Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy

Area of Science:

• Biotechnology and Nanomedicine
• Cancer Therapy
• Drug Delivery Systems

Background:

• Small interfering RNA (siRNA) shows promise for cancer therapy but faces challenges in stability and cell penetration.
• Targeted delivery systems are crucial for delivering drugs to tumors and reducing side effects.
• Overcoming tumor interstitial fluid pressure and ensuring endosomal escape are key hurdles in siRNA delivery.

Purpose of the Study:

• To design and synthesize a dual pH-responsive peptide (DPRP) for targeted drug delivery.
• To develop a pH-responsive liposomal system for co-delivering siRNA and docetaxel (DTX).
• To evaluate the synergistic anti-tumor effect of the co-delivery system.

Main Methods:

• Synthesis of a dual pH-responsive peptide (DPRP) with cell-penetrating and shielding domains.
• Development of a pH-responsive liposomal system (D-Lsi/DTX) for co-delivering polo-like kinase-1 (PLK-1) siRNA and docetaxel (DTX).
• In vitro and in vivo studies to assess tumor penetration, cellular uptake, endosomal escape, and therapeutic efficacy.

Main Results:

• The D-Lsi/DTX system demonstrated enhanced tumor penetration, cellular uptake, and cytoplasmic release of siRNA and DTX under mildly acidic conditions (pH 6.5).
• The co-delivery system significantly promoted cellular apoptosis and inhibited tumor growth compared to control groups.
• In vitro and in vivo studies confirmed the therapeutic advantage of D-Lsi/DTX, showing significant PLK-1 downregulation and tumor inhibition without detectable toxicity.

Conclusions:

• The developed multistage pH-responsive co-delivery liposomal platform holds significant potential for synergistic tumor treatment.
• Combined chemo/gene therapy using this platform offers a promising strategy for enhanced cancer therapy.
• The system effectively addresses challenges in siRNA delivery and demonstrates potent anti-tumor activity.