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Lukasz Konczak,1 Jolanta Narkiewicz-Michalek,2 Giorgia Pastorin,3 Tomasz Panczyk1 1Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Cracow, 2Department of Chemistry, Maria Curie-Sklodowska University, Lublin, Poland; 3Department of Pharmacy, National University of Singapore, Singapore Abstract: This work deals with the role of intermolecular interactions in the stability of a carbon nanotube (CNT) capped by functionalized gold nanoparticles (AuNPs). The importance of such a system is due to its potential application as a pH-controlled drug carrier. Our preliminary experimental studies showed that fabrication of such a nanobottle/nanocontainer is feasible and it is possible to encapsulate the anticancer drug cisplatin inside the inner space of a CNT and seal its ends by functionalized AuNPs. The expected behavior, that is, detachment of AuNPs at acidic pH and the release of cisplatin, was, however, not observed. On the other hand, our theoretical studies of chemically identical system led to the conclusion that the release of cisplatin at acidic pH should be observed. Therefore, in this work, a deeper theoretical analysis of various factors that could be responsible for the disagreement between experimental and theoretical results were performed. The study found that the major factor is a large dispersion interaction component acting between CNT and AuNP in solution in the case of the experimental system. This factor can be controlled to some extent by tuning the system size or the ratio between AuNP diameter and CNT diameter. Thus, such kind of a pH-sensitive drug carrier is still of great interest, but its structural parameters need to be properly adjusted. Keywords: hydrazone bond, drug delivery, dispersion interactions, cisplatin, acidic pH

Jian Li,1 Sia Lee Yoong,2 Wei Jiang Goh,2 Bertrand Czarny,1 Zhi Yang,1 Kingshuk Poddar,2,3 Michal M Dykas,2,3 Abhijeet Patra,2,3 T Venkatesan,2,3 Tomasz Panczyk,4 Chengkuo Lee,5 Giorgia Pastorin1–3 1Department of Pharmacy, National University of Singapore, 2NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences (CeLS), 3NUSNNI-NanoCore, National University of Singapore, Singapore; 4Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Cracow, Poland; 5Department of Electrical and Computer Engineering, National University of Singapore, Singapore Abstract: Carbon nanotubes’ (CNTs) hollow interior space has been explored for biomedical applications, such as drug repository against undesirable inactivation. To further devise CNTs as smart material for controlled release of cargo molecules, we propose the concept of “gold-carbon nanobottles”. After encapsulating cis-diammineplatinum(II) dichloride (cisplatin, CDDP) in CNTs, we covalently attached gold nanoparticles (AuNPs) at the open-tips of CNTs via different cleavable linkages, namely hydrazine, ester, and disulfide-containing linkages. Compared with our previous study in which more than 80% of CDDP leaked from CNTs in 2 hours, AuNPs were found to significantly decrease such spontaneous release to

The work presents correlations between the physicochemical properties of the carrier and the active substance and optimization of the conditions for creating an active system based on PAMAM dendrimers and doxorubicin. The study monitored the influence of the ionized form of the doxorubicin molecule on the efficiency of complex formation. The deprotonated form of doxorubicin occurs under basic conditions in the pH range of 9.0-10.0. In the presence of doxorubicin, changes in the zeta potential of the complex concerning the initial system are observed. These changes result from electrostatic interactions between the drug molecules and external functional groups. Based on changes in the absorbance intensity of UV-vis spectra, the binding of the drug in the polymer structure is observed depending on the pH of the environment and the molar ratio. Optimal conditions for forming complexes occur under alkaline conditions. UV-vis, Fourier transform infrared spectroscopy, and circular dichroism spectroscopy confirmed the stability of the formed dendrimer-DOX complex. Molecular dynamics simulations were conducted to gain a deeper insight into the molecular mechanism of DOX adsorption on and within the G4.0 PAMAM dendrimers. It was observed that the protonation state of both the dendrimer and DOX significantly influences the adsorption stability. The system exhibited high stability at high pH values (∼9-10), with DOX molecules strongly adsorbed on the dendrimer surface and partially within its bulk. However, under lower pH conditions, a reduction in adsorption strength was observed, leading to the detachment of DOX clusters from the dendrimer structure.

