Dual Enzymatic Reaction-Assisted Gemcitabine Delivery Systems for Programmed Pancreatic Cancer Therapy

Abstract

Dual enzymatic reactions were introduced to fabricate programmed gemcitabine (GEM) nanovectors for targeted pancreatic cancer therapy. Dual-enzyme-sensitive GEM nanovectors were prepared by conjugation of matrix metalloproteinase-9 (MMP-9) detachable poly(ethylene glycol) (PEG), cathepsin B-cleavable GEM, and targeting ligand CycloRGD to CdSe/ZnS quantum dots (QDs). The GEM nanovectors decorated with a PEG corona could avoid nonspecific interactions and exhibit prolonged blood circulation time. After GEM nanovectors were accumulated in tumor tissue by the enhanced permeability and retention (EPR) effect, the PEG corona can be removed by overexpressed MMP-9 in tumor tissue and RGD would be exposed, which was capable of facilitating cellular internalization. Once internalized into pancreatic cancer cells, the elevated lysosomal cathepsin B could further promote the release of GEM. By employing dual enzymatic reactions, the GEM nanovectors could achieve prolonged circulation time while maintaining enhanced cellular internalization and effective drug release. The proposed mechanism of the dual enzymatic reaction-assisted GEM delivery system was fully investigated both in vitro and in vivo. Meanwhile, compared to free GEM, the deamination of GEM nanovectors into inactive 2',2'-difluorodeoxyuridine (dFdU) could be greatly suppressed, while the concentration of the activated form of GEM (gemcitabine triphosphate, dFdCTP) was significantly increased in tumor tissue, thus exhibiting superior tumor inhibition activity with minimal side effects.

Rational Design of Nanoparticles with Deep Tumor Penetration for Effective Treatment of Tumor Metastasis

“…The overexpression of extracellular enzymes, especially MMPs and legumain, is another striking characteristic that can be used for programmed targeting of primary tumor or metastasis sites . Inspired by the highly expressed MMP in tumor regions, Wang and co‐workers designed an enzyme‐sensitive nanocapsule consisting of a nanovesicle core decorated with the penetrating CRGDK peptide and a MMP‐2‐degradable polymeric shell anchored on the core.…”

Site‐Specific Construction of Long‐Term Drug Depot for Suppression of Tumor Recurrence

“…As above‐mentioned, CtsB is a lysosomal cysteine protease overexpressed in various malignant tumor cells, so the cellular uptake of CPT‐LFPR nanoparticles and their colocalization with lysosomes in HeLa cells are monitored by CLSM . The green fluorescence of CPT becomes stronger with the increase of incubation time, which also can be colocalized with red fluorescence from lysosomes (stained by Lysotracker red) ( Figure a,b).…”

Recent Advances in Targeted Tumor Chemotherapy Based on Smart Nanomedicines

“…After the EPR‐mediated accumulation of drug in tumor tissue, PEG corona was detached by MMP‐9 in tumor and exposed cRGD facilitated cellular internalization. Then, the elevated lysosomal cathepsin B in tumor cells further promoted gemcitabine (GEM) release for pancreatic tumor therapy (Figure B) . In another study, pH‐triggered cRGD targeting was integrated with PDT and MMP‐sensitive DOX release for improved tumor therapy …”

“…B) Schematic illustration of dual‐enzyme‐sensitive nanovectors used to achieve tumor‐triggered targeting and efficient drug release. Adapted with permission . Copyright 2017, American Chemical Society.…”