Reza Reza Razi
email: reza.razi@ut.ac.irconverter

Behzad Asaei

Mohammad Reza Nikzad

A new battery charger for hybrid electric vehicle using back to back converter

Keywords: AC micro-grid, Back to back converter, Battery charger, PHEV application

The major drawbacks of the most battery chargers for plug-in hybrid electric vehicle (PHEV) are high volume and weight, low power, long charging time, deleterious harmonic effects on the electric utility distribution systems and low flexibility and reliability. This paper proposes a new battery charger structure for PHEV application using back to back (B2B) converter in a utility connected micro-grid. In the proposed structure, an AC micro-grid, based on the typical household circuitry configuration, is connected to the grid via a B2B converter; and the DC link is used for battery charging. In fact, the B2B converter can provide an isolated, low cost, simple and reliable connection with power-flow management between the grid, micro-grid and battery. This proposed structure, depending on the power requirement of the vehicle, can run in four different modes: battery charging mode from the grid (G2V) or microgrid (M2V), vehicle to grid mode (V2G) and vehicle to micro-grid mode (V2H). The feasibility of the proposed scheme has been validated in the simulation study for various operating conditions.

I. INTRODUCTION

LUG-IN hybrid electric vehicles (PHEV) have attracted a lot of attention for researchers these days due to their attractive properties such as their reduced fuel usage and greenhouse emissions. PHEVs have the advantage of a long driving range since fuel provides a secondary resource [1 and 2]. In fact, PHEV is a hybrid electric vehicle that uses rechargeable batteries that can be recharged by plugging it in to an external source of electric power.

In PHEVs, a power electronic converter, called battery charger, is utilized to regulate the supplied power by the electric utility or distributed generation (DG) for recharging the battery pack. Battery Charger systems are classified into the off-board and on-board types with unidirectional or bidirectional power flow. A typical battery charger has two main stages, as shown in Fig. 1: a grid-connected AC-DC [START_REF] Yilmaz | Review of Battery Charger Topologies, Charging Power Levels, and Infrastructure for Plug-In Electric and Hybrid Vehicles[END_REF].

Recently, bi-directional battery chargers are used to operate the PHEV as a DG to supply power to the grid or micro-grids [START_REF] Lee | Advanced Integrated Bidirectional AC/DC and DC/DC Converter for Plug-In Hybrid Electric Vehicles[END_REF][START_REF] Williamson | Industrial Electronics Fig. 11. The powers for the battery discharging in islanded mode under the for Electric Transportation: Current State-of-the-Art and Future Challenges[END_REF][START_REF] Du | Review of high power isolated bi-directional DC-DC converters for PHEV/EV DC charging infrastructure[END_REF][START_REF] Bozorgi | Improved grid voltage sensorless control strategy for railway power conditioners[END_REF]. As a result, connection to the grid or micro-grid allows opportunities such as ancillary services, flexibility, reliability, tracking the output of renewable energy sources, and load balance. Indeed, the battery charger can charge and discharge the battery pack for various operating conditions and we can use this property for improving the reliability and flexibility. However, the major drawbacks associated to the typical onboard battery chargers for PHEVs are high volume and weight, low power, long charging time, deleterious harmonic effects on electric utility distribution systems and low flexibility and reliability. They can be integrated in different configurations to overcome these problems.

In this paper, a new battery charger structure for PHEV application using back to back (B2B) converter in a utility connected micro-grid is proposed to implement the integration of PHEV with a micro-grid and main grid. In the proposed strategy, an AC micro-grid, based on the typical household circuitry configuration, is connected to the grid via a B2B converter; and the DC link is used for battery charging. With this configuration, grid-connected AC-DC converter of battery charger will be removed.

The proposed structure is inspired from the prior works by Majumder et al. [START_REF] Majumder | Power Management and Power Flow Control With Back-to-Back Converters in a Utility Connected Microgrid[END_REF][START_REF] Majumder | A Hybrid Microgrid with DC Connection at Back to Back Converters[END_REF][START_REF] Majumder | Some Aspects of Stability in Microgrids[END_REF]. Indeed, [START_REF] Majumder | Power Management and Power Flow Control With Back-to-Back Converters in a Utility Connected Microgrid[END_REF] proposes a method for power flow control between utility and micro-grid through back-to-back converters, which facilitates desired real and reactive power flow between the utility and the micro-grid. respectively, and i abc , i Lf , i LG , and i O are the grid, the filters, and load currents, respectively. Different bidirectional AC-DC converter topologies could be used as the micro-grid and the battery charger. The specific topology chosen depends on the micro-grid and PHEV requirements such as the flexibility, cost, reliability, volume and weight [START_REF] Singh | A review of single-phase improved power quality AC-DC converters[END_REF][START_REF] Ozorgi | Opt imu m swi tchin g p att ern of mat ri x con vert er space vect or modu lati on[END_REF][START_REF] Rahimi | Optimal placement of additional switch in the photovoltaic single-phase grid-connected transformerless full bridge inverter for reducing common mode leakage current[END_REF][START_REF] Bozorgi | Two simple overmodulation algorithms for space modulated three-phase to threephase matrix converter[END_REF][START_REF] Afshari | Analysis and modification of the single phase transformerless FB-DCB inverter modulation for injecting reactive power[END_REF]. In this paper, the converters are chosen as follows:

VSC-1: bidirectional three-phase full-bridge AC-DC converter isolation between the utility and the micro-grid.

The system configuration and four operational modes principles are described in this paper. The paper is organized as follows: Section II presents the configuration and operation of the proposed system. Section III states control methods for the islanded and grid connected converter. In section IV, the performance of the proposed structure has been investigated by extensive simulations, which confirm the effectiveness of the system. Finally, Section V concludes the paper.

II. SYSTEM CONFIGURATION AND OPERATION

The power circuit of the proposed structure is shown in Fig. 2. The parameters of the circuit are listed in Table I.

Based on Fig. 2, a mathematical model, describing the dynamics of the system can be derived as di abc With this proposed structure, different operation modes can be created that is divided into two main categories: battery charging and discharging modes. Different categories of the battery charging and discharging modes are shown in Figs. 3 and4, respectively. As can be seen in Fig. 3, charging mode is divided into two main categories: isolated mode that the battery only connects to the main grid (G2V) or micro-grid (M2V) and connected mode that depending on the DG power, the battery is charged from the main grid (G2V), micro-grid (M2V) or both of them (M&G2V). On the other hand,discharging mode is classified as similar as charging mode and only operation modes in connecting state is depends on the load power, not DG power. In this paper, for the full study, only the isolated cases are investigated that in this case the other modes are also included.

III. PROPOSED CONTROL METHODS FOR CONVERTERS

As mentioned before, there are three DC-AC converters in the proposed structure, which, depending on their application,

v abc R s i abc L s v CB1 dt (1)
are controlled. In the following, how to control the converters

i L f i i O G C dv o dt (2) are examined.
where v abc , v CB-1 and v o are the output voltage of the grid, the input voltage of the B2B converter and the load voltage,

A. Controlled voltage source inverter

In this case, the inverter should be able to support the local network or critical load with the appropriate voltage and frequency from the DC input. VSC-2 and VSC-3 can should be operated in this type. Various control methods for these inverters are available in the literature. We followed offered guidelines in the [16 and 17]. Fig. 5 shows the suggested multi-loop control scheme used in this paper. The idea of multi-loop control of the output voltage of the UPS inverter with an LC filter involves an outer voltage regulation loop and an inner current loop. An outer loop with the PR controller regulates the output voltage, while the capacitor current is selected as the feedback signal in the inner control loop and provides active damping, stability over a wide range and fast dynamic for disturbances. The controller parameters are designed in the frequency domain based on the required bandwidth and stability margin [START_REF] Razi | Multi-loop control of stand-alone inverters with minimum number of sensors[END_REF].