Poly(amidoamine) dendrimer (PAMAM)/carbon quantum dot (CQD) nanohybrids are promising candidates for many biomedical applications, including drug delivery. Effectively designing a hybrid nanocarrier requires a deep understanding of the interactions of the hybrid nanoparticle with the drug to ensure drug stability and therapeutic efficiency. In this study, we utilized fully atomistic molecular dynamics (MD) simulations to investigate the adsorption behavior of a doxorubicin (DOX) anticancer drug onto a zwitterion/PAMAM/CQD hybrid nanocarrier. The hybrid nanoparticles were composed of CQD, at two oxidation levels, grafted with PAMAM dendrimers of generation 3 (G3) or 4 (G4) decorated with zwitterion monomers. Our work reveals that the generation of the grafted dendrimer was the primary determinant of efficient adsorption of DOX, unlike the oxidation level of CQD or dendrimer surface chemistry. After grafting, the G4 dendrimers assume a more stretched conformation compared to the G3 dendrimers. This allowed DOX molecules to penetrate inside the dendritic cavities of G4 dendrimers, resulting in enhanced drug protection. The hydrophobic interaction, between the aromatic structure of DOX molecules and the nonpolar parts of dendrimers, has been proven to play a crucial role in mediating the adsorption of drug molecules. These findings provide valuable insights to assist in the design of a zwitterion/PAMAM/CQD hybrid nanoplatform for drug delivery applications.

Polypropylene (PP) and polystyrene (PS) underwent a comprehensive investigation into their mechanical and chemical degradation through reactive molecular dynamics simulations. The simulations utilized the ReaxFF force field for CHO (carbon-hydrogen-oxygen) systems in the combustion branch. The study included equilibrium simulations to determine densities and melting temperatures, non-equilibrium simulations for stress-strain and Young moduli determination, mechanical cleaving to identify surface species resulting from material fragmentation, and shock compression simulations to elucidate chemical reactions activated by some external energy sources. The results indicate that material properties such as densities, phase transition temperatures, and Young moduli are accurately reproduced by the ReaxFF-CHO force field. The reactive dynamics analysis yielded crucial insights into the surface composition of fragmented polymers. Both polymers exhibited backbone breakage, leaving -CH2· and -CH·- radicals as terminals. PP demonstrated substantial fragmentation, while PS showed a tendency to develop crosslinks. A detailed analysis of chemical reactions resulting from increasing activation due to increasing value of compression pressure is presented and discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Interaction of β-D-glucopyranuronic acid (GlcA), N-acetyl-β-D-glucosamine (GlcNAc), N-acetyl-β-D-galactosamine (GalNAc) and two natural decameric glycosaminoglycans, hyaluronic acid (HA) and Chondroitin (Ch) with carboxylated carbon nanotubes, were studied using molecular dynamics simulations in a condensed phase. The force field used for carbohydrates was the GLYCAM-06j version, while functionalized carbon nanotubes (fCNT) were described using version two of the general amber force field. We found a series of significant differences in carbohydrate-fCNT adsorption strength depending on the monosaccharide molecule and protonation state of surface carboxyl groups. GlcNAc and GalNAc reveal a strong adsorption on fCNT with deprotonated carboxyl groups, and a slightly weaker adsorption on the fCNT with protonated carboxyl groups. On the contrary, GlcA weakly adsorbs on fCNT. The change in protonation state of surface carboxyl groups leads to the reversal orientation of GlcNAc and GalNAc in reference to the fCNT surface, while GlcA is not sensitive to that factor. Adsorption of decameric oligomers on the surface of fCNT weakens with the increasing number of monosaccharide units. Chondroitin adsorbs weaker than hyaluronic acid and incorporation of four Ch molecules leads to partial detachment of them from the fCNT surface. The glycan-fCNT interactions are strong enough to alter the conformation of carbohydrate backbone; the corresponding conformational changes act toward a more intensive contact of glycan with the fCNT surface. Structural and energetic features of the adsorption process suggest the CH-π interaction-driven mechanism.

