Drug conjugated nanoparticles activated by cancer cell specific mRNA

Abstract

We describe a customizable approach to cancer therapy in which a gold nanoparticle (Au-NP) delivers a drug that is selectively activated within the cancer cell by the presence of an mRNA unique to the cancer cell. Fundamental to this approach is the observation that the amount of drug released from the Au-NP is proportional to both the presence and abundance of the cancer cell specific mRNA in a cell. As proof-of-principle, we demonstrate both the efficient delivery and selective release of the multi-kinase inhibitor dasatinib from Au-NPs in leukemia cells with resulting efficacy in vitro and in vivo. Furthermore, these Au-NPs reduce toxicity against hematopoietic stem cells and T-cells. This approach has the potential to improve the therapeutic efficacy of a drug and minimize toxicity while being highly customizable with respect to both the cancer cell specific mRNAs targeted and drugs activated.

SN-38 Conjugated Gold Nanoparticles Activated by Ewing Sarcoma Specific mRNAs Exhibit In Vitro and In Vivo Efficacy

“…Survivin mRNA is highly expressed in many cancers, including Ewing sarcoma, relative to differentiated tissues and has been previously targeted by nucleic acid functionalized Au-NPs. 1,[10][11][12]18 Accordingly, SN38-Survivin Au-NPs could be used in the therapy of other SN-38 sensitive cancers that also overexpress survivin. However, SN38-Survivin Au-NPs may cause more toxicity than SN38-EWS-FLI1 Au-NPs as survivin can be expressed in normal tissues, albeit at lower levels than in cancer cells.…”

“…The resulting crude mixture was purified on SiO 2 (0-80% gradient ethyl acetate in hexanes) to obtain the desired SN-38-azide (6.9 mg, 18% yield for two steps). 1 . All UV-active peaks were collected and lyophilized.…”

“…[10][11][12] We have also previously developed and validated drug conjugated Au-NPs activated by the survivin mRNA. 1…”

Advances and potential application of gold nanoparticles in nanomedicine

“…Therefore, when the AuNPs are internalized, the BIRC5 mRNA will bind to DNA, releasing the strand containing the drug (Figure ). This methodology significantly increases the concentration of active intracellular drug in cancer cells when compared with healthy cells . In addition, the hybrid formed by AuNP‐DNA/RNA is degraded by nucleases, suppressing a gene which is necessary for cancer cell survival and proliferation …”

Nanoparticles—Emerging Potential for Managing Leukemia and Lymphoma

“…In 2016, Gossai et al functionalized 15 nm AuNPs with dsDNA oligonucleotides with a sequence corresponding to BIRC5 , a gene is overexpressed in CML cell lines, which was further loaded with dasatinib, a potent TKI frequently used against CML. Inside the cells, the target gene mRNA binds to the antisense oligonucleotide and releases the drug-conjugated DNA oligonucleotide proportionally to level of BIRC5 mRNA in those cells (Gossai et al, 2014 ). Other studies examined the in vitro efficacy of drug-coated AuNPs on AML treatment improvement using TKIs and fludarabine (Simon et al, 2015 ; Petrushev et al, 2016 ; Song et al, 2016 ).…”