A Redox-Sensitive Micelle-Like Nanoparticle Self-Assembled from Amphiphilic Adriamycin-Human Serum Albumin Conjugates for Tumor Targeted Therapy

Abstract

The application of chemotherapeutic drug adriamycin (ADR) in cancer therapy is limited by its side effects like high toxicity and insolubility. Nanomedicine offers new hope for overcoming the shortcomings. But how to increase in vivo stability and to control intracellular drug release is a key issue for nano-based formulations. Herein, the hydrophobic ADR was successfully linked to the biocompatible human serum albumin (HSA) by disulfide bond 3-(2-pyridyldithio) propionyl hydrazide (PDPH), resulting in amphiphilic HSA-ADR. The novel ADR-HSA micellar NPs which were thus assembled exhibited a well-defined stable core shell structure with glutathione (GSH) sensitive linkers. The stable PDPH linkers at extracellular level were broken by GSH at intracellular level with a controlled ADR release profile. The in vitro cytotoxicity against gastric cancer cells (NCI-N87) was obviously enhanced by such redox-sensitive ADR-HSA NPs. Additionally, as observed by IVIS Lumina II Imaging System (Xenogen), the intratumor accumulation of ADR-HSA NPs was much higher than that of HSA/ADR NPs due to its high stability. Consequently, the in vivo tumor inhibition was significantly promoted after intravenous administration to the Balb/c nude mice bearing gastric tumors. These in vitro/vivo results indicated that disulfide-bond-containing ADR-HSA NPs were an effective nanodrug delivery system for cancer therapy.

Disulfide bond based polymeric drug carriers for cancer chemotherapy and relevant redox environments in mammals

“…The inhibition of cell proliferation was observed because of rapid CPT and DOX release in cytotoxicity studies. Chen et al . linked the hydrophobic adriamycin (ADR) to the biocompatible HSA by disulfide bond 3‐(2‐pyridyldithio) propionyl hydrazide (PDPH), forming amphiphilic HSA‐ADR.…”

Antibody-nanoparticle conjugate constructed with trastuzumab and nanoparticle albumin-bound paclitaxel for targeted therapy of human epidermal growth factor receptor�2-positive gastric cancer

“…Albumin-bound formulation for paclitaxel based on nano-drug delivery system, nab-paclitaxel, has the advantage of passive target for tumor due to EPR effect. Now, deliberate modifications of ligand or antibody to the surface of nanoparticles were conducted to achieve specific targeting to the corresponding receptor on tumor cells (22,36). The unique targeting mechanism of HSA (22,37) and passive targeting property of nab-paclitaxel along with the active targeting property of anti-HER2 antibody may introduce sequentially dual-targeting and more precise paclitaxel delivery.…”

“…Tumor volumes (V/mm 3 ) were calculated using the formula: V = ½ x a x b 2 . When tumor volumes reached ~60 mm 3 (22), the mice were randomly divided into four groups: PBS as control group, paclitaxel, nab-paclitaxel and trastuzumab/nab-paclitaxel (all the groups were treated with equivalent paclitaxel concentration at 20 mg/kg). The intravenous treatment was done twice a week for four times.…”

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

“…[54] Furthermore, stimuli-responsive materials sensitive to increased glutathione concentration inside the cells, specific enzymes or adenosine triphosphate (ATP), have also been largely applied into nanomedicines that are detailed elsewhere. [55][56][57] Active-stimuli responsive drug release is a more precise and easily controllable strategy by using external stimuli. The design of these nanosystems usually takes advantage of photoactivated, [58] thermo-activated [59] and magnetic-activated materials [60] to achieve drug delivery under a specific external signal.…”