Polydopamine-modified cyclodextrin metal-organic framework for efficient BCL-2 siRNA delivery in lung cancer therapy
Yu Sun1, Rongxin Guo2, Hongbin Xu1
1Department of Pharmacy, The First Affiliated Hospital of Ningbo University, Ningbo, China.
Abstract:
The antiapoptotic protein B-cell lymphoma 2 (BCL-2) is overexpressed in lung cancer, serving as a key mechanism for apoptosis evasion. Therapeutics targeting BCL-2, such as small interfering RNA (siRNA), hold great promise for lung cancer treatment, while delivery challenges hinder the clinical applications of BCL-2 targeting agents. Cyclodextrin metal-organic framework (CD-MOF) is a facile and edible drug delivery carrier with remarkable biocompatibility, which is a suitable candidate for gene delivery. In our study, BCL-2 siRNA (siBCL-2) was loaded into CD-MOFs and subsequently coated by polydopamine (PDA) to form siBCL-2@CD-MOF@PDA nanoplatform. PDA modification creates a protective layer, preventing siBCL-2 from hydrolytic degradation. Results showed CD-MOF@PDA effectively overcame the intrinsic limitations of siRNA and the agarose gel electrophoresis confirmed that CD-MOF@PDA significantly enhanced the stability of siRNA. Western blot results demonstrated that siBCL-2@CD-MOF@PDA markedly reduced the expression level of BCL-2 protein compared with free siBCL-2. In an A549 tumor model, both in vivo and ex vivo biodistribution assays demonstrated the outstanding intratumor retention capacity of siBCL-2@CD-MOF@PDA. Moreover, siBCL-2@CD-MOF@PDA achieved excellent therapeutic effects compared with other groups while maintaining favorable biocompatibility in vivo. This work may provide a potential alternative to precise gene therapy for cancer.
Insights
This study developed a novel nanoplatform using cyclodextrin metal-organic framework and polydopamine to deliver BCL-2 siRNA, effectively inhibiting lung cancer growth and enhancing gene therapy delivery.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- B-cell lymphoma 2 (BCL-2) overexpression promotes lung cancer survival by inhibiting apoptosis.
- Effective delivery of BCL-2 targeting agents like siRNA is crucial but faces significant challenges.
- Cyclodextrin metal-organic framework (CD-MOF) offers biocompatible drug delivery potential.
Purpose of the Study:
- To develop a novel nanoplatform for enhanced delivery of BCL-2 siRNA (siBCL-2) for lung cancer therapy.
- To overcome the limitations of siRNA stability and delivery using CD-MOF and polydopamine (PDA).
- To evaluate the therapeutic efficacy and biocompatibility of the siBCL-2@CD-MOF@PDA nanoplatform in vitro and in vivo.
Main Methods:
- siBCL-2 was loaded into CD-MOFs and coated with PDA to create the siBCL-2@CD-MOF@PDA nanoplatform.
- Agarose gel electrophoresis was used to assess siRNA stability.
- Western blot analysis measured BCL-2 protein expression levels.
- In vivo and ex vivo biodistribution assays were performed in an A549 tumor model.
Main Results:
- The CD-MOF@PDA nanoplatform significantly enhanced the stability of siRNA against degradation.
- siBCL-2@CD-MOF@PDA markedly reduced BCL-2 protein expression compared to free siBCL-2.
- The nanoplatform demonstrated excellent intratumor retention and superior therapeutic effects in vivo.
- Favorable biocompatibility was observed for the siBCL-2@CD-MOF@PDA nanoplatform.
Conclusions:
- The siBCL-2@CD-MOF@PDA nanoplatform effectively overcomes siRNA delivery challenges for lung cancer treatment.
- This novel nanoplatform shows significant potential as an alternative for precise cancer gene therapy.
- Further research into this delivery system could advance targeted cancer therapeutics.
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