Dual-sensitive hydrogel composite for local release and selective uptake of chemotherapy for the treatment of breast cancer

摘要

Introduction: The use of drug delivery device, in particular biodegradable polymeric materials, has generated a huge scientific and economic impact on cancer treatment. Ideally, cancer-treatment should encompass selective delivery of therapeutics to the tumor site in a sustained manner, and rapidly kill cancer cells after their uptake. However, neither hydrogel nor nanoparticles, the two most commonly used drug delivery devices, are capable of fulfilling these requirements alone. Herein, we developed a pH and redox dual-sensitive composite hydrogel that selectively delivers chemotherapy to triple negative breast cancer cells in a sustained manner. The drug is only being released while in the cell and efficiently eradicates the tumor. Materials and Methods: Dual-sensitive nanogels were composed of dextran and cystamine. Hydrogels were fabricated by crosslinking Dextran and G5 Dendrimer. Doxorubicin release rate from both nanogels and composite hydrogels were evaluated. RGD has been conjugated onto nanogels to improve selectivity to cancer cells, which were characterized by in vitro cell culture. Treatment efficacy of biosensitive composite hydrogels was evaluated using mice with orthotopic triple negative breast cancer. Results and Discussion: The composite hydrogel composed of dual-sensitive Dextran nanogels embedded in Dextran:Dendrimer hydrogel (Fig 1 A). Dextran was oxidized and formed prodrug with Doxorubicin, confirmed by 1H-NMR. In vitro drug release study showed that releasing rate differs under various pH and redox solution (Fig. 1B). The local and controlled drug release rate was enabled by pro-drug formation and protection of the particles by their embedding in the hydrogel. This was then followed by a rapid drug release when inside the cancer cells afforded by fast degradation of the nanogels under the acidic and reductive environment in the cell. The dual-sensitive nanogels have high selectivity towards cancer cells only as evidenced by confocal images and flow cytometry assays and show rapid therapeutic effect when applied in vitro to cancer cells with no effect on healthy cells (Fig 1C, D). The biosensitive composite hydrogels provide sustained and selective release in vivo for up to 11 d enabling high tumor shrinkage compared to systemic administration of dual sensitive nanogels and non-sensitive composite hydrogels (Fig 2). The promising results of the in vivo animal studies demonstrate that the dual-sensitive composite hydrogels provides a successful approach for breast cancer treatment. Conclusion: We exploited the tumor-targeting peptide to enable selective chemotherapy uptake to cancer cells while sparing healthy cells. Local delivery of drug enabled sustained release, uptake and then fast release while inside the cancer cell through both pH and redox-triggered release. This dual-sensitive device can be exploited to deliver many types of anti-cancer therapeutics to treat the tumor of interests. The success of the presented biosensitive composite hydrogels may present a paradigm shift in designing cancer-treating device.