B. Controlled current source inverter

In this case, the voltage is imposed by main grid or another inverter. Therefore, the output voltage of this type of inverter is specified and it must control its current. VSC-1, VSC-2 and VSC-3 can be operated in this type.

In this case, also, there are different control methods. An appropriate control method is presented in [START_REF] Gholami-Khesht | Low computational burden grid voltage estimation for grid connected voltage source converter-based power applications[END_REF], as shown in Fig. 6 (a), which consists of the current control loop and a power control loop. The current control loop uses the PR controllers and harmonic compensators (HCs) to regulate the grid current and eliminate the low-order harmonic components [START_REF]Uninterruptible Power Systems (UPS)-Part 3: Method of Specifying the Performance and Test Requirements[END_REF], [START_REF] Razi | Multi-loop control of UPS inverter with a plug-in odd-harmonic repetitive controller[END_REF]. Furthermore, the power control loop sets deliver active and reactive power in desirable amounts.

C. Active voltage source rectifier

In the last converter, active voltage source rectifier is investigated, where VSC-1 and VSC-2 can be operated in this type. Fig. 6 (b) shows the suggested control scheme for the active voltage source rectifier [START_REF] Dabbaghjamanesh | High performance control of grid connected cascaded H-Bridge active rectifier based on type II-fuzzy logic controller with low frequency modulation technique[END_REF]. As shown in Fig. 6 (b), the controller uses the outer voltage loop to generate the magnitude reference for the inner current loop and the magnitude is multiplied with the phase reference supplied directly by the grid voltage. In fact, it is important to follow two aims in this controller:

1. set up DC link in a specified amount 2. Drag the current from the main grid in the same phase with the voltage of the source. These aims are achieved in the simulations as have been investigated in the next section.

IV. SIMULATION STUDIES

To confirm the feasibility and performance of the proposed scheme, the structure of Fig. 2 has been extensively investigated using MATLAB/SIMULINK simulations. The simulation parameters are listed in Table I. As mentioned before, in this paper, only isolated cases are investigated that connected states are also included. Fig. 7 shows the voltage and current waveforms for the battery charging operation in the grid-connected mode. As can be seen in Fig. 7, the power factor is good (nearly one) and the DC-link voltage is reached to the desired value. Furthermore, the currents of source are sinusoidal with the total harmonic distortion (THD) of 3.48%.

Fig. 8 presents the performance of the system for the battery charging operation in the island mode. In this case, the DG is the only source and therefore, is responsible for load power and battery charging power supply. It can be seen that the load voltage and current are also sinusoidal even without the main grid, which are very good results. In fact, the load voltage remains almost unchanged during the charging mode change from grid-connected mode to island mode. Again, the DC link voltage is also set at desirable amount. This excellent performance is achieved due to the proper control of the inverter of micro-grid (VSC-3). In another case, the battery discharging operation in the grid-connected mode is investigated and results are shown in Fig. 9. In this case, it is assumed that the battery pack delivers 2 KW to the main grid. Therefore, the actual injected power tracks the reference one accurately in simulations and transient-state dies out rapidly. Furthermore, injected currents to the main grid are sinusoidal with the THD of 3.95%.

Finally, as the worst case operation, the battery discharging in island mode is investigated. In this case, it is assumed that the DG is working at the rated power (1200 W), in other words, DG works in PQ mode and battery charger (VSC-2) acts as a controlled voltage source. Therefore, the load type is important and this study is investigated in two cases. In the first case, the nominal linear load is investigated and the load waveforms are depicted in Fig. 10 (a). The load voltage is a perfect sinusoidal waveform with a negligible THD value (THD = 0.39%). Furthermors, the powers are shown in Fig. 11 that shows the power of the load is provided by the both battery and DG.

In the second case, the performance of the proposed scheme was evaluated under a highly nonlinear load; and the results are shown in Fig. 10 (b). The nonlinear load, shown in Fig. 12, consists of a diode rectifier bridge feeding an RC circuit through a small resistor. The values of R1, R2 and C are 3Ω, 30Ω and 400uF, respectively. This nonlinear load is designed according to the requirements of IEC 62040-3 standard (Annex E) [START_REF]Uninterruptible Power Systems (UPS)-Part 3: Method of Specifying the Performance and Test Requirements[END_REF]. One can see in Fig. 10 (b) that while the load current is highly distorted, with a THD of about 60%, the voltage waveform remains sinusoidal (THD = 0.64%). In fact, this excellent performance is achieved due to the proper control of VSC-2.

V. CONCLUSION

The feasibility and performance of a battery charger for PHEV application using back to back (B2B) converter in a utility connected micro-grid has been investigated in this paper. A structure has been proposed involving three parts: an AC micro-grid, in which the load is fed from the DG source, a battery charger, in which the bi-directional DC/DC converter is used, and main grid. The system infrastructure and operational principles are illustrated. The best controllers have been utilized to achieve better performances in V2M, V2G, G2V, M2V modes. In principle, the proposed scheme is very flexible and reliable, particularly for sensitive loads. The excellent performance of the proposed structure has been confirmed through extensive simulations on MATLAB/SIMULINK for various operating conditions.

Fig. 1 .Fig. 2 .

 12 Fig. 1. A typical battery charger.

Fig. 3 .

 3 Fig. 3. Operation modes of battery charging.

Fig. 4 .

 4 Fig. 4. Operation modes of battery discharging.

Fig. 5 .

 5 Fig. 5. Suggested control scheme for controlled voltage source inverter [15].

Fig. 6 .

 6 Suggested control scheme for: (a) controlled current source inverter, and[START_REF] Razi | Simple control scheme for single-phase uninterruptible power supply inverters with Kalman filter-based estimation of the output voltage[END_REF] (b) active voltage source rectifier[START_REF] Dabbaghjamanesh | High performance control of grid connected cascaded H-Bridge active rectifier based on type II-fuzzy logic controller with low frequency modulation technique[END_REF].

Fig. 7 .

 7 Fig. 7. Waveforms for the battery charging in grid-connected mode.

Fig. 8 .

 8 Fig. 8. Waveforms for the battery charging in islanded mode.

Fig. 10 .

 10 Waveforms for the battery discharging in islanded mode: (a) under the nominal linear load, and (b) under a highly nonlinear load.

Fig. 12 .

