Multistage pH-responsive codelivery liposomal platform for synergistic cancer therapy
Ting Zhao1, Ce Liang2, Yanrong Zhao3
1Key Laboratory of Hebei Province for Innovative Drug Research and Evaluation, School of Pharmaceutical Sciences, Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
Background:
Small interfering RNA (siRNA) is utilized as a potent agent for cancer therapy through regulating the expression of genes associated with tumors. While the widely application of siRNAs in cancer treatment is severely limited by their insufficient biological stability and its poor ability to penetrate cell membranes. Targeted delivery systems hold great promise to selectively deliver loaded drug to tumor site and reduce toxic side effect. However, the elevated tumor interstitial fluid pressure and efficient cytoplasmic release are still two significant obstacles to siRNA delivery. Co-delivery of chemotherapeutic drugs and siRNA represents a potential strategy which may achieve synergistic anticancer effect. Herein, we designed and synthesized a dual pH-responsive peptide (DPRP), which includes three units, a cell-penetrating domain (polyarginine), a polyanionic shielding domain (ehG)n, and an imine linkage between them. Based on the DPRP surface modification, we developed a pH-responsive liposomal system for co-delivering polo-like kinase-1 (PLK-1) specific siRNA and anticancer agent docetaxel (DTX), D-Lsi/DTX, to synergistically exhibit anti-tumor effect.
Results:
In contrast to the results at the physiological pH (7.4), D-Lsi/DTX lead to the enhanced penetration into tumor spheroid, the facilitated cellular uptake, the promoted escape from endosomes/lysosomes, the improved distribution into cytoplasm, and the increased cellular apoptosis under mildly acidic condition (pH 6.5). Moreover, both in vitro and in vivo study indicated that D-Lsi/DTX had a therapeutic advantage over other control liposomes. We provided clear evidence that liposomal system co-delivering siPLK-1 and DTX could significantly downregulate expression of PLK-1 and inhibit tumor growth without detectable toxic side effect, compared with siPLK-1-loaded liposomes, DTX-loaded liposomes, and the combinatorial administration.
Conclusion:
These results demonstrate great potential of the combined chemo/gene therapy based on the multistage pH-responsive codelivery liposomal platform for synergistic tumor treatment.
Insights
This study developed a pH-responsive liposomal system for co-delivering chemotherapy and small interfering RNA (siRNA) to enhance anti-tumor effects. The dual drug delivery system showed improved tumor penetration and synergistic therapeutic advantages.
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.
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