Metal-Organic Frameworks Facilitate Nucleic Acids for Multimode Synergistic Therapy of Breast Cancer

Abstract

Compared with traditional medical methods, gene therapy and photodynamic therapy are the new fields of cancer treatment, and they more accurately and effectively obtain preferable therapeutic effects. In this study, a chemotherapy drug-free nanotherapeutic system based on ZIF-90 encapsulated with Ce6-G3139 and Ce6-DNAzyme for gene and photodynamic therapies was constructed. Once entering the cancer cell, the therapy system will decompose and release Zn2+, Ce6-G3139, and Ce6-DNAzyme in the acidic environment. On the one hand, G3139 binds to the antiapoptotic gene BCL-2 in tumor cells and downregulates related proteins to inhibit tumor proliferation. On the other hand, Zn2+ produced by the decomposition of ZIF-90 can be used as a cofactor to activate the cleavage activity of DNAzyme to initiate gene therapy. Proliferation and metastasis of tumors were further inhibited by DNAzyme, targeting and cutting the gene of human early growth factor-1 (EGR-1). In addition, the photosensitizer Ce6 carried by the nucleic acid will produce cytotoxic ROS to kill cancer cells after irradiation. The results of this study demonstrated that the designed nanoplatform, which synergistically combines gene and photodynamic therapies, has shown great potential for cancer treatment.

Biomimetic Construction of Degradable DNAzyme-Loaded Nanocapsules for Self-Sufficient Gene Therapy of Pulmonary Metastatic Breast Cancer

“… Similar to the functional genome contained in the nucleocapsid of a virus, DNAzymes are incorporated into an amorphous Mn/Zn-IP6 nanocapsule that can protect DNAzymes from enzymatic degradation during in vivo circulation. This DNAzyme biocapsule presents multiple prominent features for gene therapy: (i) the negatively charged IP6 protective shell guarantees a long blood circulation time of the developed DNAzyme biocapsule and consequently prevents rapid premature clearance; (ii) the modification with cyclo-(RGDyK) (cRGD) peptides endows with the targeting ability via the specific recognition of α v β 3 integrin receptors overexpressed in the tumor, mimicking the integrin-mediated endocytosis pathway for the cell entry of a virus; , (iii) once the DNAzyme biocapsule is endocytosed, the Mn/Zn-IP6 shell is degraded specifically in response to the acidic lysosomal environment along with the release of DNAzymes and self-supply of a high concentration of Mn 2+ /Zn 2+ , followed by the PEI-triggered lysosomal escape; and (iv) the released DNAzymes together with the self-supplied Mn 2+ /Zn 2+ cofactors specifically catalyze the cleavage of EGR-1 mRNA, ,, inducing the apoptotic death of cancer cells. It is revealed that IP6 significantly inhibits the Bcl-2 expression along with the EGR-1 downregulation, , thereby synergistically enhancing the DNAzyme-mediated gene therapy.…”