 12 Fig. 12. Non-linear load.


Clifford W Fong Eigenenergy
email: cwfong@internode.on.net

Cucurbiturils as potential free radical chemoradiosensitizers for enhanced cisplatin treatment of cancers: A quantum mechanical study

Keywords: cucurbit[7]uril, cisplatin, free radicals, chemoradiotherapy, anti-cancer, adiabatic electron affinity

Abbreviations Cucurbiturils CBs or CB[n], cucurbit[7]uril CB[7], cisplatin CisPt, cisplatin-cucurbit[7]uril complex {CisPt@CB[7]}, free radical species {CB[7]CisPt•}, free energy change ΔG, highest occupied molecular orbital HOMO, lowest unoccupied molecular orbital LUMO, basis set supposition error BSSE,

Introduction

Cisplatin is a widely used chemotherapy drug used to treat testicular, cervical, germ cell, ovarian, bladder, head and neck, and non-small cell lung cancer. Radiation therapy is also used in conjunction with cisplatin for treating cervical, bladder, and head and neck cancers.

Comparisons of concurrent chemotherapy and radiation with radiation alone in cervical cancer treatments have shown that chemoradiation reduces the risk of death by 30-50% [START_REF] Koivusalo | Chemoradiation of cervical cancer cells: targeting human papillomavirus E6 and p53 leads to either augmented or attenuated apoptosis depending on the platinum carrier ligand[END_REF][ [START_REF] Koivusalo | Chemoradiation of cervical cancer cells: targeting human papillomavirus E6 and p53 leads to either augmented or attenuated apoptosis depending on the platinum carrier ligand[END_REF]]. Similarly trials have show an overall survival advantage of 30% for cisplatin-based chemotherapy given concurrently with radiation therapy [START_REF] Berclaz | Long-term follow-up of concurrent radiotherapy and chemotherapy for locally advanced cervical cancer: 12-Year survival after radiochemotherapy[END_REF] [START_REF] Berclaz | Long-term follow-up of concurrent radiotherapy and chemotherapy for locally advanced cervical cancer: 12-Year survival after radiochemotherapy[END_REF]]. It is thought that the molecular mechanism involves the induction of strand breaks by the ionizing radiation adds to platinum crosslinks and interferes with DNA repair processes. The molecular mechanism of this synergistic interaction between cisplatin and ionizing radiation has been investigated. The cisplatin-ionizing radiation synergistic interaction requires the DNA-dependent protein kinase-dependent nonhomologous end joining catalysed repair of DNA double-strand breaks, and the presence of a cisplatin lesion on the DNA blocks this pathway. [3][Broeckman 2005] The efficacy of various radiosensitizers on Pt based cervical cancer treatments has been reviewed. [START_REF] Candelaria | Radiosensitizers in cervical cancer. Cisplatin and beyond[END_REF] [START_REF] Candelaria | Radiosensitizers in cervical cancer. Cisplatin and beyond[END_REF]] In one study, with cisplatin or Lipoplatin (a liposomal cisplatin), followed by irradiation, it was observed that drug concentrations higher than IC50 were found to be synergistic, but concentrations lower than the IC50 were antagonistic, indicating a schedule dependence of the synergism of platinum-based drugs and radiation which has important implications for drug and radiation time administration in the clinic. [START_REF] Tippayamontri | Synergism in Concomitant Chemoradiotherapy of Cisplatin and Oxaliplatin and their Liposomal Formulation in the Human Colorectal Cancer HCT116 Model[END_REF] [START_REF] Tippayamontri | Synergism in Concomitant Chemoradiotherapy of Cisplatin and Oxaliplatin and their Liposomal Formulation in the Human Colorectal Cancer HCT116 Model[END_REF] Despite the success of Pt based anti-cancer treatments, severe side effects are well documented, and include neurotoxicity, nephrotoxicity, ototoxicity and retinopathy. Resistance is also a well known side effect. [START_REF] Boulikas | Designing platinum compounds in cancer: structures and mechanisms[END_REF][7][START_REF] Dasari | Cisplatin in cancer therapy: molecular mechanisms of action[END_REF][Boulikas 2007, Apps 2015, [START_REF] Dasari | Cisplatin in cancer therapy: molecular mechanisms of action[END_REF] Cucurbiturils (CBs) are a class of macrocycle which have unusual host-guest properties. Cucurbit[n]uril (CB[n], n = 5, 6,7, 8,10,13,14 and 15) for example contain five to ten glycoluril units, which have a hydrophobic cavity accessible though two identical outward facing carbonyl-fringed portals. Wheate et al [START_REF] Wheate | Cucurbit[n]uril binding of platinum anticancer complexes[END_REF][START_REF] Wheate | Improving platinum(II)-based anticancer drug delivery using cucurbit[n]urils[END_REF][ [START_REF] Wheate | Cucurbit[n]uril binding of platinum anticancer complexes[END_REF][START_REF] Wheate | Improving platinum(II)-based anticancer drug delivery using cucurbit[n]urils[END_REF]] and [START_REF] Jeon | Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug[END_REF]Jeon [START_REF] Jeon | Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug[END_REF]] have shown that CB[n] can be a effective drug delivery vehicle for a variety of Pt(II) complexes, as well as many other drugs. [START_REF] Hettiarachchi | Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers[END_REF] [START_REF] Hettiarachchi | Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers[END_REF] The {CisPt@CB [7]} complex showed a significant effect on in vivo cytotoxicity using human tumour xenografts. It was just as effective on the human ovarian tumours compared with free cisplatin, and in the cisplatin-resistant A2780/cp70 tumours. {CisPt@CB [7]} markedly slowed tumour growth, which was attributable to a pharmacokinetic effect. [START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF] [START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF]] CB [7] and {CisPt@CB [7]} have also been examined for their neuro-, myo-and cardiotoxic activity, and it was found that CB [7] had negligible side effects, while {CisPt@CB [7]} had a reduced myo-and cardiotoxic effect compared to the free CisPt. [START_REF] Oun | The ex vivo neurotoxic, myotoxic and cardiotoxic activity of cucurbituril-based macrocyclic drug delivery vehicles[END_REF] [START_REF] Oun | The ex vivo neurotoxic, myotoxic and cardiotoxic activity of cucurbituril-based macrocyclic drug delivery vehicles[END_REF] The various properties of CBs in drug delivery have been extensively reviewed, and include the suppression of polymorphism, improvement of the drug's in vivo as well as thermal and chemical stabilities (required to allow long term storage), the masking of unwanted taste, increase in the drug's solubility in water, enhancement of the ability to cross internal membranes, optimization of the drug's in vivo distribution and/or metabolism, the bioprotection of the delivered drug from binding to serum proteins in systemic circulation, the modification of the clearance mechanism, and the influence on the drug pharmacokinetic effects. It is noted that CB [7] has the greatest solubility of the available CBs and its cavity can accommodate most drugs, making it an attractive delivery vehicle, particularly when many drugs have limited water solubility, since inside the cavity of CB7, solubilities are enhanced owing to the higher solubility of CB [7]. [START_REF] Wheate | Cucurbit[n]urils as excipients in pharmaceutical dosage forms[END_REF][START_REF] Saleh | Cucurbiturils in Drug Delivery And For Biomedical Applications[END_REF][ [START_REF] Wheate | Cucurbit[n]urils as excipients in pharmaceutical dosage forms[END_REF][START_REF] Saleh | Cucurbiturils in Drug Delivery And For Biomedical Applications[END_REF] To date the anti-cancer effects of {CisPt@CB [7]} have focussed on the drug delivery aspects and side effects, the assumption being that the CisPt released from the CB [7]CisPt complex is the active agent that forms Pt-DNA adducts via the intermediate formation of the (H 3 N) 2 PtCl(H 2 O) + species, which is considered to be the major pathway by which CisPt exerts its anti-cancer effect. However, recently Fong [START_REF] Fong | Platinum anti-cancer drugs: Free radical mechanism of Pt-DNA adduct formation and anti-neoplastic effect[END_REF][START_REF] Fong | Platinum based radiochemotherapies: free radical mechanisms and radiotherapy sensitizers[END_REF][ Fong 2016Fong , 2016] ] has provided evidence that a free radical mechanism may also be a pathway by which Pt-DNA adducts are formed, and may also induce apoptosis and cell death where Pt-DNA adducts are not involved. [START_REF] Mezencev | Interactions of cisplatin with non-DNA targets and their influence on anticancer activity and drug toxicity: the complex world of the platinum complex[END_REF] [START_REF] Mezencev | Interactions of cisplatin with non-DNA targets and their influence on anticancer activity and drug toxicity: the complex world of the platinum complex[END_REF]] Such a free radical mechanism may also be dominant in combined radiation chemotherapy regimens commonly used in treating solid cancerous tumours.

