A stimuli-responsive Janus peptide dendron-drug conjugate as a safe and nanoscale drug delivery vehicle for breast cancer therapy

摘要

Smart nanoscale drug delivery systems have been investigated as potential candidates for drug delivery vehicles. Here, we used a breast cancer model to determine if the enzyme-responsive Janus dendron (mPEGylated dendron PVGLIG DOX) conjugate-based nanoscale system would be an effective and safe drug delivery vehicle for chemotherapy. To this end, we prepared and characterized the matrix metalloprotease-2 (MMP-2)/MMP-9-sensitive linker of the proline-valine-glycine-leucine-isoleucine-glycine (Pro-Val-Gly-Leu-Ile-Gly, PVGLIG) oligopeptide via a convenient and fast liquid-phase synthesis. Second, using a rational design strategy, the Janus dendron (Boc-G2L-G3L-OMe) was successfully modified with mPEG and PVGLIG-DOX via a two-step highly efficient copper-catalyzed alkyne azide click cycloaddition (CuAAC) reaction. Morphology studies such as dynamic light scattering, scanning electron microscopy, and atomic force microscopy were performed to confirm that the Janus mPEGylated dendron PVGLIG-DOX conjugate self-assembled into compact nanoparticles with a slightly negatively charged surface. The nanoscale system, which included nanoparticles with 4.0 wt% (weight percent) of doxorubicin (DOX), was analyzed using ultraviolet-visible absorption spectra, fluorescence emission spectra, and matrix assisted laser desorption/ionization time-of-flight. Nanoscale systems incubated with exogenous MMP-2 killed breast cancer cells were more effective than those lacking MMP-2. Compared to free DOX, the nanoscale system substantially reduced the side effects accompanied by a similar antitumor efficacy. Moreover, it had minimal systemic toxicities, especially DOX-induced toxicities to the normal organs of both tumor bearing and healthy mice, as determined by changes in the body weight and histological analysis. These data demonstrate that the Janus dendron drug conjugate-based nanoscale system may be an effective chemotherapy delivery vehicle for breast cancer.