Hierarchically stimuli-responsive nanovectors for improved tumor penetration and programed tumor therapy†
Poor drug delivery to solid tumors remains a great challenge for effective antitumor therapy. Herein, multistage stimuli-responsive nanovectors based on hollow mesoporous silica nanoparticles (HMSNs) were prepared to avoid delivery barriers for improved penetration and programmed tumor therapy. The versatile nanosystem was constructed through electrostatic complexation between the functional HMSNs loaded with gemcitabine (GEM) and the small-sized platinum prodrug-conjugated poly(amidoamine) dendrimer (PAMAM-Pt). The HMSNs were functionalized with dimethylmaleic anhydride tethered chitosan oligosaccharide to endow the particles of HMSN-CS(DMA) with charge-reversal properties. The as-prepared nanosystem had a stable structure of size ∼130 nm at pH 7.4, which is beneficial for blood circulation and tumor vessel extravasation of nanocarriers. Once it reaches the tumor site, the nanosystem can dissociate into HMSN@GEM-CS (∼120 nm) and PAMAM-Pt dendrimer nanocarriers (∼5 nm) in response to the acidic tumor microenvironment because of the acid-mediated charge-reversal, then the HMSN@GEM can play the antitumor role in surface tumor tissues. The dissociated PAMAM-Pt showed excellent performance in tumor penetration, cell uptake and intracellular trafficking due to the small size and positive charge, which was supported by the study of three-dimensional multicellular spheroids in vitro. Finally, the active cisplatin was released from the PAMAM-Pt dendrimer under the intracellular reducing environment to kill cells in deep tumor tissues. The significant tumor suppression of this system in vivo was validated in the A549 tumor xenografted mouse model. Such a stimuli-responsive nanosystem that integrates simple preparation, biocompatibility, biodegradability and programmed tumor therapy manifests great potential for clinical trials.