This paper examines a possible free radical mechanism for {CisPt@CB [7]} complexes, and the possible synergistic effect of CB [7] as a chemoradiosensitizer in treating solid cancers by combined CisPt -radiation therapy.

Results

To establish the absolute cavity size in a water solvated environment which can allow a solvated CisPt to enter the CB [7] cavity, a 2,2'-dimethyl 3,3'-di(t-butyl) 4,4'dimethylpentane molecule was inserted centrally into the CB [7] cavity. It is noted that CB [7] can accommodate large molecules with the cavity, such as adamantine derivatives and carborane (see discussion below). This insertion effectively fills most of the cavity. By comparing the water solvated insertion complex with the bare CB [7] host, using the SMD solvation model, it can be computed that the CB [7] cavity has a solvent accessible volume of 87 cm 3 mol -1 and water molecules within the cavity have a ΔG solv,CDS 6.2 kcal/mol, where the ΔG solv,CDS is the free energy of solvation in the cavity dispersion solvent structure (CDS), which is the non-electrostatic first solvent shell solvation term. The CDS involves atomic surface tension (geometry dependent proportionality constants). The CDS has been parameterized using extensive experimental data sets for optimization, and has the advantage of including a realistic experimentally based hydrogen bonding model. The CDS covers shorter-range polarization effects and shorter-range non-electrostatic effects such as cavitation, dispersion, and solvent structural effects (which includes both hydrogen bonding) and exchange repulsion effects. [START_REF] Marenich | Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions[END_REF] [START_REF] Marenich | Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions[END_REF] The solvated free CisPt has a ΔG solv,CDS 4.6 kcal/mol and solvent accessible volume of 88 cm 3 mol -1 (or a volume of 84 cm 3 mol -1 in the gas phase) which indicates that insertion of CisPt into the centre of the CB [7] cavity requires the displacement of water molecules from the cavity costing the equivalent of at least 1.6 kcal/mol. The inserted CisPt occupies a significant portion of the solvent accessible volume in the cavity for the neutral {CisPt@CB [7]} complex but some water molecules are still present in the cavity with the guest CisPt. The SMD/PCM solvent model solvent used in this study can "solvate" the inserted CisPt guest within the CB [7] cavity, as evidenced by the 48% decrease in NPA positive atomic charge on the Pt atom when comparing {CisPt@CB [7]} in the gas phase to the water "solvated" environment, where water molecules in the cavity reduce the positive charge on the Pt atom.

An important issue that must be addressed is that after CisPt enters the CB [7] cavity, there is considerable room for the CisPt guest to dynamically reorient within the cavity. So a large number of configurations are possible for the guest molecule, which can involve movement away from the centroid position of the cavity. Previous studies of the {CisPt@CB [7]} complex have allowed for hydrogen bonding between the N-H of CisPt and the outer portal C=O groups, and it is known that host CB [7] is capable of significant flexibility and deformation. [START_REF] Wheate | Cucurbit[n]uril binding of platinum anticancer complexes[END_REF][START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF][START_REF] Suvitha | Theoretical insights into the formation, structure, and electronic properties of anticancer oxaliplatin drug and cucurbit[n]urils n=5 to 8[END_REF][START_REF] Venkataramanan | Theoretical Prediction of the Complexation Behaviors of Antitumor Platinum Drugs with Cucurbiturils[END_REF][ [START_REF] Wheate | Cucurbit[n]uril binding of platinum anticancer complexes[END_REF], Suvitha 2009, Venkataramanan 2012[START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF] However it is possible to fully immerse the CisPt centrally within the hydrophobic cavity a configuration which would provide maximum shielding of the CisPt from biological entities to maximise CisPt delivery integrity and minimise side effects.

Figure 1 shows a {CisPt@CB [7]} complex with the CisPt centrally located within the cavity using van der waals radii. Figure 2 shows the HOMO largely on the CB [7] and LUMO largely on the Pt atom which indicate that the addition of an electron to the complex would mainly locate to the Pt atom. It is also found that the addition of a second and third electron to the {CB [7]CisPt•} also largely locate to the LUMOs on the Pt atoms. The notable feature of the {CB [7]CisPt ΔG form for the {CisPt@CB [7]} species is the substantial bond lengthening of the Pt-Cl bonds and the Pt-N bonds which form planar trigonal structure comprising the N-Pt(-N)-Cl atoms with an elongated Pt-Cl bond at an angle of 144 o to the trigonal plane. (Figure 3, see Table 1 for details) We have previously shown [START_REF] Fong | Platinum anti-cancer drugs: Free radical mechanism of Pt-DNA adduct formation and anti-neoplastic effect[END_REF][START_REF] Fong | Platinum based radiochemotherapies: free radical mechanisms and radiotherapy sensitizers[END_REF] [ Fong 2016] that adiabatic electron attachments to cisplatin in water results in relatively large changes to the bond lengths and bond angles configurations of the cisplatin substrate, particularly the lengthening of the Pt-Cl bond. Bond lengthening is required to induce bond rupture. The lengthening of the Pt-Cl bond following electron addition has been previously shown to be the precursor to the transition state leading to formation of the (H 3 N) 2 PtCl• radical. [START_REF] Fong | Platinum anti-cancer drugs: Free radical mechanism of Pt-DNA adduct formation and anti-neoplastic effect[END_REF][START_REF] Fong | Platinum based radiochemotherapies: free radical mechanisms and radiotherapy sensitizers[END_REF] It is noted that many different spatially oriented configurations of the {CisPt@CB [7]} are possible even when the CisPt guest is notionally centrally located within the CB [7] cavity, partly due to the flexibility of the CB [7] ring. A comparison of three slightly different configurations of {CisPt@CB [7]} have been made where the CisPt orientations (all centrally located in the cavity) within the CB [7] are given in Table 1, with their corresponding radical anion geometries. Configuration A of {CisPt@CB [7]} has the CisPt plane lying close to the horizontal long axis of CB [7] as per Figure 1, B has the CisPt close to horizontal to the horizontal long axis of CB [7], but the Pt-Cl 1 tilted upwards to the portal opening, and C has the CisPt plane tilted away from the horizontal long axis of the CB [7] towards the portal openings exposing the NH 3 and Cl groups externally. Based on electronic energies, A is more stable than B which is more stable than C. There are small changes in geometries and the resultant AEAs and the atomic charges differ slightly. It is not computationally feasible to identify all possible low energy configurations. The AEA values in Table 1 for the various radical species are not unique as many slightly different configurations are also possible. However the key result from the data in Table 1 is that electron attachment to {CisPt@CB [7]} results in bond elongation, mainly of the Pt-Cl bond in the various radical anions.

