Abstract
A novel multifunctional nano-drug delivery system based on reversal of peptide charge was successfully developed for anticancer drug delivery and imaging. Mesoporous silica nano-particles (MSN) ~50 nm in diameter were chosen as the drug reservoirs, and their surfaces were modified with HIV-1 transactivator peptide-fluorescein isothiocyanate (TAT-FITC) and YSA-BHQ1. The short TAT peptide labeled with FITC was used to facilitate intranuclear delivery, while the YSA peptide tagged with the BHQ1 quencher group was used to specifically bind to the tumor EphA2 membrane receptor. Citraconic anhydride (Cit) was used to invert the charge of the TAT peptide in neutral or weak alkaline conditions so that the positively charged YSA peptide could combine with the TAT peptide through electrostatic attraction. The FITC fluorescence was quenched by the spatial approach of BHQ1 after the two peptides bound to each other. However, the Cit-amino bond was unstable in the acidic atmosphere, so the positive charge of the TAT peptide was restored and the positively charged YSA moiety was repelled. The FITC fluorescence was recovered after the YSA-BHQ1 moiety was removed, and the TAT peptide led the nano-particles into the nucleolus. This nano-drug delivery system was stable at physiological pH, rapidly released the drug in acidic buffer, and was easily taken up by MCF-7 cells. Compared with free doxorubicin hydrochloride at an equal concentration, this modified MSN loaded with doxorubicin molecules had an equivalent inhibitory effect on MCF-7 cells. This nano-drug delivery system is thus a promising method for simultaneous cancer diagnosis and therapy.
Highlights
Chemotherapy has greatly increased the survival rates of patients with cancer, but traditional chemotherapeutic drugs lack specificity and damage healthy cells/tissues, resulting in serious side-effects that immensely reduce the therapeutic effects [1,2,3]
Mesoporous silica nano-particles (MSN) ~50 nm in diameter were chosen as the drug reservoirs, and their surfaces were modified with HIV-1 transactivator peptidefluorescein isothiocyanate (TAT-FITC) and YSA-BHQ1
The synthesis procedure of MSN/COOH/TATFITC/Citraconic anhydride (Cit)/YSA-BHQ1/doxorubicin hydrochloride (DOX) is illustrated in Scheme 1
Summary
Chemotherapy has greatly increased the survival rates of patients with cancer, but traditional chemotherapeutic drugs lack specificity and damage healthy cells/tissues, resulting in serious side-effects that immensely reduce the therapeutic effects [1,2,3]. The specific targeting and pharmacology of nano-particles could be improved by means of a decorating targeting segment on the surface, such as a vitamin, antibody, protein, aptamer, or peptide This active targeting strategy could vastly improve the antineoplastic effects of anticancer drugs and increase the imaging sensitivity of tumor tissues by enhancing the signal-to-noise ratio [6,7,8,9]. It has been reported that the drug release from carrier systems occurs mainly in the cytoplasm, so the maximal anticancer effects cannot be achieved against targets inside the cell nucleus [10] One solution to this has been to incorporate a nuclear localization signal (NLS) peptide into the carrier system, such as simian virus 40 T-antigen (SVT) or human immunodeficiency virus 1 transactivator protein (HIV TAT) [11,12,13]. To solve all the abovementioned problems, our research group designed a drug delivery system based on peptide charge inversion, in order to achieve continuous multistage targeting and simultaneously perform fluorescent imaging and nuclear drug delivery
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