Coadsorption of Doxorubicin and Selected Dyes on Carbon Nanotubes. Theoretical Investigation of Potential Application as a pH-Controlled Drug Delivery System

This work shows results of a theoretical survey, based on molecular dynamics simulation, of potential applicability of doxorubicin coadsorption with various dyes molecules on/in carbon nanotubes as a drug delivery system. The central idea is to take advantage of the dyes charge distribution change upon switching the pH of the environment from neutral (physiological 7.4) to acidic one (∼5.5 which is typical for tumor tissues). This work discusses results obtained for four dye molecules revealing more or less interesting behavior. These were bromothymol blue, methyl red, neutral red, and p-phenylenediamine. All of them reveal p<i>K</i>_a in the range 5–7 and thus will undergo protonation in that pH range. We considered coadsorption on external walls of carbon nanotubes and sequential filling of the nanotubes inner hollow space by drug and dyes. The latter approach, with the application of neutral red and <i>p</i>-phenylenediamine as blockers of doxorubicin, led to the most promising results. Closer analysis of these systems allowed us to state that neutral red can be particularly useful as a long-term blocker of doxorubicin encapsulated in the inner cavity of (30,0) carbon nanotube at neutral pH. At acidic pH we observed a spontaneous release of neutral red from the nanotube and unblocking of doxorubicin. We also confirmed, by analysis of free energy profiles, that unblocked doxorubicin can spontaneously leave the nanotube interior at the considered conditions. Thus, that system can realize pH controlled doxorubicin release in acidic environment of tumor tissues

Multimodal, pH Sensitive, and Magnetically Assisted Carrier of Doxorubicin Designed and Analyzed by Means of Computer Simulations

This work deals with an analysis of drugs carriers based on the structure of a carbon nanotube using large-scale atomistic molecular dynamics simulations. The analyzed systems link several functions in a single architecture. They are as follows: (i) the sidewalls and tips of carbon nanotubes are covalently functionalized by polyethylene glycol–folic acid conjugates, and this approach allows for creation of hydrophytic and biocompatible systems; (ii) doxorubicin is kept in the internal space of a carbon nanotube as a mixture with dyes (<i>p</i>-phenylenediamine or neutral red)it allows for pH-controlled release or alteration of the interaction topology; (iii) the mixture of doxorubicin and dyes in the nanotube interior is additionally sealed by fullerene nanoparticles which act as pistons at acidic pH and loosen the tangle of polyethylene glycol chains at the nanotube tips. This enhances the release of doxorubicin from the nanotube when compared to the analogous system but without the fullerene caps; (iv) another function of the carrier can be activated by filling of the fullerenes by magnetic materialthen, the carrier can be visualized by means of magnetic resonance imaging, it can realize magnetic hyperthermia of tumor cells, and intense rotation of the nanoparticles can be induced by the application of an external magnetic field. That rotation enhances the release of doxorubicin from the nanotube and leads to the increase of the rotational temperature. The studies show that the proposed design of the drug–doxorubicin carrier reveals very promising properties. Its fabrication is absolutely feasible, as all individual stages necessary for its construction have been confirmed in the literature

Corking and Uncorking Carbon Nanotubes by Metal Nanoparticles Bearing pH-Cleavable Hydrazone Linkers. Theoretical Analysis Based on Molecular Dynamics Simulations

In this work we determine and discuss free-energy barriers associated with the detachment of metal (gold) nanoparticles covered by an organic shell from carbon nanotubes functionalized by hydrazide segments. At neutral pH, both compounds can form hydrazone bonds which in turn lead to the chemically corked form of the nanotube. At slightly acidic pH, the hydrazone bonds undergo hydrolysis, leading to chemically unbonded nanotube and gold nanoparticles. We found that at this state the dispersion interactions between the nanotube and gold nanoparticles are still very strong and spontaneous detachment of gold nanoparticles does not occur. Therefore, the uncorked state of the nanotube cannot be realized at normal conditions. The presence of guest molecules (cisplatin) in the inner cavity of the nanotube affects the energetic balance of the system, and spontaneous uncorking can occur with some small activation barrier. However, the uncorking is in this case related to the shift of the nanoparticle from the nanotube tip to its sidewall. That model system can thus realize the mechanism of pH-controlled drug release from the inner cavities of carbon nanotubes. Determination of the free-energy barriers in the considered systems architectures required a special treatment. Standard application of the weighted histogram analysis of biased probability distributions turned out to be totally ineffective. Therefore, we developed a special version of that method which tolerates weak overlapping of the probability histograms. This method may be useful for fast survey of free-energy barriers in any other system architectures