Similar geometries to that shown in Figure 3 are also observed for the addition of two and three electrons to the {CisPt@CB[7]}. Figure 4 shows the {CB [7]CisPt••}dianion. The observation that electron addition to the {CisPt@CB [7]} complex largely resides on the Pt is also reinforced by explicitly placing the electron on the CisPt using a two layered ONIOM model (6-31G(d,p)/SDD pseudo potential for the CisPt moiety) with the CB [7] treated with the UFF force field or the semi-empirical PM6 with zero charges. The resultant optimised CisPt geometries are very similar to that found in Figure 3 with small differences in bond lengths but all showing much larger elongation of the Pt-Cl bonds and higher AEA values.

The free energy of formation ΔG form for the {CisPt@CB [7]}in the configuration as portrayed in Figure 1 is ca. 24.8 kcal/mol in water using a thermodynamic cycle (see Experimental Methods) corrected for the basis set supposition error (BSSE) of 119.4 kcal/mol. This value compares to a literature value of 80.7 kcal/mol for a quite different configuration where there are 4 hydrogen bonds between the CB [7] outer portal C=O groups and the N-H moieties of the CisPt in the "pointing in" configuration. [START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF][Plumb 2012] It is not known whether this "pointing in" configuration with four hydrogen bonds is favoured over other non-hydrogen boned configurations, since the kinetic and thermodynamic factors must be in play during insertion of a guest molecule. This study suggests that a solvated or partially solvated CisPt can enter the CB [7] cavity, which would mitigate against such a "pointing in hydrogen bonded" configuration being significant. Also NMR studies show a slow exchange between internal bound CisPt and free CisPt. [START_REF] Wheate | Cucurbit[n]uril binding of platinum anticancer complexes[END_REF][START_REF] Jeon | Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug[END_REF][START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF] [ [START_REF] Wheate | Cucurbit[n]uril binding of platinum anticancer complexes[END_REF][START_REF] Jeon | Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug[END_REF][START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF]] Finally the ΔG form for the centrally located configuration in Figure 1 is considerably lower than the "pointing in hydrogen bonded" configuration, indicating that this hydrogen bonded configuration is not thermodynamically favoured.

The configuration in Figure 1 does not allow for any hydrogen bonding and the CisPt is completely enclosed within the CB [7] cavity, and hence is more shielded from the external environment. The ΔG form (BSSE corrected) in water for the {CB [7]CisPt•}anion and {CB [7]CisPt••}dianion in the configurations shown in Figure 2 and 4 are -39.8 and -111.5 kcal/mol.

The attachment of electrons to the {CisPt@CB [7]} can conceivably occur via two pathways ie via the CB [7] or directly to the CisPt guest. The CB [7] offers multiple sites for hydrated electron attachment which can then allow fast transfer to the Pt guest via a Marcus inner sphere mechanism. [START_REF] Fong | Platinum based radiochemotherapies: free radical mechanisms and radiotherapy sensitizers[END_REF][START_REF] Marcus | Electron transfers in chemistry and biology[END_REF] [ [START_REF] Marcus | Electron transfers in chemistry and biology[END_REF], Fong 2016] Alternately, the direct attachment of an electron to the Pt atom is indicated by the location of the LUMO on the Pt atom, as observed in Figures 1(d) and 1(e). It is possible that both pathways can occur almost simultaneously in an excess electron environment, and electron attachments to the CB [7] may be favoured since the CB [7] has multiple possible attachment sites. The adiabatic electron affinity (AEA) for 1, 2 and 3 electron attachment of the configuration in Figure 1 are 0.65, 1.8 and 2.2 eV respectively, with the geometries shown in Table 1. Electron attachment is accompanied by elongations of the Pt-Cl bond in particular, (and the Pt-N bonds less so), indicative of a dissociative electron transfer (DET) mechanism previously observed for the free CisPt, carboplatin and some pyrophosphate-Pt drugs. [START_REF] Fong | Platinum anti-cancer drugs: Free radical mechanism of Pt-DNA adduct formation and anti-neoplastic effect[END_REF][START_REF] Fong | Platinum based radiochemotherapies: free radical mechanisms and radiotherapy sensitizers[END_REF][START_REF] Maran | Dissociative electron transfer[END_REF][Fong 2016, [START_REF] Maran | Dissociative electron transfer[END_REF]] Explicit placement of an electron on the Pt in the {CisPt@CB[7]} (by using a two layer ONIOM model with the CisPt guest treated at the 6-31G(d,p) level and the CB [7] at the PM6 or UFF level) results in a elongated Pt-Cl bond configuration very similar to the configuration for {CB [7]CisPt••} dianion where the two electrons are not specifically placed in the starting complex. These observations are consistent with electron density being initially located to the CB [7] host as well as the CisPt guest when electrons are attached to the starting complex. There is considerable evidence of charge transfer effects between the host and guest in {CB[n]-guest}complexes. [START_REF] Saleh | Cucurbiturils in Drug Delivery And For Biomedical Applications[END_REF][START_REF] Suvitha | Theoretical insights into the formation, structure, and electronic properties of anticancer oxaliplatin drug and cucurbit[n]urils n=5 to 8[END_REF][START_REF] Venkataramanan | Theoretical Prediction of the Complexation Behaviors of Antitumor Platinum Drugs with Cucurbiturils[END_REF][START_REF] Chaban | Ionization of Cucurbiturils as a Pathway to More Stable Host-Guest Complexes[END_REF] [Suvitha 2009, Venkataramanan 2012, Saleh 2015, [START_REF] Chaban | Ionization of Cucurbiturils as a Pathway to More Stable Host-Guest Complexes[END_REF]]. These observations are consistent with a Marcus type inner sphere electron transfer in {CB [7]CisPt•} complexes from the CB [7] host to the CisPt guest.

Other configurations of the CisPt within the CB [7] cavity have been investigated and similar results are seen when an electron is added to the Pt centre, ie bond elongation particularly of the Pt-Cl bonds occurs. The further away of the Pt atom is from the centroid position of CB [7] the less stable is the complex, which is reflected in larger counterpoise BSSEs as expected. However it is not computationally feasible to identify the most favoured configurations of {CisPt@CB [7]}. The AEA data in Table 1 identifies two modes of electron attachment to {CisPt@CB [7]}: attachment to the CB [7] host and or attachment to the CisPt guest, either directly or via transfer from the CB [7] host.

An important feature of CB[n] is their flexibility and ability to deform to allow guests to insert into the CB cavity, particularly deformations of the portal carbonyl groups. [START_REF] Venkataramanan | Theoretical Prediction of the Complexation Behaviors of Antitumor Platinum Drugs with Cucurbiturils[END_REF][Venkataramanan 2012] This configurational flexibility is particularly evident when the CisPt guest is hydrogen bonded to the CB [7] carbonyls, where significant distortion of the CB [7] is observed.