Due to their unique structure, poly(amidoamine) (PAMAM) dendrimers can bind active ingredients in two ways: inside the structure or on their surface. The location of drug molecules significantly impacts the kinetics of active substance release and the mechanism of internalization into the cell. This study focuses on the effect of the protonation degree of the G4PAMAM dendrimer and the anticancer drug 5-fluorouracil (5FU) on the efficiency of complex formation. The most favorable conditions for constructing the G4PAMAM-5FU complex are a low degree of protonation of the dendrimer molecule with the drug simultaneously present in a deprotonated form. The fluorine components in the XPS spectra confirm the formation of the stable complex. Through SAXS and DLS methods, a decrease in the dendrimer's molecular size resulting from protonation changes at alkaline conditions was demonstrated. The gradual closure of the dendrimer structure observed at high pH values makes it difficult for the 5FU molecules to migrate to the interior of the support structure, thereby promoting drug immobilization on the surface. The 1 H NMR and DOSY spectra indicate that electrostatic interactions determine the complex formation process. Through MD simulations, the localization profile and the number of 5FU molecules forming the complex were visualized on an atomic scale.

In this paper, we present a number of novel pure-carbon structures generated from cyclo[18]carbon. Due to the very high reactivity of cyclo[18]carbon, it is possible to link these molecules together to form bigger molecular systems. In our studies, we generated new structures containing 18, 36 and 72 carbon atoms. They are of different shapes including ribbons, sheets and tubes. All these new structures were obtained in virtual reactions driven by external forces. For every reaction, the energy requirement was evaluated exactly when the corresponding transition state was found or it was estimated through our new approach. A small HOMO-LUMO gap in these nanostructures indicates easy excitations and the multiple bonds network indicates their high reactivity. Both of these factors suggest that some potential applications of the new nanostructures are as components of therapeutically active carbon quantum dots, terminal fragments of graphene or carbon nanotubes obtained after fracture or growing in situ in catalytic reactions leading to the formation of carbonaceous materials.

The work deals with molecular dynamics (MD) simulations of protonated, human telomeric i-motif deoxyribonucleic acid (DNA) with functionalized graphene. We studied three different graphene sheets: unmodified graphene with hydrogen atoms attached to their edges and two functionalized ones. The functionalization of graphene edge consists in attaching partially protonated or dissociated amine and carboxyl groups. We found that in all cases the protonated i-motif adsorbs strongly on the graphene surface. The biased MD simulations showed that the work necessary to drag the i-motif out from amine-doped graphene is about twice larger than that in other cases. In general, the system i-motif/amine-doped graphene stands out from the rest, e.g., in this case, the i-motif adsorbs its side with 3' and 5' ends oriented in the opposite to surface direction. In other cases, the DNA fragment is adsorbed to graphene by 3' and 5' ends. In all cases, the adsorption on graphene influences the i-motif internal structure by changing the distances between i-motif strands as well as stretching or shortening the DNA chain, but only in the case of amine-doped graphene the adsorption affects internal H-bonds formed between nucleotides inside the i-motif structure.

Cytosine-rich DNA sequences are able to fold into noncanonical structures, in which semi-protonated cytosine pairs develop extra hydrogen bonds, and these bonds are responsible for the overall stability of a structure called the i-motif. The i-motif can be formed in many regions of the genome, but the most representative is the telomeric region in which the CCCTAA sequences are repeated thousands of times. The ability to reverse folding/unfolding in response to pH change makes the above sequence and i-motif very promising components of nanomachines, extended DNA structures, and drug carriers. Molecular dynamics analysis of such structures is highly beneficial due to direct insights into the microscopic structure of the considered systems. We show that Amber force fields for DNA predict the stability of the i-motif over a long timescale; however, these force fields are not able to predict folding of the cytosine-rich sequences into the i-motif. The reason is the kinetic partitioning of the folding process, which makes the transitions between various intermediates too time-consuming in atomistic force field representation. Application of coarse-grained force fields usually highly accelerates complex structural transitions. We, however, found that three of the most popular coarse-grained force fields for DNA (oxDNA, 3SPN, and Martini) were not able to predict the stability of the i-motif structure. Obviously, they were not able to accelerate the folding of unfolded states into an i-motif. This observation must be strongly highlighted, and the need to develop suitable extensions of coarse-grained force fields for DNA is pointed out. However, it will take a great deal of effort to successfully solve these problems.

