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Published on: February 8, 2017
An Orthogonally Clickable and Stimuli-Responsive Poly(β-amino ester) for the Co-delivery of Doxorubicin and BCL‑2
Andrea Martí Del Rio1, David Sánchez-García1
1Grup d'Enginyeria de Materials, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, Barcelona 08017, Spain.
Abstract:
A potent drug delivery system (DDS) based on poly-(β-amino ester)-s (pBAEs) to tackle multidrug resistance (MDR) in lung cancer by codelivering siRNA targeting antiapoptotic BCL-2 and doxorubicin (DOX) has been prepared. Engineered via strain-promoted azide-alkyne cycloaddition (SPAAC) to attach a tripeptide end-chain moiety and thiol-disulfide exchange to conjugate DOX, the system employs a hydrazone linker for dual pH- and redox-responsive release. This ensures precise tumor targeting with minimal leakage in the circulation. In multidrug-resistant lung cancer cells (GLC-4/ADR), it sharply downregulates BCL-2 expression, amplifying DOX's therapeutic impact.
Insights
This study presents a novel drug delivery system (DDS) using poly-(β-amino ester)-s to combat multidrug resistance (MDR) in lung cancer. The system co-delivers BCL-2 siRNA and doxorubicin (DOX) for enhanced cancer therapy.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Cancer Therapeutics
Background:
- Multidrug resistance (MDR) significantly limits the efficacy of lung cancer chemotherapy.
- Targeted delivery of therapeutic agents is crucial for improving treatment outcomes and reducing side effects.
Purpose of the Study:
- To develop a novel poly-(β-amino ester)-based drug delivery system (DDS) for co-delivery of siRNA and doxorubicin (DOX).
- To address multidrug resistance (MDR) in lung cancer by targeting the antiapoptotic BCL-2 gene.
Main Methods:
- Utilized strain-promoted azide-alkyne cycloaddition (SPAAC) for tripeptide conjugation and thiol-disulfide exchange for DOX conjugation.
- Incorporated a hydrazone linker for dual pH- and redox-responsive drug release.
- Engineered the DDS for precise tumor targeting and minimal systemic leakage.
Main Results:
- The DDS effectively downregulated BCL-2 expression in multidrug-resistant lung cancer cells (GLC-4/ADR).
- Co-delivery of siRNA and DOX amplified the therapeutic impact of doxorubicin.
- Demonstrated precise tumor targeting with reduced off-target effects.
Conclusions:
- The developed poly-(β-amino ester)-based DDS is a promising strategy for overcoming MDR in lung cancer.
- Dual-responsive release and targeted delivery enhance the efficacy of combined siRNA and chemotherapy.
- This approach offers a potential new avenue for lung cancer treatment.