A configuration very similar to that investigated by Plumb where the CisPt has 4 hydrogen bonds joining the Pt-N-H to the carbonyl oxygen atoms in the configuration with the two Pt-Cl bonds "pointing in" to the cavity was also investigated. (Figure 5) The HOMO was located on the CB [7] with the LUMO located on the Pt. Attachment of an electron to the Pt centre resulted in small elongations of the Pt-Cl and Pt-N bonds, bit the elongations were not as large as those where the inserted CisPt configuration was not hydrogen bonded and centrally placed within the cavity. The AEA for a one and two electron attachment are about 2.3-2.7 and 7.1-7.5 eV, which are considerably larger values than those for the non hydrogen bonded centrally located configuration in Figure 1. However these values are estimates only since there is considerable change to the CisPt(N-H) to CB [7] (C=O) hydrogen bonds upon electron attachment. It is clear that significant configurational deformation occurs for the CB [7] host in the hydrogen bonded configuration shown in Figure 5, and a measure of the deformation can be gauged from the counterpoise BSSE of 136.4 kcal/mol compared to the BSSE for the Figure 1 configuration of 119.4 kcal/mol. This observation parallels the difference in ΔG solv in water where the Figure 1 configuration has a value of -172.0 kcal/mol compared to the value for the Figure 5 hydrogen bonded configuration of -137.4 kcal/mol.

Discussion

The cavity of CB [7] is large enough to accommodate large guest molecules, such as adamantanes, ferrocenes or carboranes. The affinity equilibrium constant of CB [7] with the positively charged 1-aminoadamantane hydrochloride is 4.23x10 12 [26] [START_REF] Liu | The Cucurbit[n]uril Family: Prime Components for Self-Sorting Systems[END_REF]] and for some ferrocene derivatives can reach up to 10 15 M -1 [START_REF] Ko | Ultrastable Host-Guest Complexes and Their Applications[END_REF][ [START_REF] Ko | Ultrastable Host-Guest Complexes and Their Applications[END_REF]] values on a par with the highest known binding constants (biotin-avidin) The binding constants become highest when the ratio of the guest volume and the inner cavity volume of the CB are close to 0.55. The cavity of CB [7] is reported to be 242 Å 3 based on x-ray crystal data, and the polarity of the cavity resembles that of alcohols (e.g., n-octanol), while its polarizability is low, close to the gas phase. The driving force for binding of hydrophobic guests by CBs is dominated by hydrophobic effects related to the removal of very high energy water molecules from the cavity. Dispersion interactions are not important, owing to the low polarizability of the cavity. It has also been concluded from molecular dynamics that the insertion of guest molecules into the CB [7] cavity requires the explusion of 8 high energy water molecules. [START_REF] Nau | Deep Inside Cucurbiturils: Physical Properties and Volumes of their Inner Cavity Determine the Hydrophobic Driving Force for Host-Guest Complexation[END_REF] [START_REF] Nau | Deep Inside Cucurbiturils: Physical Properties and Volumes of their Inner Cavity Determine the Hydrophobic Driving Force for Host-Guest Complexation[END_REF] The affinity constant for CB [7]CisPt has been estimated to be < 10 4 M -1 , [START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF] [START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF]] while that for CB [7]OxaliPt is be 2.4x10 5 M -1 [START_REF] Jeon | Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug[END_REF]]. Solution NMR studies of both complexes show that there is a slow exchange of free and guest Pt species in both complexes, despite the relatively high affinity constants. [START_REF] Wheate | Cucurbit[n]uril binding of platinum anticancer complexes[END_REF][START_REF] Jeon | Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug[END_REF][START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF] [Jeon 2005, Plumb 2012, [START_REF] Wheate | Cucurbit[n]uril binding of platinum anticancer complexes[END_REF]] The {CisPt@CB [7]} complex can exist in various configurations, with one study showing a "pointing out" configuration where the amines of CisPt are hydrogen bonded to the portal carbonyls with the two Cl atoms pointing out from the cavity, and another "pointing in" configuration with the Cl atoms buried into the cavity which is estimated to be 0.24 kcal/mol more stable than the other configuration. [START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF] [START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF]].

Computations of the {CB [7]OxaliPt} (in gas it appears) have shown that the binding energy between the OxaliPt and CB [7] is very large (2.17 hartrees) and virtually the same as the BSSE corrected binding energy. The very large binding energy is attributed to the very large 2.4x10 5 M -1 affinity constant. The HOMO is centred on the Pt (which sits outside the cavity) and the LUMO is centred on the CB [7] moiety, with charge transfer occurring from the Pt to the CB [7] as evidenced by NBO charges. [START_REF] Suvitha | Theoretical insights into the formation, structure, and electronic properties of anticancer oxaliplatin drug and cucurbit[n]urils n=5 to 8[END_REF] [Suvitha 2009] The ΔG form for {CB [7]OxaliPt} and {CisPt@CB [7]} in water are -0.590 and 80.73 kcal/mol, the negative value for the {CB [7]OxaliPt} complex indicating spontaneous complex formation. [START_REF] Venkataramanan | Theoretical Prediction of the Complexation Behaviors of Antitumor Platinum Drugs with Cucurbiturils[END_REF] [Venkataramanan 2012] Extensive electron attachment charge transfer processes have been shown to occur electrochemically in water within the {CB [7]MV 2+ } complex (methyl viologen dication) cavity. The binding constants for 1, 2 and 3 electron reductions are 2x10 5 M -1 , 1x10 5 M -1 and 2x10 2 M -1 respectively. [START_REF] Lee | Cucurbituril Homologues and Derivatives: New Opportunities in Supramolecular Chemistry[END_REF][ [START_REF] Lee | Cucurbituril Homologues and Derivatives: New Opportunities in Supramolecular Chemistry[END_REF] The results from this study are consistent with a mechanism whereby CisPt can easily enter the CB [7] cavity with substantial desolvation of the cavity being required, costing ca. 1.6 kcal/mol. This is consistent with Nau's results whereby 8 water molecules were explicitly expelled upon insertion of various guest molecules. NMR evidence [START_REF] Jeon | Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug[END_REF][START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF] [ [START_REF] Jeon | Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug[END_REF][START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF]] is consistent with a slow exchange between the cavity bound CisPt and the free CisPt despite the high binding affinities. Many configurations of the bound CisPt in the CB [7] cavity are possible. In all cases investigated, the addition of an electron to the {CisPt@CB [7]} results in bond elongation, particularly of the Pt-Cl bond. (Table 1) We have previously observed this behaviour in the free CisPt (as well as in carboplatin, nedaplatin and the protonated form of oxaliplatin where elongation of the Pt-O bonds also occur [Fong 2016]). There are substantial charge transfer interactions between the CB [7] host and the CisPt guest when electrons are attached to the {CisPt@CB [7]} complex, and deformations of the CB [7] occur simultaneously. The calculated ΔG form for the {CB [7]CisPt•}anion and {CB [7]CisPt••}dianion are consistent with high binding constants for the 1, 2 and 3 electrochemical electron attachments to the {CB [7]MV 2+ } complexes [Lee 2013] indicating strong charge transfers. However, as previously shown, [START_REF] Jeon | Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug[END_REF][START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF][START_REF] Saleh | Cucurbiturils in Drug Delivery And For Biomedical Applications[END_REF][START_REF] Suvitha | Theoretical insights into the formation, structure, and electronic properties of anticancer oxaliplatin drug and cucurbit[n]urils n=5 to 8[END_REF][START_REF] Venkataramanan | Theoretical Prediction of the Complexation Behaviors of Antitumor Platinum Drugs with Cucurbiturils[END_REF][START_REF] Chaban | Ionization of Cucurbiturils as a Pathway to More Stable Host-Guest Complexes[END_REF]

The results from this study and literature reports are indicative of {CisPt@CB[7]} being a source of Pt based free radicals such as (H 3 N) 2 PtCl• and (H 3 N) 2 Pt•• species in water within a radiation environment which can produce hydrated electrons.