We found that carmustine can be stored in the carbon nanotube (CNT) interior for a long time due to hydrophobic interactions. The access of water to carmustine phase in the CNT interior can be controlled by the state of cytosine rich DNA fragments covalently bound to the CNT tips and to the presence of doxorubicin molecules intercalated within bundles of DNA fragments. More effective control of water access and subsequent decomposition of carmustine due to the contact with water was observed when some small amount of doxorubicin molecules cork the CNT ends. Our analysis shows that carmustine decomposition products naturally separate when decomposition occurs within the CNT. The alkylating agent, chloroethyl carbonium cation, spontaneously escapes from the CNT but the carbamylation agent, chloroethyl isocyanate, is still kept within the nanotube interior. The separation process and release of the alkylating agent needs uncorking the nanotube by doxorubicin molecules. The latter process is likely to occur spontaneously at acidic pH when intercalation of doxorubicin within the DNA fragments becomes ineffective. The features of the proposed molecular model, obtained from molecular dynamics simulations, can be beneficial in design of novel smart drugs carriers to a tumor microenvironment revealing the reduced extracellular pH., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Dermal delivery of bioactive molecules remains an attractive route of administration in osteoarthritis (OA) due to the local accumulation of drugs while avoiding their systemic side effects. In this study we propose a proniosome gel comprising non-ionic surfactants that self-assemble into de-hydrated vesicles for the delivery of the natural anti-inflammatory compound berberine. By modulating the hydrating ability of the proniosome gel, berberine can be efficiently released with minimal mechanical force. A combination of sorbitan oleate (S80) and polyethlene glycol sorbitan monolaurate (T20) in a sorbitan stearate (S60)-based proniosome enables a readily hydrated gel to deliver berberine into the skin, as confirmed by ex vivo skin permeation studies. Concurrently, an in vitro model of OA using primary mouse chondrocytes demonstrated that the release of berberine at a concentration as low as 1 μg mL -1 is sufficient to restore the production of sulphated glycosaminoglycans (sGAG) to levels comparable to healthy chondrocytes while avoiding the cytotoxic concentrations (IC 50 = 33 μg mL -1 ) on skin keratinocytes. In a mouse model of OA, the optimized formulation is able to attenuate inflammation and pain and minimize cartilage degeneration. Taken together, these data demonstrate the feasibility of adopting proniosome gels as a suitable platform to deliver active molecules for the management of osteoarthritis.

This works deals with analysis of properties of a carbon nanotube, the tips of which were functionalized by short cytosine-rich fragments of ssDNA. That object is aimed to work as a platform for storage and controlled release of doxorubicin in response to pH changes. We found that at neutral pH, doxorubicin molecules can be intercalated between the ssDNA fragments, and formation of such knots can effectively block other doxorubicin molecules, encapsulated in the nanotube interior, against release to the bulk. Because at the neutral pH, the ssDNA fragments are in form of random coils, the intercalation of doxorubicin is strong. At acidic pH, the ssDNA fragments undergo folding into i-motifs, and this leads to significant reduction of the interaction strength between doxorubicin and other components of the system. Thus, the drug molecules can be released to the bulk at acidic pH. The above conclusions concerning the storage/release mechanism of doxorubicin were drawn from the observation of molecular dynamics trajectories of the systems as well as from analysis of various components of pair interaction energies.

In this work, we studied, using computational methods, the protonation reactions of telomeric DNA fragments being due to interaction with carboxylated carbon nanotubes. The applied computational methodology is divided into two stages. (i) Using classical molecular dynamics, we generated states in which carboxyl groups are brought to the vicinity of nitrogen atoms within the cytosine rings belonging to the DNA duplex. (ii) From these states, we selected two systems for systematic quantum chemical studies aimed at the analysis of proton-transfer reactions between the carboxyl groups and nitrogen atoms within the cytosine rings. Results of molecular dynamics calculations led to the conclusion that sidewall-functionalized carbon nanotubes deliver carboxyl groups slightly more effectively than the on-tip-functionalized ones. The latter can provide carboxyl groups in various arrangements and more diverse quality of approach of carboxyl groups to the cytosines; however, the differences between various arrangements of carboxyl groups are still not big. It was generally observed that narrow nanotubes can access the cytosine pocket easier than wider ones. Quantum chemical calculations led however to the conclusion that a direct proton transfer from the carboxyl group to the nitrogen atom within the cytosine ring is impossible under normal conditions. Precisely, we detected either very high activation barrier for the proton-transfer reaction or instability of the reaction product, i.e., its spontaneous decomposition toward reaction substrates.

