Broaden sources and reduce expenditure: Tumor-specific transformable oxidative stress nanoamplifier enabling economized photodynamic therapy for reinforced oxidation therapy

Theranostics. 2020 Aug 21;10(23):10513-10530. doi: 10.7150/thno.49731. eCollection 2020.

Abstract

Cancer cells immersed in inherent oxidative stress are more vulnerable to exogenous oxidative damages than normal cells. Reactive oxygen species (ROS)-mediated oxidation therapy preferentially aggravating tumor oxidative stress to disrupt redox homeostasis, has emerged as an effective and specific anticancer treatment. Herein, following an ingenious strategy of "broaden sources and reduce expenditure", we designed a versatile tumor-specific oxidative stress nanoamplifier enabling economized photodynamic therapy (PDT), to achieve synergistic oxidative stress explosion for superior oxidation therapy. Methods: Cinnamaldehyde (CA) as a therapeutic ROS generator was first conjugated to hyaluronic acid (HA) through acid-labile hydrazone bond to synthesize tailored amphiphilic HA@CA conjugates, which could surprisingly self-assemble into uniform nanofibers in aqueous media. Photosensitizer protoporphyrin (PpIX) was efficiently encapsulated into HA@CA nanofibers and transformed HA@CA nanofibers to final spherical HA@CAP. Results: With beneficial pH-responsiveness and morphology transformation, improved bioavailability and selective tumor accumulation, HA@CAP combining ROS-based dual chemo/photodynamic treatment modalities could induce cytotoxic ROS generation in a two-pronged approach to amplify tumor oxidative stress, termed "broaden sources". Moreover, utilizing CA-induced H2O2 production and cascaded Fenton reaction in mitochondria to consume intracellular overloaded Fe(II), HA@CAP could skillfully block endogenic heme biosynthesis pathway on site to restrain undesired elimination of PpIX for economized PDT, termed "reduce expenditure". Both in vitro and in vivo results demonstrated the superior antitumor performance of HA@CAP. Conclusion: This study offered an inspiring strategy of "broaden sources and reduce expenditure" to specifically boost tumor oxidative stress for reinforced oxidation therapy.

Keywords: Oxidative stress; broaden sources and reduce expenditure; economized photodynamic therapy; oxidation therapy; reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrolein / analogs & derivatives
  • Acrolein / chemistry
  • Acrolein / pharmacokinetics
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Biological Availability
  • Cell Line, Tumor / transplantation
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Drug Carriers / chemistry
  • Drug Carriers / pharmacokinetics*
  • Drug Compounding / methods
  • Drug Synergism
  • Female
  • Humans
  • Hyaluronic Acid / chemistry
  • Hyaluronic Acid / pharmacokinetics
  • Mice
  • NIH 3T3 Cells
  • Nanospheres / chemistry
  • Nanospheres / radiation effects
  • Nanospheres / therapeutic use
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Oxidative Stress / drug effects
  • Photochemotherapy / methods*
  • Photosensitizing Agents / administration & dosage*
  • Photosensitizing Agents / chemistry
  • Photosensitizing Agents / pharmacokinetics
  • Protoporphyrins / administration & dosage
  • Protoporphyrins / chemistry
  • Protoporphyrins / metabolism
  • Protoporphyrins / pharmacokinetics
  • Reactive Oxygen Species / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Drug Carriers
  • Photosensitizing Agents
  • Protoporphyrins
  • Reactive Oxygen Species
  • Acrolein
  • Hyaluronic Acid
  • protoporphyrin IX
  • cinnamaldehyde