Jeon 2005 [START_REF] Jeon | Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug[END_REF] has shown that inclusion complexes of oxaliplatin with cucurbit [7]uril has moderate cytotoxicity with larger decrease in reactivity towards guanosine and L-methionine respectively. Plumb 2012 [START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF] has shown that {CisPt@CB [7]} is effective against CisPt resistant human ovarian xenografts by a pharmacokinetic effect. Although the peak plasma level and tissue distribution were the same for {CisPt@CB [7]} and free cisplatin, the total concentration of circulating {CisPt@CB [7]} over a period of 24 hours was significantly higher than for free cisplatin when administered at the equivalent dose.

The efficacy of anti-cancer drugs such as CisPt in solid tumours is dependent on drug delivery to the tumour compared to normal tissue where the cytotoxicity causes unwanted side effects. The enhanced permeability and retention effect (EPR) is a well documented mechanism that enhances the anti-tumour effect of large drugs (> 40k Da) as a result of defective lymphatic flow and leaky tumour blood vessels. Encapsulating CisPt with high molecular weight lipophilic polymeric materials (eg Lipoplatin) has been one approach to improving the anti-cancer efficacy. However there are reports which suggest that CisPt itself can show higher retention in tumours compared to normal tissue. In a study of concurrent chemoradiotherapy schedules, cisplatin adduct levels in tumours were significantly higher than in normal tissues (white blood cells and buccal cells). No evidence of a correlation was found between adduct levels in normal tissues and primary tumour biopsies. [START_REF] Hoebers | Cisplatin-DNA adduct formation in patients treated with cisplatin-based chemoradiation: lack of correlation between normal tissues and primary tumor[END_REF] [START_REF] Hoebers | Cisplatin-DNA adduct formation in patients treated with cisplatin-based chemoradiation: lack of correlation between normal tissues and primary tumor[END_REF] It is known that many anti-cancer drugs including CisPt can bind to intra-and extra-cellular macromolecules such as proteins, serum proteins and nucleic acids. Spheroids (3D cellular structures) which show the characteristics of solid tumours have been used to test the efficacy of chemotherapy and radiotherapy protocols. For example doxorubicin and paclitaxel bind to cellular macromolecules that remain localized in the periphery of spheroids. [START_REF] Jain | Solid Tumours: A Review[END_REF][START_REF] Timerbaev | Interactions of Antitumor Metallodrugs with Serum Proteins: Advances in Characterization Using Modern Analytical Methodology[END_REF][Jain 2011, [START_REF] Timerbaev | Interactions of Antitumor Metallodrugs with Serum Proteins: Advances in Characterization Using Modern Analytical Methodology[END_REF] It has been shown that CisPt penetrates well into a multicellular tumour spheroid produced from a squamous lung carcinoma cell line whereas doxorubicin did not, but pre-treatment of the spheroid with CisPt followed by doxorubicin produced a synergistic lethality. [START_REF] Kaku | Timing of cisplatin administration for chemoradiotherapy in transgenic mice bearing lens tumors[END_REF] [START_REF] Kohno | Interactions of doxorubicin and cisplatin in squamous carcinoma cells in culture[END_REF]] Similar results were seen using a multicellular tumour spheroid produced from a human lung cancer cell line. [START_REF] Kohno | Interactions of doxorubicin and cisplatin in squamous carcinoma cells in culture[END_REF] [START_REF] Inoue | Effects of Doxorubicin and Cisplatin on Multicellular Tumor Spheroids from Human Lung Cancer[END_REF]] It is probable that CisPt may bind to proteins or other macromolecules within solid tumours, hence producing high molecular weight intermediates that show an EPR effect.

It is also well known that the timing and sequence of combined chemotherapies have an influence on anti-cancer efficacy. For example in a study of combined radiation-CisPt treatment, it was found that administration of CisPt before radiation was less effective than concurrent treatments or administration of CisPt after radiation (while the side effects were similar). [START_REF] Inoue | Effects of Doxorubicin and Cisplatin on Multicellular Tumor Spheroids from Human Lung Cancer[END_REF] [START_REF] Kaku | Timing of cisplatin administration for chemoradiotherapy in transgenic mice bearing lens tumors[END_REF]] These reports indicate that chemotherapy of solid tumours is highly dependent on delivery and timing influences, and that delivery of CisPt to solid tumours may involve an induced form of the EPR through binding with cellular macromolecules. It is also been shown that encapsulated CBs can cross cell membranes, since CBs can be internalized in macrophages. CBs appear to have two possible mechanisms for delivering drugs to their targets: direct transport across cell membranes, or by releasing its guest molecule which can then be transported across the cell membrane. [START_REF] Hettiarachchi | Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers[END_REF][START_REF] Montes-Navajas | Cucurbituril complexes cross the cell membrane[END_REF][Montes-Navajas 2009, [START_REF] Hettiarachchi | Toxicology and Drug Delivery by Cucurbit[n]uril Type Molecular Containers[END_REF] It is possible that the observation by Plumb 2012 that {CisPt@CB [7]} was effective against human ovarian xenografts (but not in vitro cell cultures) may be a result of such an EPR induced by binding of the {CisPt@CB [7]} with cellular macromolecules in the xenograft tumours, which is not possible with in vitro cell cultures. The known timing and schedule modality dependence of combined radiochemotherapies are also consistent with delivery and EPR dependence.

It is predicted that encapsulating CisPt with CB [7] may not only invoke superior drug delivery through preventing unwanted side effects in blood serum and normal tissue, but may increase interaction with cellular macromolecules (over that of CisPt itself) since the CB [7] carrier host has multiple possible-N-C(=O)-binding sites. It has been shown that the dye brilliant green (BG) can be transferred from being encapsulated inside CB [7] to forming a complex with bovine serum albumin (BSA) by the presence of Na + ions. This reaction involves a ternary {BG-CB [7]-BSA} ternary complex. [START_REF] Bhasikuttan | Efficient Fluorescence Enhancement and Cooperative binding of an Organic Dye in a Supra-biomolecular Host-Protein Assembly[END_REF] [START_REF] Bhasikuttan | Efficient Fluorescence Enhancement and Cooperative binding of an Organic Dye in a Supra-biomolecular Host-Protein Assembly[END_REF]] A ternary complex involving a dendrimer, CB and DNA has also been identified. [START_REF] Lim | Self-Assembled Ternary Complex of Cationic Dendrimer, Cucurbituril, and DNA: Noncovalent Strategy in Developing a Gene Delivery Carrier[END_REF] [START_REF] Lim | Self-Assembled Ternary Complex of Cationic Dendrimer, Cucurbituril, and DNA: Noncovalent Strategy in Developing a Gene Delivery Carrier[END_REF]] Since DNA is a known target of CisPt, this is a pertinent observation. Complexation of encapsulated guest CBs with proteins is well documented [START_REF] Saleh | Cucurbiturils in Drug Delivery And For Biomedical Applications[END_REF] [START_REF] Saleh | Cucurbiturils in Drug Delivery And For Biomedical Applications[END_REF]] which also raises the possibility that {CisPt@CB[7]} could complex with target cellular proteins that are involved in Pt induced apoptosis and necrosis.