The controlled delivery and release of drug molecules at specific targets increases the therapeutic efficacy of treatment. This paper presents a triple complex which is a new potential drug delivery system. Triple complex contains single-walled carbon nanotubes, Congo red, and doxorubicin. Nanotubes are built of a folded graphene layer providing a large surface for binding Congo red via "face-to-face" stacking which markedly increases the binding capacity of the carrier. Congo red is a compound that self-associates to form supramolecular ribbon-like structures, which are able to bind some drugs by intercalation. The nanotube-Congo red complex can bind the model drug doxorubicin. Thus, a new triple carrier system was obtained. The aim of this paper is to present studies on the controlled release of a model anticancer drug from a triple carrier system through pH changes. The specific aim of the study was to model the structure of the obtained experimental systems and to compare the changes in the average energy of interaction between its components induced by pH changes. The studies also aimed to compare the intensity of pH-dependent changes in hydrodynamic diameters of individual components of the triple carrier system. The effect of pH changes on the stability of the analyzed systems was examined using the molecular modeling method and dynamic light scattering. The decrease in pH influenced the structure and stability of the analyzed triple systems and ensured efficient drug release. The changes in hydrodynamic diameters of the obtained fractions were examined with the use of dynamic light scattering and were confirmed by computer simulation methods. The formulation presented in this paper shows potential for a therapeutic application owing to its high drug binding capacity and pH-dependent release. This ensures prolonged local action of the drug. The results reveal that the studied complex fulfills the basic requirements for its potential use as drug carrier, thus reducing side effects and enhancing pharmacological efficacy of drugs.

This work deals with molecular dynamics simulations of systems composed of telomeric dsDNA fragments, iG, and functionalized carbon nanotubes, fCNT. The iG contains 90 nucleotides in total and in its middle part the noncanonical i-motif and G-quadruplex are formed. Two chiralities of the fCNT were used, i.e., (10,0) and (20,0) and these nanotubes were either on-tip functionalized by guanine containing functional groups or left without functionalization. We proposed a dedicated computational procedure, based on the replica exchange concept, for finding a thermodynamically optimal conformation of iG and fCNT without destroying the very fragile noncanonical parts of the iG. We found that iG forms a V-shape spatial structure with the noncanonical fragments located at the edge and the remaining dsDNA strands forming the arms of V letter. The optimal configuration of iG in reference to fCNT strongly depends on the on-tip functionalization of the fCNT. The carbon nanotube without functionalization moves freely between the dsDNA arms, while the presence of guanine residues leads to immobilization of the fCNT and preferential location of the nanotube tip near the junction between the dsDNA duplex and i-motif and G-quadruplex. We also studied how the presence of fCNT affects the stability of the i-motif at the neutral pH when the cytosine pairs are nonprotonated. We concluded that carbon nanotubes do not improve the stability of the spatial structure of i-motif also when it is a part of a bigger structure like the iG. Such an effect was described in literature in reference to carboxylated nanotubes. Our current results suggest that the stabilization of i-motif is most probably related to easy formation of semiprotonated cytosine pairs at neutral pH due to interaction with carboxylated carbon nanotubes.

This work deals with molecular dynamics simulations of human telomeric i-motif DNA interacting with functionalized single-walled carbon nanotubes. We study two kinds of i-motifs differing by the protonation state of cytosines, i.e., unprotonated ones representative to neutral pH and with half of the cytosines protonated and representative to acidic conditions. These i-motifs interact with two kinds of carbon nanotubes differing mainly in chirality (diameter), i.e., (10, 0) and (20, 0). Additionally, these nanotubes were on-tip functionalized by amino groups or by guanine- containing residues. We found that protonated i-motif adsorbs strongly, although not specifically, on the nanotube surfaces with its 3' and 5' ends directed toward the surface and that adsorption does not affect the i-motif shape and hydrogen bonds existing between C:C + pairs. The functional groups on the nanotube tips have minimal effect either on position of i-motif or on its binding strength. Unprotonated i-motif, in turn, deteriorates significantly during interaction with the nanotubes and its binding strength is rather high as well. We found that (10, 0) nanotubes destroy the i-motif shape faster than (20, 0). Moreover the i-motif either tries to wrap the nanotube or migrates to its tip and becomes immobilized due to interaction with guanine residue localized on the nanotube tip and attempts to incorporate its 3' end into the nanotube interior. No hydrogen bonds exist within the unprotonated i-motif prior to and after adsorption on the nanotube. Thus, carbon nanotubes do not improve the stability of unprotonated i-motif due to simple adsorption or just physical interactions. We hypothesize that the stabilizing effect of carbon nanotubes reported in the literature is due to proton transfer from the functional group in the nanotube to cytosines and subsequent formation of C:C + pairs.

