RESUMO
BAY55-9837, a potential therapeutic peptide in the treatment of type 2 diabetes mellitus (T2DM), is capable of inducing glucose (GLC)-dependent insulin secretion. However, the therapeutic benefit of BAY55-9837 is limited by its short half-life, lack of targeting ability, and poor blood GLC response. How to improve the blood GLC response of BAY55-9837 is an existing problem that needs to be solved. In this study, a method for preparing BAY55-9837-loaded exosomes coupled with superparamagnetic iron oxide nanoparticle (SPIONs) with pancreas islet targeting activity and an enhanced blood GLC response with the help of an external magnetic force (MF) is demonstrated. The plasma half-life of BAY55-9837 loaded in exosome-SPION is 27-fold longer than that of BAY55-9837. The active targeting property of SIPONs enables BAY-exosomes to gain a favorable targeting property, which improves the BAY55-9837 blood GLC response capacity with the help of an external MF. In vivo studies show that BAY-loaded exosome-based vehicle delivery enhances pancreas islet targeting under an external MF and markedly increases insulin secretion, thereby leading to the alleviation of hyperglycemia. The chronic administration of BAY-exosome-SPION/MF significantly improves glycosylated hemoglobin and lipid profiles. BAY-exosome-SPION/MF maybe a promising candidate for a peptide drug carrier for T2DM with a better blood GLC response.
Assuntos
Exossomos/química , Pâncreas/metabolismo , Animais , Diabetes Mellitus Tipo 2/sangue , Ácidos Graxos/metabolismo , Compostos Férricos/química , Humanos , Camundongos , Nanopartículas/química , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Alpha-momorcharin (alpha-MMC) is a ribosome-inactivating protein (RIP) with excellent cytotoxicity to tumor cells. However, its strong immunogenicity and short plasma half-life limit its clinical applications. To overcome this, we have to PEGylated alpha-MMC using a branched 20 kDa (mPEG) (2)-Lys-NHS. Homogeneous mono-, di- and tri-PEGylated alpha-MMCs were synthesized, purified and characterized. In vitro and in vivo analysis indicated that the serial PEG-conjugates preserved moderate anti-tumor activity with 36% acute toxicity and at most 66% immunogenicity decrease. These results suggested the potential application of alpha-MMC-PEG conjugates as an anti-tumor agent.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Proteínas Inativadoras de Ribossomos/química , Proteínas Inativadoras de Ribossomos/farmacologia , Animais , Antineoplásicos/imunologia , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Humanos , Dose Letal Mediana , Camundongos , Camundongos Endogâmicos BALB C , Polietilenoglicóis/toxicidade , Coelhos , Proteínas Inativadoras de Ribossomos/imunologia , Proteínas Inativadoras de Ribossomos/toxicidadeRESUMO
Tumor necrosis factor (TNF-α) is capable of inducing apoptosis and is a promising candidate for genetic engineering drugs in cancer therapy; however, the serious side-effects of TNF-α hinder their clinical application. In the present study, a method for preparing fusion proteins of cell-penetrating peptides (CPP) and TNF-α (CTNF-α)-anchored exosomes coupled with superparamagnetic iron oxide nanoparticles (CTNF-α-exosome-SPIONs) with membrane targeting anticancer activity has been demonstrated. To acquire exosomes with TNF-α anchored in its membrane, a CTNF-α expression vector was constructed and a stable mesenchymal stem cell cell line that expressed CTNF-α was established. Conjugating transferrin-modified SPIONs (Tf-SPIONs) onto CTNF-α-exosomes through transferrin-transferrin receptor (Tf-TfR) interaction yields CTNF-α-exosome-SPIONs with good water dispersibility. The incorporation of TNF-α into exosomes and the conjugation of SPIONs significantly enhanced the binding capacity of TNF-α to its membrane-bound receptor TNFR I, thus increasing the therapeutic effects. CTNF-α-exosome-SPIONs significantly enhanced tumor cell growth inhibition via induction of the TNFR I-mediated apoptotic pathway. In vivo studies using murine melanoma subcutaneous cancer models showed that TNF-α-loaded exosome-based vehicle delivery enhanced cancer targeting under an external magnetic field and suppressed tumor growth with mitigating toxicity. Taken together, our results suggest that CTNF-α-exosome-SPIONs showed great potential in membrane targeting therapy.