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Synthesis, Cellular Delivery and In vivo Application of Dendrimer-based pH Sensors
Published on: September 10, 2013
Dendrimer Conjugates for Light-activated Delivery of Antisense Oligonucleotides
Ahu Yuan1, Yiqiao Hu2, Xin Ming3
1Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA ; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
Abstract:
Therapeutic oligonucleotides, such as splice switching ONs (SSOs), provide opportunities for treating serious, life-threatening diseases. However, the development of ONs as therapeutic agents has progressed slowly, because difficult cytosolic delivery of SSOs into the cytosol and nucleus remains a major barrier. Photochemical internalization (PCI), a promising strategy for endosomal escape, was introduced to disrupt the endosomal membrane using light and a photosensitizer. Here we constructed Poly(amido amine) (PAMAM) dendrimer conjugates to simultaneously deliver SSOs and photosensitizers into endo/lysosomal compartments. After photo-irradiation, considerable ONs were observed to diffuse into the cytosol and accumulate in the nucleus. Furthermore, the PCI mediated cytosolic delivery of SSOs effectively enhanced their nuclear splice switching activity.
Insights
This study introduces a novel method for delivering therapeutic splice switching oligonucleotides (SSOs) into cells. By using Poly(amido amine) dendrimers and photochemical internalization, SSO delivery to the nucleus was significantly improved, enhancing splice switching activity.
Area of Science:
- Biotechnology
- Molecular Biology
- Drug Delivery
Background:
- Therapeutic oligonucleotides, like splice switching oligonucleotides (SSOs), hold promise for treating severe diseases.
- A major challenge in SSO therapy is their inefficient delivery into the cell's cytosol and nucleus.
- Photochemical internalization (PCI) is a technique that uses light and photosensitizers to facilitate endosomal escape.
Purpose of the Study:
- To develop a method for enhanced cytosolic and nuclear delivery of SSOs.
- To investigate the efficacy of Poly(amido amine) (PAMAM) dendrimer conjugates for co-delivering SSOs and photosensitizers.
- To evaluate the impact of PCI on SSO splice switching activity.
Main Methods:
- Construction of PAMAM dendrimer conjugates for simultaneous SSO and photosensitizer delivery.
- Loading of SSOs and photosensitizers into endo/lysosomal compartments using PAMAM conjugates.
- Application of photo-irradiation to induce PCI and promote endosomal escape.
- Assessment of SSO localization in the cytosol and nucleus post-PCI.
- Quantification of nuclear splice switching activity mediated by PCI-delivered SSOs.
Main Results:
- PAMAM dendrimer conjugates successfully co-delivered SSOs and photosensitizers into endo/lysosomal compartments.
- Photo-irradiation via PCI led to significant diffusion of SSOs into the cytosol and their accumulation in the nucleus.
- PCI-mediated delivery substantially enhanced the nuclear splice switching activity of the delivered SSOs.
Conclusions:
- PAMAM dendrimer-based conjugates combined with PCI offer an effective strategy for overcoming SSO delivery barriers.
- This approach significantly improves the cytosolic and nuclear delivery of therapeutic oligonucleotides.
- Enhanced SSO delivery via PCI holds potential for advancing the treatment of genetic diseases.
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