In this work we studied the unfolding processes of the noncanonical telomeric DNA fragments, i.e. G-quadruplex and i-motif. These transitions were analyzed in details by applying biased molecular dynamics simulations. The bias is imposed on the root of mean square displacement of selected atoms from the reference states which are ideal G-quadruplex and i-motif structures. The unfolding is carried out using the telomeric duplex fragment within which these both noncanonical structures are formed in the same place and exist together. The unfolding of one of the structures is carried out without affecting the second one. In the next stage of the studies the unfolding of the i-motif was also studied starting from the already unfolded G-quadruplex. We found that the work necessary to destroy G-quadruplexes are high at both acidic and neutral pH. The same was observed in the unfolding of i-motif at acidic pH. However, at the neutral pH the obtained work was small though still nonzero. It means that the presence of the complementary guanine rich strand enhances the stability of the i-motif which normally spontaneously unfolds to the hairpin at the neutral pH. Moreover, we found that unfolded G-quadruplex fragment is able to interact with the still existing i-motif and this leads to significant stabilization of the i-motif at the neutral pH. Thus, the presence of the complementary G-quadruplex at the neutral pH stabilizes the i-motif to some extent but even stronger stabilizing effect is observed after unfolding and relaxing the G-quadruplex., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Carbon nanotubes (CNTs) have emerged as promising drug delivery systems particularly for cancer therapy, due to their abilities to overcome some of the challenges faced by cancer treatment, namely non-specificity, poor permeability into tumour tissues, and poor stability of anticancer drugs. Encapsulation of anticancer agents inside CNTs provides protection from external deactivating agents. However, the open ends of the CNTs leave the encapsulated drugs exposed to the environment and eventually their uncontrolled release before reaching the desired target. In this study, we report the successful encapsulation of cisplatin, a FDA-approved chemotherapeutic drug, into multi-walled carbon nanotubes and the capping at the ends with functionalised gold nanoparticles to achieve a "carbon nanotube bottle" structure. In this proof-of-concept study, these caps did not prevent the encapsulation of drug in the inner space of CNTs; on the contrary, we achieved higher drug loading inside the nanotubes in comparison with data reported in literature. In addition, we demonstrated that encapsulated cisplatin could be delivered in living cells under physiological conditions to exert its pharmacological action.

Molecular dynamics simulations were employed to study the properties of G-quadruplex and i-motif secondary DNA structures formed within the canonical telomere fragment of the Watson-Crick duplex. These secondary structures were built symmetrically in the same place of the duplex and were subjected to the analysis in standard unbiased simulations and using metadynamics scheme for the determination of potential of mean force associated with the enforced unfolding of the i-motif parts of the systems. Also, enforced formation of i-motif structures, starting from partially unfolded duplex, were studied in order to find whether formation of i-motif facilitates spontaneous formation of G-quadruplex. We found that i-motif formed from single stranded DNA is unstable at neutral pH and room temperature. On the other hand, the i-motif is strongly stabilized by the presence of complementary G-quadruplex, which should be the most likely configuration when these secondary structures form from double stranded DNA. The stabilization is observed either in neutral or in acidic pH though in the neutral case the i-motif can also reveal considerable stability in the hairpin configuration. We did not observe spontaneous folding of the guanine-rich strand into the G-quadruplex when the cytosine rich strand was dragged to i-motif configuration. This observation suggests that both folding and unfolding transitions are kinetically blocked.

This work deals with a molecular dynamics analysis of the protonated and deprotonated states of the natural sequence d[(CCCTAA) 3 CCCT] of the telomeric DNA forming the intercalated i-motif or paired with the sequence d[(CCCTAA) 3 CCCT] and forming the Watson-Crick (WC) duplex. By utilizing the amber force field for nucleic acids we built the i-motif and the WC duplex either with native cytosines or using their protonated forms. We studied, by applying molecular dynamics simulations, the role of hydrogen bonds between cytosines or in cytosine-guanine pairs in the stabilization of both structures in the physiological fluid. We found that hydrogen bonds exist in the case of protonated i-motif and in the standard form of the WC duplex. They, however, vanish in the case of the deprotonated i-motif and protonated form of the WC duplex. By determining potentials of mean force in the enforced unwrapping of these structures we found that the protonated i-motif is thermodynamically the most stable. Its deprotonation leads to spontaneous and observed directly in the unbiased calculations unfolding of the i-motif to the hairpin structure at normal temperature. The WC duplex is stable in its standard form and its slight destabilization is observed at the acidic pH. However, the protonated WC duplex unwraps very slowly at 310 K and its decomposition was not observed in the unbiased calculations. At higher temperatures (ca. 400 K or more) the WC duplex unwraps spontaneously., (Copyright © 2018. Published by Elsevier B.V.)

