Dual Bioresponsive Mesoporous Silica Nanocarrier as an “AND” Logic Gate for Targeted Drug Delivery Cancer Cells

Abstract

Despite the rapid development of drug delivery vehicles that react to a specific biological environment, the complexity of triggering drug release in a particular target area remains an enduring challenge. Here, the engineering of bioresponsive polymer‐mesoporous silica nanoparticles (MSNs) with function akin to an AND logic gate is described. Polycaprolactone (esterase degradable) is immobilized into the core of MSNs while polyacrylic acid (PAA), which is pH responsive, covered the outside of the MSNs to create a PAA‐PCL‐MSNs construct. Fluorescence spectroscopy indicates that the construct releases the payload (doxorubicin, cancer drugs) in the presence of, and only in the presence of, both low pH AND esterase. Confocal microscopy and fluorescence lifetime microscopy (FLIM) demonstrate uptake of the intact construct and subsequent intracellular doxorubicin (DOX) delivery into the nucleus. Further in vitro IC50 studies demonstrate the AND logic gate delivery system results in more than an eightfold efficacy against neuroblastoma (SK‐N‐BE(2)) cells in comparison with normal fibroblasts (MRC‐5). These results demonstrate the utility of MSN‐polymer construct to create an AND gate capable of selectively delivering a drug payload.

How to exploit different endocytosis pathways to allow selective delivery of anticancer drugs to cancer cells over healthy cells

“…2). The release prole of DOX is consistent with our previous work 32 and the work by others. 33 Here, DOX-NR-Cy5.5 is expected to be taken by the cells and DOX is released inside cellular organelles such as endosomes or lysosomes where the pH is more acidic.…”

How to exploit different endocytosis pathways to allow selective delivery of anticancer drugs to cancer cells over healthy cells

“…2). The release prole of DOX is consistent with our previous work 32 and the work by others. 33 Here, DOX-NR-Cy5.5 is expected to be taken by the cells and DOX is released inside cellular organelles such as endosomes or lysosomes where the pH is more acidic.…”

Engineered modular biomaterial logic gates for environmentally triggered therapeutic delivery

“…The AND-gated materials (R∧E, E∧P, R∧P) also functioned properly, fully degrading only when both programmed cues were present. The observed release selectivity (>7-fold) is as or more specific than the most successful dual-input degradable materials previously reported 12 , 14 – 16 . Of the three-input materials containing two logic gates, six of eight [i.e., E∨(R∧P), P∨(R∧E), R∧(E∨P), P∧(R∨E), R∨E∨P, R∨(E∧P)] behaved fully as designed, degrading with high selectivity only when the respective cues were present.…”

Glucometer Readout for Portable Detection of Heterogeneous Circulating Tumor Cells in Lung Cancer Captured on a Dual Aptamer Functionalized Wrinkled Cellulose Hydrogel Interface

“…Meanwhile, the stretching vibration peaks of CO in carboxyl and amino groups of AuNPs were both observed at 1648 and 1559 cm –1 , proving the successful functionalization of Cys on AuNPs. A new peak at 1559 cm –1 , ascribed to the amino group, appeared, and meanwhile, the asymmetric vibration absorption peak of Si-OH disappeared, indicating that the amination of MSN was complete . Additionally, as seen from the X-ray diffraction (XRD) spectra of Au-G-MSN (Figure S7), four peaks around 37.8, 44.6, 64.7, and 77.8°, ascribed to (111), (200), (220), and (311) lattice planes of AuNPs, were observed, further confirming the attachment of AuNPs on MSN.…”

“…A new peak at 1559 cm –1 , ascribed to the amino group, appeared, and meanwhile, the asymmetric vibration absorption peak of Si-OH disappeared, indicating that the amination of MSN was complete . Additionally, as seen from the X-ray diffraction (XRD) spectra of Au-G-MSN (Figure S7), four peaks around 37.8, 44.6, 64.7, and 77.8°, ascribed to (111), (200), (220), and (311) lattice planes of AuNPs, were observed, further confirming the attachment of AuNPs on MSN. As displayed in Figure S5G, both of MSN and Au-G-MSN had characteristic peaks of C 1s, O 1s, Si 2p, and N 1s at 284.9, 532.1, 102.9, and 400.3 eV, respectively.…”

How to exploit different endocytosis pathways to allow selective delivery of anticancer drugs to cancer cells over healthy cells

“…2). The release prole of DOX is consistent with our previous work 32 and the work by others. 33 Here, DOX-NR-Cy5.5 is expected to be taken by the cells and DOX is released inside cellular organelles such as endosomes or lysosomes where the pH is more acidic.…”

Engineered modular biomaterial logic gates for environmentally triggered therapeutic delivery

