Dataset Information

Cytoplasmic delivery of functional siRNA using pH-Responsive nanoscale hydrogels.

ABSTRACT: The progress of short interfering RNA (siRNA) technologies has unlocked the development of novel alternatives for the treatment of a myriad of diseases, including viral infections, autoimmune disorders, or cancer. Nevertheless, the clinical use of these therapies faces significant challenges, mainly overcoming the charged and large nature of these molecules to effectively enter the cell. In this work, we developed a cationic polymer nanoparticle system that is able to load siRNA due to electrostatic interactions. The pH-responsiveness and membrane-disrupting ability of these carriers make them suitable intracellular delivery vehicles. In the work presented herein we synthesized, characterized, and evaluated the properties of nanoparticles based on 2-diethylaminoethyl methacrylate and tert-butyl methacrylate copolymers. A disulfide crosslinker was incorporated in the nanogels to enable the degradation of the nanoparticles in reductive environments, showing no significant changes on their physicochemical properties. The capability of the developed nanogels to be internalized, deliver siRNA, and induce gene knockdown were demonstrated using a human epithelial colorectal adenocarcinoma cell line. Overall, these findings suggest that this platform exhibits desirable characteristics as a potential siRNA-delivery platform.

SUBMITTER: Liechty WB

PROVIDER: S-EPMC6814015 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Cytoplasmic delivery of functional siRNA using pH-Responsive nanoscale hydrogels.

Liechty William B WB Scheuerle Rebekah L RL Vela Ramirez Julia E JE Peppas Nicholas A NA

International journal of pharmaceutics 20190308

The progress of short interfering RNA (siRNA) technologies has unlocked the development of novel alternatives for the treatment of a myriad of diseases, including viral infections, autoimmune disorders, or cancer. Nevertheless, the clinical use of these therapies faces significant challenges, mainly overcoming the charged and large nature of these molecules to effectively enter the cell. In this work, we developed a cationic polymer nanoparticle system that is able to load siRNA due to electrost ...[more]

PMID: 30858114

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Project description:Pulsatile chemotherapeutic delivery profiles may provide a number advantages by maximizing the anticancer toxicity of chemotherapeutics, reducing off-target side effects, and combating adaptive resistance. While these temporally dynamic deliveries have shown some promise, they have yet to be clinically deployed from implantable hydrogels, whose localized deliveries could further enhance therapeutic outcomes. Here, several pulsatile chemotherapeutic delivery profiles were tested on melanoma cell survival in vitro and compared to constant (flatline) delivery profiles of the same integrated dose. Results indicated that pulsatile delivery profiles were more efficient at killing melanoma cells than flatline deliveries. Furthermore, results suggested that parameters like the duration of drug "on" periods (pulse width), delivery rates during those periods (pulse heights), and the number/frequency of pulses could be used to optimize delivery profiles. Optimization of pulsatile profiles at tumor sites in vivo would require hydrogel materials capable of producing a wide variety of pulsatile profiles (e.g., of different pulse heights, pulse widths, and pulse numbers). This work goes on to demonstrate that magnetically responsive, biphasic ferrogels are capable of producing pulsatile mitoxantrone delivery profiles similar to those tested in vitro. Pulse parameters such as the timing and rate of delivery during "on" periods could be remotely regulated through the use of simple, hand-held magnets. The timing of pulses was controlled simply by deciding when and for how long to magnetically stimulate. The rate of release during pulse "on" periods was a function of the magnetic stimulation frequency. These findings add to the growing evidence that pulsatile chemotherapeutic delivery profiles may be therapeutically beneficial and suggest that magnetically responsive hydrogels could provide useful tools for optimizing and clinically deploying pulsatile chemotherapeutic delivery profiles.

Project description:Doxorubicin is a chemotherapeutic drug typically administered systemically which frequently leads to cardiac and hepatic toxicities. Local delivery to a tumor has a chance to mitigate some of these toxicities and can further be mitigated by including a means of tumor-specific drug release. Our laboratory has explored the use of molecular interactions to control the rate of drug release beyond that capable of diffusion alone. To this system, we added an additional affinity group (adamantane) to doxorubicin through a pH-sensitive hydrazone bond. The result was a modified doxorubicin which had an even higher affinity to our drug delivery polymer, and virtually no release in normal conditions, but showed accelerated release of drug in tumor-like low pH. Further, we show that adamantane-modified doxorubicin (adamantane-doxorubicin) and cleaved adamantane-doxorubicin showed equivalent capacity to kill human U-87 glioblastoma cells in vitro as unmodified doxorubicin. Taken together, these data demonstrate our ability to load high levels of modified chemotherapeutic drugs into our affinity-based delivery platform and deliver these drugs almost exclusively in the acidic microenvironments, such as those surrounding the tumor tissue via pH-cleavable bond while minimizing drug delivery in neutral pH tissue, with the ultimate goal of reducing systemic through better local delivery. Impact statement Doxorubicin (DOX) is especially cytotoxic to the heart, liver, kidneys, and healthy tissues surrounding the tumor microenvironment. This systemic toxicity can be partially addressed by local, tumor-specific drug delivery systems. While pH-sensitive DOX delivery systems have been developed by several other groups, many lack a prolonged and consistent release profile required to successfully treat heterogeneous tumors. Our system of a chemically modified form of DOX combined with an affinity-based cyclodextrin delivery system is capable of delivering DOX for 87 days while maintaining its the drug cytotoxicity. This finding is particularly relevant to improving cancer treatments because it enables regulated local delivery of DOX specifically to tumor tissue and allows the drug to be continuously delivered over a therapeutically relevant amount of time.

Dataset Information

Cytoplasmic delivery of functional siRNA using pH-Responsive nanoscale hydrogels.

Publications

Cytoplasmic delivery of functional siRNA using pH-Responsive nanoscale hydrogels.

Similar Datasets

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