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 (p-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.

This work deals with an analysis of the covalent functionalization of a carbon nanotube using polyethylene glycol chains terminated by folic acid fragments. The analysis is focused on theoretical predictions, using molecular dynamics simulations, of the properties of such constructs as pH controlled carriers of the anticancer drug doxorubicin. The analyzed systems are expected to hold the doxorubicin in the inner cavity of the carbon nanotube at neutral pH and unload the drug at slightly acidic pH. This property comes from incorporation into the nanotube of some dye molecules (p-phenylenediamine or neutral red) which undergo protonation at slightly acidic pH. We found that both dyes lead to the formation of a stable, co-absorbed phase of a doxorubicin-dye mixture inside the nanotube at physiological pH. At acidic pH we observed a spontaneous release of dyes from the nanotube, leading finally to the state with only doxorubicin encapsulated in the nanotube interior. Thus, the analyzed constructs can be considered as carriers of doxorubicin that are selective to tumor microenvironments (which exhibit reduced pH due to hypoxia and overexpression of folate receptors). However, we also found that the release of doxorubicin from the nanotube at acidic pH is kinetically blocked, at least in the case of the system sizes studied here. Thus, we also discussed some possible ways of reducing the activation barriers against doxorubicin release at acidic pH.

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 pKa 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 p-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.

In this work we have analyzed the influence of various factors on the transverse relaxation times T2 of water protons in suspension of magnetic nanoparticles. For that purpose we developed a full molecular dynamics force field which includes the effects of dispersion interactions between magnetic nanoparticles and water molecules, electrostatic interactions between charged nanoparticles and magnetic dipole-dipole and dipole-external field interactions. We also accounted for the magnetization reversal within the nanoparticles body frames due to finite magnetic anisotropy barriers. The force field together with the Langevin dynamics imposed on water molecules and the nanoparticles allowed us to monitor the dephasing of water protons in real time. Thus, we were able to determine the T2 relaxation times including the effects of the adsorption of water on the nanoparticles' surfaces, thermal fluctuations of the orientation of nanoparticles' magnetizations as well as the effects of the core-shell architecture of nanoparticles and their agglomeration into clusters. We found that there exists an optimal cluster size for which T2 is minimized and that the retardation of water molecules motion, due to adsorption on the nanoparticles surfaces, has some effect in the measured T2 times. The typical strengths of the external magnetic fields in MRI are enough to keep the magnetizations fixed along the field direction, however, in the case of low magnetic fields, we observed significant enhancement of T2 due to thermal fluctuations of the orientations of magnetizations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Carbon nanotubes (CNTs) are promising drug delivery systems due to their external functionalizable surface and their hollowed cavity that can encapsulate several bioactive molecules. In this study, the chemotherapeutic drug cisplatin or an inert platinum(IV) complex were entrapped inside functionalized-multi-walled-CNTs and intravenously injected into mice to investigate the influence of CNTs on the biodistribution of Pt-based molecules. The platinum levels in vital organs suggested that functionalized-CNTs did not affect cisplatin distribution, while they significantly enhanced the accumulation of Pt(IV) sample in some tissues (e.g. in the lungs, suggesting their potential application in lung cancer therapy) and reduced both kidney and liver accumulation (thus decreasing eventual nephrotoxicity, a typical side effect of cisplatin). Concurrently, CNTs did not induce any intrinsic abnormal immune response or inflammation, as confirmed by normal cytokine levels and histological evaluations. Therefore, functionalized nanotubes represent an efficient nano-carrier to improve accumulation of Pt species in targeted tissues/organs. From the clinical editor: In this preclinical study functionalized carbon nanotubes are reported to be safe and efficient for targeted delivery of platinum-containing compounds in rodents. Approaches like this may improve the treatment of specific cancers, since platinum based chemotherapies are commonly used, yet limited by toxicity and relatively poor target tissue concentration., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In the realm of drug delivery, carbon nanotubes (CNTs) have gained tremendous attention as promising nanocarriers, owing to their distinct characteristics, such as high surface area, enhanced cellular uptake and the possibility to be easily conjugated with many therapeutics, including both small molecules and biologics, displaying superior efficacy, enhanced specificity and diminished side effects. While most CNT-based drug delivery system (DDS) had been engineered to combat cancers, there are also emerging reports that employ CNTs as either the main carrier or adjunct material for the delivery of various non-anticancer drugs. In this review, the delivery of small molecule drugs is expounded, with special attention paid to the current progress of in vitro and in vivo research involving CNT-based DDSs, before finally concluding with some consideration on inevitable complications that hamper successful disease intervention with CNTs., (© 2013.)

