Reduction/Oxidation-Responsive Hierarchical Nanoparticles with Self-Driven Degradability for Enhanced Tumor Penetration and Precise Chemotherapy

Abstract

Deep tumor penetration, long blood circulation, rapid drug release, and sufficient stability are the most concerning dilemmas of nano-drug-delivery systems for efficient chemotherapy. Herein, we develop reduction/oxidation-responsive hierarchical nanoparticles co-encapsulating paclitaxel (PTX) and pH-stimulated hyaluronidase (pSH) to surmount the sequential biological barriers for precise cancer therapy. Poly­(ethylene glycol) diamine (PEG-dia) is applied to collaboratively cross-link the shell of nanoparticles self-assembled by a hyaluronic acid–stearic acid conjugate linked via a disulfide bond (HA–SS–SA, HSS) to fabricate the hierarchical nanoparticles (PHSS). The PTX and pSH coloaded hierarchical nanoparticles (PTX/pSH-PHSS) enhance the stability in normal physiological conditions and accelerate drug release at tumorous pH, and highly reductive or oxidative environments. Functionalized with PEG and HA, the hierarchical nanoparticles preferentially prolong the circulation time, accumulate at the tumor site, and enter MDA-MB-231 cells via CD44-mediated endocytosis. Within the acidic tumor micro-environment, pSH would be partially reactivated to decompose the dense tumor extracellular matrix for deep tumor penetration. Interestingly, PTX/pSH-PHSS could be degraded apace by the completely activated pSH within endo/lysosomes and the intracellular redox micro-environment to facilitate drug release to produce the highest tumor inhibition (93.71%) in breast cancer models.

Tumor microenvironment-activated cancer cell membrane-liposome hybrid nanoparticle-mediated synergistic metabolic therapy and chemotherapy for non-small cell lung cancer

“…Anabatic drug release was observed with a single trigger; for example, DTX release reached 43.7% in the presence of 50 mM DTT at pH 7.4 and 42.0% without DTT at pH 5 after 6 h. When CLip-PC@CO-LC NPs were incubated with a release medium at pH = 5 containing DTT, DTX release reached 79.0% with a fast release after 6 h. These results may be attributed to reduction-triggered disulfide bond destruction and the charge-reversal core leading to the disruption of the CLip, indicating that the biomimetic nano-delivery system remains stable in the blood circulation system and has less drug leakage. Nevertheless, the burst release of the drug can be triggered by high GSH and low pH in the TME when the NPs reach the tumor site [ 50 , 51 ].…”

Bioenzyme-based nanomedicines for enhanced cancer therapy

“…Although these recent promising progresses of bioenzyme-based nanomedicines in the field of cancer therapy Mesoporous silica Ribonuclease A Catalyze RNA degradation [37] Large-pore mesoporous silica Ribonuclease A Degrade mRNA and tRNA [38] Polymer-based nanoparticles Ribonuclease A Degrade cellular RNA [39] Hollow organosilica Glucose oxidase Consume glucose [40] Mesoporous polydopamine Glucose oxidase Consume glucose [41] Liposomes Glucose oxidase Consume glucose [42] Porous silica nanoparticles Hyaluronidase Decompose HA-DOX to produce toxic dissociative DOX [43] Micelles Collagenase Digest collagen fibers in tumor ECM [45] Nanogels Collagenase Digest tumor ECM [46] Heavy-chain ferritin nanocages Collagenase Degrade the collagen in tumor ECM [47] PCL-PEG nanoparticles Collagenase IV Degrade the collagen component of ECM [48] Chitosan nanoparticles Bromelain Digest tumor ECM [49] Hierarchical nanoparticles Hyaluronidase Degrade hyaluronic acid in tumor ECM [51] Micelles Hyaluronidase Degrade hyaluronic acid in tumor ECM [52] PTT Ultrasmall platinum nanoparticles Glucose oxidase Catalyze glucose to produce H 2 O 2 and D-glucono-δ-lactone [58] Semiconducting polymer nanoparticles Bromelain Digest collagen in tumor ECM [59] Gold/mesoporous polydopamine nanoparticles Papain Degrade tumor ECM [60] Liquid metal nanoparticles Glucose oxidase Inhibit ATP and HSP levels [61] Porous hollow Prussian blue nanoparticles…”

“…In addition to collagen, HA is another main component in tumor ECM, and thus HAase that effectively degrades HA can allows enhanced chemotherapy. For instance, Li's group developed a reduction/oxidation-responsive hierarchical nanoparticle with coencapsulation of PTX and pH-stimulated HAase to achieve self-driven degradability for enhanced tumor penetration and precise chemotherapy [51]. A HAbased amphiphilic conjugate synthesized by conjugating stearic acid on HA via disulfide bonds was used to entrap PTX to form nanoparticles through self-assembly, and then pH-stimulated HAase was loaded onto the shell of nanoparticles.…”

Effect of the disulfide bond and polyethylene glycol on the degradation and biophysicochemical properties of polyurethane micelles

“…A reductive environment has been recognized as the characteristic of cancer cells and significantly differs from local redox microenvironments within normal tissue. 32 Glutathione (GSH), a tripeptide involved glutamate, cysteine, and glycine produced in the cell cytoplasm cleave the disulfide bond through a thiol–disulfide exchange reaction. 33 The level of GSH in the extracellular compartment (2–20 μM) is considerably lower than that in the intracellular fluid (2–10 mM).…”