Hepatoma-Targeting and ROS-Responsive Polymeric Micelle-Based Chemotherapy Combined with Photodynamic Therapy for...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Combining nanoplatform chemotherapy with photodynamic therapy (PDT) offers a promising strategy for cancer treatment.
• Celastrol (Cela) demonstrates potent anti-hepatoma activity but suffers from poor solubility, bioavailability, targeting, and significant side effects.
• Targeted and reactive oxygen species (ROS)-responsive polymeric micelles (PMs) can potentially overcome Cela's limitations and enhance antitumor efficacy when combined with PDT.

Purpose of the Study:

• To develop and characterize novel glycyrrhetinic acid-modified carboxymethyl chitosan-thioketal-rhein (GCTR) polymeric micelles (PMs) co-loaded with Celastrol (Cela) and chlorin e6 (Ce6).
• To evaluate the safety, ROS-sensitive drug release, and intracellular ROS generation of these PMs.
• To investigate the in vitro and in vivo anti-hepatoma effects, including cellular uptake, pharmacokinetics, tissue distribution, and antitumor efficacy.

Main Methods:

• Preparation and characterization of Cela/Ce6/GCTR PMs with controlled particle size and high drug loading.
• Assessment of PM safety, hemocompatibility, and ROS-responsive drug release kinetics.
• In vitro evaluation of cellular uptake and ROS-induced cytotoxicity in HepG2 and BEL-7402 hepatoma cell lines.
• In vivo studies in H22 tumor-bearing mice to assess pharmacokinetics, tissue distribution, and antitumor efficacy.

Main Results:

• Successfully synthesized Cela/Ce6/GCTR PMs with desirable nanometer particle size, drug loading, and encapsulation efficiency.
• Demonstrated a strong safety profile and improved hemocompatibility of the PMs, with reduced damage to normal tissues.
• Observed enhanced ROS-responsiveness and accelerated Cela release upon PDT activation, leading to efficient targeting of liver tumor cells and potent ROS-mediated cell killing.
• Achieved increased bioavailability of Cela and Ce6, improved liver tumor targeting, and superior anti-hepatoma effects in vivo compared to monotherapy.

Conclusions:

• Hepatoma-targeting and ROS-responsive GCTR PMs co-loaded with Cela and Ce6, when combined with PDT, significantly improve primary hepatic carcinoma treatment.
• This nanoplatform overcomes the limitations of monotherapy, offering reduced toxicity to normal tissues.
• The developed PMs provide a novel and effective strategy for enhancing tumor treatment outcomes.