Cocoon-Like Self-Degradable DNA Nanoclew for Anticancer Drug Delivery
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Abstract:
A bioinspired cocoon-like anticancer drug delivery system consisting of a deoxyribonuclease (DNase)-degradable DNA nanoclew (NCl) embedded with an acid-responsive DNase I nanocapsule (NCa) was developed for targeted cancer treatment. The NCl was assembled from a long-chain single-stranded DNA synthesized by rolling-circle amplification (RCA). Multiple GC-pair sequences were integrated into the NCl for enhanced loading capacity of the anticancer drug doxorubicin (DOX). Meanwhile, negatively charged DNase I was encapsulated in a positively charged acid-degradable polymeric nanogel to facilitate decoration of DNase I into the NCl by electrostatic interactions. In an acidic environment, the activity of DNase I was activated through the acid-triggered shedding of the polymeric shell of the NCa, resulting in the cocoon-like self-degradation of the NCl and promoting the release of DOX for enhanced therapeutic efficacy.Keywords:
Nanogel
Anticancer drug
Deoxyribonucleases
Nanocapsules
Electrostatic interaction
Targeted drug delivery
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Deoxyribonuclease II (DNase II) is also known as acid deoxyribonuclease because it has optimal activity at the low pH environment of lysosomes where it is typically found in higher eukaryotes. Interestingly, DNase II has also been identified in a few genera of bacteria and is believed to have arisen via horizontal transfer. Here, we demonstrate that recombinant Burkholderia thailandensis DNase II is highly active at low pH in the absence of divalent metal ions, similar to eukaryotic DNase II. The crystal structure of B. thailandensis DNase II shows a dimeric quaternary structure which appears capable of binding double-stranded DNA. Each monomer of B. thailandensis DNase II exhibits a similar overall fold as phospholipase D (PLD), phosphatidylserine synthase (PSS) and tyrosyl-DNA phosphodiesterase (TDP), and conserved catalytic residues imply a similar mechanism. The structural and biochemical data presented here provide insights into the atomic structure and catalytic mechanism of DNase II.
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Abstract The presence of neutral deoxyribonuclease activity in highly purified preparation of acid deoxyribonuclease from sheep spleen (deoxyribonuclease II, EC 3.1.4.6) is described. The activity at pH 7.0 differs from the activity at pH 4.5 in its optimal ionic strength, its inhibition by tRNA, inhibition by EDTA, and activation by divalent cations. The deoxyribonuclease activity at neutral pH is not due to contamination by deoxyribonuclease I (EC 3.1.4.5) as judged from the differences between the various divalent cations activation curves, the inhibition by tRNA, and the inhibition of deoxyribonuclease I and II by purified deoxyribonuclease I inhibitor. While deoxyribonuclease I was completely inhibited by the inhibitor, deoxyribonuclease II was not inhibited at all either when assayed at pH 4.5 or at pH 7.0. Furthermore, we have shown that pH, ionic strength, and requirements for divalent cations are interdependent variables. The higher the pH at which deoxyribonuclease II is assayed, the lower its requirements for ionic strength, while its requirements for divalent cations are increased. It is highly probable that the neutral and acid deoxyribonuclease activities in our highly purified preparation of splenic deoxyribonuclease II are due to the same protein molecule.
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Staphylococci isolated from different infections in dogs have been investigated for production of coagulase, deoxyribonuclease (DNase) and heat-stable DNase. Alll coagulase-positive strains (220) also produced DNase and heat-stable nuclease. However, 4 out of 15 coagulase-negative strains were also positive in both the DNase and the heat-stable DNase tests. Several tests for DNase and heat-stable DNase were evaluated. No strains were DNase-positive, heat-stable DNase-negative, or vice-versa.
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