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Porous Silicon Microparticles for Delivery of siRNA Therapeutics
Published on: January 15, 2015
Charge reversible calcium phosphate lipid hybrid nanoparticle for siRNA delivery
Rong-Qiao Cai1, Dao-Zhou Liu1, Han Cui1
1Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
Abstract:
Bcl-2 gene is an important target to treat lung cancer. The small interference RNA (siRNA) of Bcl-2 gene (siBcl-2) can specifically silence Bcl-2 gene. However, naked siBcl-2 is difficult to accumulate in the tumor tissue to exert its activity. In this paper, a calcium phosphate lipid hybrid nanoparticle that possessed charge reversible property was prepared to enhance the activity of siBcl-2 in vivo. The average diameter and zeta potential of siBcl-2 loaded calcium phosphate lipid hybrid nanoparticles (LNPS@siBcl-2) were 80 nm and -13 mV at pH7.4 whereas the diameter and zeta potential changed to 1506 nm and +9 mV at pH5.0. LNPS@siBcl-2 could efficiently deliver siBcl-2 to the cytoplasm and significantly decreased the expression of Bcl-2 in A549 cells. Moreover, the in vivo experimental results showed that most of the Cy5-siBcl-2 accumulated in tumor tissue after LNPS@Cy5-siBcl-2 was administered to tumor-bearing mice by tail vein injection. Meanwhile, the expression of Bcl-2 was decreased but the expression of the BAX and Caspase-3 was increased in tumor tissue. LNPS@siBcl-2 significantly inhibited the growth of tumor in tumor-bearing mice without any obvious systemic toxicity. Thus, the charge reversible calcium phosphate lipid hybrid nanoparticle was an excellent siBcl-2 delivery carrier to improve the activity of siBcl-2 in vivo. LNPS@siBcl-2 has potential in the treatment of lung cancer.
Insights
Charge-reversible nanoparticles effectively deliver small interfering RNA (siRNA) targeting the Bcl-2 gene (siBcl-2) to lung tumors. This enhanced delivery inhibits tumor growth with minimal toxicity, offering a promising new strategy for lung cancer treatment.
Area of Science:
- Biotechnology
- Nanomedicine
- Oncology
Background:
- The Bcl-2 gene is a critical therapeutic target for lung cancer.
- Small interfering RNA (siRNA) against Bcl-2 (siBcl-2) can specifically silence this gene.
- Challenges exist in delivering naked siBcl-2 to tumor tissues for effective therapeutic action.
Purpose of the Study:
- To develop a novel charge-reversible calcium phosphate lipid hybrid nanoparticle (LNPS) for enhanced in vivo delivery of siBcl-2.
- To evaluate the efficacy of LNPS-delivered siBcl-2 in a lung cancer model.
- To assess the safety profile of the developed nanoparticle system.
Main Methods:
- Preparation and characterization of siBcl-2 loaded calcium phosphate lipid hybrid nanoparticles (LNPS@siBcl-2), including size and zeta potential measurements at different pH values.
- In vitro assessment of siBcl-2 delivery efficiency and Bcl-2 gene silencing in A549 lung cancer cells.
- In vivo biodistribution studies using fluorescently labeled nanoparticles (LNPS@Cy5-siBcl-2) in tumor-bearing mice.
- Evaluation of therapeutic efficacy through tumor growth inhibition and analysis of apoptosis-related gene expression (Bcl-2, BAX, Caspase-3) in tumor tissues.
Main Results:
- LNPS@siBcl-2 exhibited charge-reversible properties, transitioning from negative at pH 7.4 to positive at pH 5.0, with an average diameter of 80 nm at physiological pH.
- Efficient delivery of siBcl-2 to the cytoplasm of A549 cells was achieved, leading to significant downregulation of Bcl-2 expression.
- In vivo studies demonstrated preferential accumulation of LNPS@Cy5-siBcl-2 in tumor tissues following intravenous administration.
- Treatment with LNPS@siBcl-2 resulted in decreased Bcl-2 expression and increased BAX and Caspase-3 expression in tumors, indicating apoptosis induction.
- Significant inhibition of tumor growth was observed in tumor-bearing mice treated with LNPS@siBcl-2, without apparent systemic toxicity.
Conclusions:
- Charge-reversible calcium phosphate lipid hybrid nanoparticles serve as an effective carrier for siBcl-2 delivery in lung cancer.
- This nanoparticle system enhances the in vivo activity of siBcl-2, leading to improved therapeutic outcomes.
- LNPS@siBcl-2 demonstrates significant potential for the treatment of lung cancer with a favorable safety profile.