“…The AND-gated materials (R∧E, E∧P, R∧P) also functioned properly, fully degrading only when both programmed cues were present. The observed release selectivity (>7-fold) is as or more specific than the most successful dual-input degradable materials previously reported 12 , 14 – 16 . Of the three-input materials containing two logic gates, six of eight [i.e., E∨(R∧P), P∨(R∧E), R∧(E∨P), P∧(R∨E), R∨E∨P, R∨(E∧P)] behaved fully as designed, degrading with high selectivity only when the respective cues were present.…”

Glucometer Readout for Portable Detection of Heterogeneous Circulating Tumor Cells in Lung Cancer Captured on a Dual Aptamer Functionalized Wrinkled Cellulose Hydrogel Interface

“…Meanwhile, the stretching vibration peaks of CO in carboxyl and amino groups of AuNPs were both observed at 1648 and 1559 cm –1 , proving the successful functionalization of Cys on AuNPs. A new peak at 1559 cm –1 , ascribed to the amino group, appeared, and meanwhile, the asymmetric vibration absorption peak of Si-OH disappeared, indicating that the amination of MSN was complete . Additionally, as seen from the X-ray diffraction (XRD) spectra of Au-G-MSN (Figure S7), four peaks around 37.8, 44.6, 64.7, and 77.8°, ascribed to (111), (200), (220), and (311) lattice planes of AuNPs, were observed, further confirming the attachment of AuNPs on MSN.…”

“…A new peak at 1559 cm –1 , ascribed to the amino group, appeared, and meanwhile, the asymmetric vibration absorption peak of Si-OH disappeared, indicating that the amination of MSN was complete . Additionally, as seen from the X-ray diffraction (XRD) spectra of Au-G-MSN (Figure S7), four peaks around 37.8, 44.6, 64.7, and 77.8°, ascribed to (111), (200), (220), and (311) lattice planes of AuNPs, were observed, further confirming the attachment of AuNPs on MSN. As displayed in Figure S5G, both of MSN and Au-G-MSN had characteristic peaks of C 1s, O 1s, Si 2p, and N 1s at 284.9, 532.1, 102.9, and 400.3 eV, respectively.…”

How to exploit different endocytosis pathways to allow selective delivery of anticancer drugs to cancer cells over healthy cells

“…2). The release prole of DOX is consistent with our previous work 32 and the work by others. 33 Here, DOX-NR-Cy5.5 is expected to be taken by the cells and DOX is released inside cellular organelles such as endosomes or lysosomes where the pH is more acidic.…”

Engineered modular biomaterial logic gates for environmentally triggered therapeutic delivery

“…The AND-gated materials (R∧E, E∧P, R∧P) also functioned properly, fully degrading only when both programmed cues were present. The observed release selectivity (>7-fold) is as or more specific than the most successful dual-input degradable materials previously reported 12 , 14 – 16 . Of the three-input materials containing two logic gates, six of eight [i.e., E∨(R∧P), P∨(R∧E), R∧(E∨P), P∧(R∨E), R∨E∨P, R∨(E∧P)] behaved fully as designed, degrading with high selectivity only when the respective cues were present.…”

Glucometer Readout for Portable Detection of Heterogeneous Circulating Tumor Cells in Lung Cancer Captured on a Dual Aptamer Functionalized Wrinkled Cellulose Hydrogel Interface

“…Meanwhile, the stretching vibration peaks of CO in carboxyl and amino groups of AuNPs were both observed at 1648 and 1559 cm –1 , proving the successful functionalization of Cys on AuNPs. A new peak at 1559 cm –1 , ascribed to the amino group, appeared, and meanwhile, the asymmetric vibration absorption peak of Si-OH disappeared, indicating that the amination of MSN was complete . Additionally, as seen from the X-ray diffraction (XRD) spectra of Au-G-MSN (Figure S7), four peaks around 37.8, 44.6, 64.7, and 77.8°, ascribed to (111), (200), (220), and (311) lattice planes of AuNPs, were observed, further confirming the attachment of AuNPs on MSN.…”

“…A new peak at 1559 cm –1 , ascribed to the amino group, appeared, and meanwhile, the asymmetric vibration absorption peak of Si-OH disappeared, indicating that the amination of MSN was complete . Additionally, as seen from the X-ray diffraction (XRD) spectra of Au-G-MSN (Figure S7), four peaks around 37.8, 44.6, 64.7, and 77.8°, ascribed to (111), (200), (220), and (311) lattice planes of AuNPs, were observed, further confirming the attachment of AuNPs on MSN. As displayed in Figure S5G, both of MSN and Au-G-MSN had characteristic peaks of C 1s, O 1s, Si 2p, and N 1s at 284.9, 532.1, 102.9, and 400.3 eV, respectively.…”