In this paper we propose an implicit solvent model which can be used in molecular dynamics simulations of systems comprising colloid nanoparticles and carbon nanotubes. Such systems, due to finite nanometer sizes of both components cannot be accurately approximated by a smaller slab geometry and thus represent a particularly difficult case in terms of computer simulations. In particular, nanoparticle sizes of a few tens of nanometers lead to billions of solvent molecules in a simulation box and require very long cut-off distances which drastically increases computation time. To overcome this difficulty we develop an implicit solvent model based on Hamaker theory of dispersive interactions. The predictions of our model are verified by comparison with the exact model, involving all atoms and full description of pair interactions. The proposed model correctly predicts the work of adhesion and average configuration in colloid - carbon nanotube systems. Moreover, application of the Langevin dynamics reproduces the dynamic behaviour of the exact model either., (Copyright © 2012 Elsevier Inc. All rights reserved.)

This work focuses on a molecular dynamics (MD) study of the initial sticking probability of water on the Pt{110}-(1 x 2) surface. Previous studies of the system [T. Panczyk et al., J. Chem. Phys. 131, 064703 (2009)] led to the following conclusions: (i) adsorption of water is controlled by the efficiency of the dissipation of the initial kinetic energy during collision with the surface and (ii) the process is probably dominated by the electron-hole pair excitation mechanism. In the current work, we extend this study to understand the influence of the orientation of the water molecule and its rotational energy on the probability of the energy exchange during collision. The simulated MD trajectories correspond to various orientations of water molecule at different rotational energies. We found that assuming the angular dependence on the probability of the energy exchange can explain the experimental results obtained using supersonic molecular beams, especially for high incident molecular beam energies. For low beam energies, dispersion of the incident kinetic energy must be incorporated into the model. These are the key factors that enable to model the experimental results on a good qualitative level.

Recent experimental studies of water adsorption on Pt{110}-(1x2) using supersonic molecular beams [F. R. Laffir et al., J. Chem. Phys. 128, 114717 (2008)] have revealed that the translational energy dependence of the initial sticking probability is a stepwise function with a threshold energy of 5 kJ/mol. The initial sticking probability increases sixfold from approximately 0.1 (at translational energies less than 5 kJ/mol) to approximately 0.64 (at translational energies greater than 10 kJ/mol). The aim of this work is to study the adsorption dynamics of water using classical molecular dynamics simulation in order to assess what physical factors are responsible for the observed behavior of the initial sticking probability. The simulations were performed using a purpose-designed code; water molecules were modeled using the well-known TIP4P water model, whereas the water-platinum potential energy function was determined using the ab initio density functional theory calculations. We conclude that the main factor controlling the initial sticking probability is a relatively weak energy transfer between the water molecule and the surface substrate during collision. This energy transfer is enhanced when the total energy of the water molecule increases. The assumption of an exponential increase of the probability of the energy transfer as a function of total energy of water molecule gives initial sticking probabilities very similar to those experimentally obtained. The same model was applied for the simulation of the coverage dependent sticking probability using a hybrid method comprising molecular dynamics and kinetic Monte Carlo approaches. We found a reasonable agreement between our results and the experimental data. The sticking probability as a function of coverage initially increases due to an increasing amount of the adsorbate island edges; it reaches a maximum and finally decreases as the islands merge together at high coverage. The saturation coverage was determined to be 2.8 ML at surface temperature 165 K, where water forms a puckered almost regular lattice with each water molecule having four nearest neighbors. At the studied temperature we did not observe the existence of stable water multilayers on the surface which is consistent with the experimental findings.