Real-Time Monitoring of ATP-Responsive Drug Release Using Mesoporous-Silica-Coated Multicolor Upconversion Nanoparticles

Abstract

Stimuli-responsive drug delivery vehicles have garnered immense interest in recent years due to unparalleled progress made in material science and nanomedicine. However, the development of stimuli-responsive devices with integrated real-time monitoring capabilities is still in its nascent stage because of the limitations of imaging modalities. In this paper, we describe the development of a polypeptide-wrapped mesoporous-silica-coated multicolor upconversion nanoparticle (UCNP@MSN) as an adenosine triphosphate (ATP)-responsive drug delivery system (DDS) for long-term tracking and real-time monitoring of drug release. Our UCNP@MSN with multiple emission peaks in UV-NIR wavelength range was functionalized with zinc-dipicolylamine analogue (TDPA-Zn2+) on its exterior surface and loaded with small-molecule drugs like chemotherapeutics in interior mesopores. The drugs remained entrapped within the UCNP-MSNs when the nanoparticles were wrapped with a compact branched polypeptide, poly(Asp-Lys)-b-Asp, because of multivalent interactions between Asp moieties present in the polypeptide and the TDPA-Zn2+ complex present on the surface of UCNP-MSNs. This led to luminescence resonance energy transfer (LRET) from the UCNPs to the entrapped drugs, which typically have absorption in UV–visible range, ultimately resulting in quenching of UCNP emission in UV–visible range while retaining their strong NIR emission. Addition of ATP led to a competitive displacement of the surface bound polypeptide by ATP due to its higher affinity to TDPA-Zn2+, which led to the release of the entrapped drugs and subsequent elimination of LRET. Monitoring of such ATP-triggered ratiometric changes in LRET allowed us to monitor the release of the entrapped drugs in real-time. Given these results, we envision that our proposed UCNP@MSN-polypeptide hybrid nanoparticle has great potential for stimuli-responsive drug delivery as well as for monitoring biochemical changes taking place in live cancer and stem cells.

Mesoporous silica nanoparticles for stimuli-responsive controlled drug delivery: advances, challenges, and outlook

“…Owning to the upregulated ATP level, many researchers have tried to design ATP-responsive drug-release systems that can specifically recognize ATP as well as the competitive binding with ATP aptamer. [122][123][124][125][126] Lai et al 122 developed an ATP-responsive DDS for realtime monitoring of drug release. As shown in Figure 11, the mesoporous-silica-coated up-conversion nanoparticle (UCNP@MSN) was wrapped with a compact branched polypeptide, poly(Asp-Lys)-b-Asp, and then functionalized with zinc-dipicolylamine analogue (TDPA-Zn 2+ ) on its exterior surface.…”

Using hyaluronic acid-functionalized pH stimuli-responsive mesoporous silica nanoparticles for targeted delivery to CD44-overexpressing cancer cells

“…5,9,20,23 Briefly, 2.4 g of CTAB was dissolved in deionized water (800 mL) with vigorous stirring at 80°C. Then 3.6 mL of NaOH (2 mol/L) was dissolved into the solution and stirred vigorously for 2 continual hours.…”

“…HeLa cells were seeded in a 12-well plate (5×10 4 cells per well) and incubated for 8 h. After washing twice with PBS, the cells were incubated with FITC-labeled MSNs, PL-MSNs, or HA-PL-MSNs in 2 mL of the serum-free DMEM medium for 5 h. The cells were subsequently washed three times with 4°C PBS to remove the remaining nanoparticles and dead cells, and the cells were investigated under a confocal laser scanning microscope (CLSM, Leica [Wetzlar, Germany], TCS SP8). 3,23 For competitive inhibition studies, the medium was replaced with 2 mL serum-free culture medium containing HA polymer (10 mg/mL) and then FITC-labeled HA-PLMSNs (20 mg/mL) in HeLa cells, 28,29 followed by the same treatment as described earlier. In order to further confirm competitive inhibition studies of HA to CD44, NIH3T3 cells 5,6,19 were cultured in the same way.…”

Recent Advances on Inorganic Nanoparticle-Based Cancer Therapeutic Agents

“…They found that the tumor growth inhibition effect of this platform was much higher than that of chemotherapy or photothermal therapy alone. More recently, Lai et al monitored the real-time ATP-stimulated drug release with mesoporous-silica coated multicolor UCPs, as shown in Figure 5 [83]. The mesoporous-silica coated UCPs were functionalized with zinc-dipicolyamine analog on their surface and loaded with polypeptide wrapped chemotherapeutics in mesopores.…”