in the acid tumor microenvironment. In addition, the SPD micelles showed 2.3-fold higher accumulation in tumors after 48 h compared to the micelles lacking the SA moiety. The overexpression of E-selectin on the inflammatory vascular endothelial cells surrounding the tumors increased the accumulation of SPD micelles in tumor tissues, whereas that on the tumor cells increased the internalization of micelles. Consequently, SPDD micelles exerted remarkable antitumor effects in both orthotopic and ectopic models. Application of SPDD micelles in the in situ model reduced the tumor volume (77.57 mm3 vs 62.13 mm3) and metastasis after treatment for 25 days. These results suggest that SA-driven targeted DDS with a pH-responsive switch has the potential to treat hepatocarcinoma effectively both ectopically and orthotopically.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Hepáticas/tratamento farmacológico , Micelas , Ácido N-Acetilneuramínico/química , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/toxicidade , Portadores de Fármacos/química , Feminino , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Targeted drug delivery systems (TDDS) have attracted wide attention for their reduced drug side effects and improved antitumor efficacy in comparison with traditional preparations. While targeting moieties in existing TDDS have principally focused on recognition of receptors on the surface of tumor cells, accumulation into tumor tissue only could be performed by enhanced permeability and retention effects and active transportation into tumor cells. Doxorubicin (DOX)-loaded sialic acid-dextran (Dex)-octadecanoic acid (OA) micelles (SA-Dex-OA/DOX) were designed for targeting hepatocellular carcinoma effectively. The synthesized conjugates could self-aggregate to form micelles with a critical micelle concentration of 27.6 µg·mL-1 and diameter of 54.53 ± 3.23 nm. SA-Dex-OA micelles incorporated with 4.36% DOX-loading content could prolong in vitro drug release to 96 h with 80% of final release. Cellular transportation studies revealed that SA-Dex-OA micelles mediated more efficient DOX delivery into Bel-7402 cells than those without SA modification. In vivo biodistribution testing demonstrated that SA-Dex-OA/ICG micelles showed 3.05-fold higher accumulation into Bel-7402 tumors. The recognition of overexpressed E-selectin in inflammatory tumor vascular endothelial cells led to a large accumulation of SA-Dex-OA/ICG micelles into tumor tissue, and the E-selectin upregulated on the surface of tumor cells contributed to active cellular transportation into tumor cells. Accordingly, SA-Dex-OA/DOX exhibited prior suppression of Bel-7402 tumor growth greater than that of Dex-OA/DOX micelles and free DOX (the tumor inhibition: 79.2% vs 61.0 and 51.3%). These results suggest that SA-functionalized micelles with dual targeting properties have high potential for liver cancer therapy.
Assuntos
Dextranos/química , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Micelas , Ácido N-Acetilneuramínico/química , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Selectina E/química , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos Nus , Ácidos Esteáricos/químicaRESUMO
Effective treatment and real-time monitoring of hepatic cancer are essential. A multifunctional calcium phosphate nanoparticles loading chemotherapeutic agent doxorubicin and magnetic resonance imaging contrast agent diethylenetriaminepentaacetic acid gadolinium (A54-CaP/Gd-DTPA/DOX) was developed for visual targeted therapy of hepatic cancer via T1-weighted MRI in real-time. A54-CaP/Gd-DTPA/DOX exhibited a higher longitudinal relaxivity (6.02â¯mM-1â¯s-1) than commercial MR contrast agent Gd-DTPA (3.3765â¯mM-1â¯s-1). The DOX release from the nanoparticles exhibited a pH dependent behavior. The cellular uptake results showed that the internalization of A54-CaP/Gd-DTPA/DOX into BEL-7402 cells was1.9-fold faster than that of HepG2 cells via A54 binding. In vivo experiments presented that A54-CaP/Gd-DTPA/DOX had higher distribution and longer retention time in tumor tissue than CaP/Gd-DTPA/DOX and free DOX, and also displayed great antitumor efficacy (95.38% tumor inhibition rate) and lower toxicity. Furthermore, the Gd-DTPA entrapped in the nanoparticles could provide T1-weighted MRI for real-time monitoring the progress of tumor treatment.