Near Infrared-Guided Smart Nanocarriers for MicroRNA-Controlled Release of Doxorubicin/siRNA with Intracellular ATP as Fuel

Abstract

In chemotherapy, it is a great challenge to recruit endogenous stimuli instead of external intervention for targeted delivery and controlled release; microRNAs are the most promising candidates due to their vital role during tumorigenesis and significant expression difference. Herein, to amplify the low abundant microRNAs in live cells, we designed a stimuli-responsive DNA Y-motif for codelivery of siRNA and Dox, in which the cargo release was achieved via enzyme-free cascade amplification with endogenous microRNA as trigger and ATP (or H(+)) as fuel through toehold-mediated strand displacement. Furthermore, to realize controlled release in tumor cells, smart nanocarriers were constructed with stimuli-responsive Y-motifs, gold nanorods, and temperature-sensitive polymers, whose surfaces could be reversibly switched between PEG and RGD states via photothermal conversion. The PEG corona kept the nanocarriers stealth during blood circulation to protect the Y-motifs against nuclease digestion and enhance passive accumulation, whereas the exposed RGD shell under near-infrared (NIR) irradiation at tumor sites facilitated the specific receptor-mediated endocytosis by tumor cells. Through modulating NIR laser, microRNA, or ATP expressions, the therapy efficacies to five different cell lines were finely controlled, presenting NIR-guided accumulation, massive release, efficient gene silence, and severe apoptosis in HeLa cells; in vivo study showed that a low dosage of nanocarriers synergistically inhibited the tumor growth by silencing gene expression and inducing cell apoptosis under mild NIR irradiation, though they only brought minimum damage to normal organs. The combination of nanomaterials, polymers, and DNA nanomachines provided a promising tool for designing smart nanodevices for disease therapy.

Monitoring the effects of doxorubicin on 3D-spheroid tumor cells in real-time

“…In our humble opinion, the increased metabolic resistance seen in 293T from Day 3 to Day 5 could be attributed to enhanced ceramide production and over-expression of glucosylceramide genes (GCS). It might also be theorized that DXR increased ceramide production by activating sphingomyelinase 34. Taken together, these two processes were suspected to induce a positive feedback cycle through Sp1, generating an anti-apoptotic force.…”

“…DXR could also induce H 2 O 2 formation by an iron-mediated reaction, catalyzed by ferredoxin reductase 33. A report from Zhang et al showed that the penetration depth of DXR in vivo and in vitro was dependent on the composition and function of the ECM within a given tumor or spheroid 34. Understanding these properties would be essential in the development of efficient non-toxic anti-cancer vehicles.…”

How Can We fine-tune Nanoparticles to Improve Drug delivery?

“…This allows the drug to target only specific cells and thus maintain a concentration above the therapeutic concentration for a particular length of time. The main and popular stimuli for remotely triggered systems are near infrared (NIR) light, ultrasound and alternating magnetic field (AMF) [12]. NIR light can be used to stimulate plasmonic metallic nanoparticles (i.e., gold nanoparticles [GNPs]).…”

Phototriggered Drug Delivery Using Inorganic Nanomaterials

“…66 Tumor phototargeting has been achieved in vivo with a gold nanostructure under irradiation with a NIR laser. 52 …”