Conclusions

It has been shown in this study that the {CisPt@CB [7]} complex can be a source of Pt based free radicals such as (H 3 N) 2 PtCl• and (H 3 N) 2 Pt•• species in water within a radiation environment which can produce hydrated electrons. Encapsulating CisPt within the CB [7] host takes advantage of the previously described drug delivery and reduced side effect advantages of CBs. Based on quantum mechanical modelling and literature results, it is predicted that {CisPt@CB [7]} may interact with cellular macromolecules and engage in an enhanced permeation and retention mechanism in solid tumours, offering further synergistic advantages for a radiation-{CisPt@CB [7]} regimen over that of the conventional radiation-CisPt regimens in current use in anti-cancer chemoradiotherapies.

Experimental Methods

Energy optimisations were done at the DFT/B3LYP/LANL2DZ, and DFT/B3LYP/3-21G level of theory for all atoms except for Pt where the relativistic ECP SDD Stuttgart-Dresden basis set for transition metals was used. Optimisations were also conducted using a two layer ONIOM model, at the LANL2DZ, 6-31G(d,p) and 6-31+G(d) levels for the high level CisPt moiety, and using the UFF force field or semi-empirical PM6 at the low level. Atomic charges were natural population charges (NPA) from NBO calculations. HOMO and LUMO included both delocalized and localized orbitals (NBO). To investigate if dispersion effects were influencing geometries, the wB97XD functional was also used, since the B3LYP functional can give errors where dispersion effects are significant. This functional is a long range corrected hybrid with damped dispersion correction which gives good results with noncovalent and covalent systems and have been shown to give quite accurate results when compared to experimental data. [START_REF] Fong | Platinum anti-cancer drugs: Free radical mechanism of Pt-DNA adduct formation and anti-neoplastic effect[END_REF][START_REF] Fong | Platinum based radiochemotherapies: free radical mechanisms and radiotherapy sensitizers[END_REF][START_REF] Peverati | The quest for a universal density functional: the accuracy of density functionals across a broad spectrum of databases in chemistry and physics[END_REF] [Fong 2016, Peverati 2014] The ΔG electronattach in water is -73 kcal/mol for the B3LYP functional, and -65 kcal/mol for the wB97XD functional, which are effectively equivalent within experimental error. It appears that dispersion effects are not greatly influencing structural parameters for these complexes.

There were small differences in geometries for the B3LYP, LANL2DZ and wB97XD functionals. These computations show a small dependency on the choice of functional/basis set or UFF or PM6 combination, but this small dependency is always much less than the Pt----Cl and Pt----N bond elongations found in the radical anions. Energy calculations were conducted at the B3LYP/6-31G(d,p)/SDD level. (Table 1) Adiabatic electron affinities (AEA) in eV were calculated as previously described. [START_REF] Fong | Platinum anti-cancer drugs: Free radical mechanism of Pt-DNA adduct formation and anti-neoplastic effect[END_REF][START_REF] Fong | Platinum based radiochemotherapies: free radical mechanisms and radiotherapy sensitizers[END_REF] [Fong 2016] It has been shown that the B3LYP functional gives accurate electron affinities when tested against a large range of molecules, atoms, ions and radicals with an absolute maximum error of 0.2 eV. [START_REF] Rienstra-Kiracofe | Atomic and molecular electron affinities: Photoelectron experiments and theoretical computations[END_REF] [Rienstra-Kiracofe 2002] It has been found that B3LYP/LANL2DZ mixed basis sets gave the lowest errors in calculating IP values for transition metal compounds for 12 DFT functional, and compared well with all electron calculations. [START_REF] Yang | Assessment of the '6-31+G** + LANL2DZ Mixed Basis Set Coupled with Density Functional Theory Methods and Effective Core Potential: Prediction of Heats of Formation and Ionization Potentials for First Row Transition Complexes[END_REF] [START_REF] Yang | Assessment of the '6-31+G** + LANL2DZ Mixed Basis Set Coupled with Density Functional Theory Methods and Effective Core Potential: Prediction of Heats of Formation and Ionization Potentials for First Row Transition Complexes[END_REF]] Independent tests of the accuracy of the AEA calculations were performed on trimethylmethylcyclopentadienylplatinum(IV) which has a known gas phase AEA in the range from 0-0.5(max) eV. [START_REF] Engmann | Gas phase low energy electron induced decomposition of the focused electron beam induced deposition (FEBID) precursor trimethyl (methylcyclopentadienyl) platinum(IV)[END_REF][START_REF] Engmann | Low Energy Electron Interactions with Precursor Molecules Relevant to Focused Electron Beam Induced Deposition[END_REF] [Engmann] The calculated gas AEA using various DFT combinations of B3LYP and WB97XD with LANL2DZ and 6-31G++(d,p)/SDD were 0.3-0.5 eV, in good agreement with the literature values.

The free energy of formation of the {CisPt@CB [7]} complex ΔG form,Complex in a particular solvent is calculated from the thermodynamic cycle at standard conditions, T = 298.15 K and P = 1 atm: ΔG form,Complex = ΔG form,Gas + ΔG solv,Complex -ΔG solv,CB [7] -ΔG solv,CisPt where ΔG form,Gas is the free energy of formation of the complex in the gas phase, and ΔG solv is the free energy of solvation. The ΔG form,Complex are corrected for the BSSE (basis set supposition error) using the counterpoise method.

  [START_REF] Plumb | Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect[END_REF], Jeon 2005, Suvitha 2009, Venkataramanan 2012, Saleh 2015, Chaban 2015] despite high binding values, there is a slow interchange between encapsulated CisPt and free CisPt in solution.

Figure 1 (Figure 3 .

 13 Figure 1(b). {CisPt@CB[7]} complex Top View

Table 1 . Changes in geometry of CisPt guest inside host CB[7] after electron additions to {CisPt@CB[7]} Pt-Cl 1 Å Pt-Cl 2 Å Pt-N 1 Å Pt-N 2 Å Angle: Cl 1 -Pt-N 1 NPA Pt Charge

 1

	AEA
	eV


Single port access surgery is a common minimally Invasive Surgery technique, which uses a single small incision or a natural orifice in human anatomy to insert surgical instruments and laparoscopic cameras. Shared usage of a standard trocar endoscope camera and surgical instruments through a single incision reduces dexterity in both dexterity of surgical instruments and the field of views of laparoscopic cameras. A magnetic driven wireless camera is designed to overcome this conflict. Due to the unique nonlinear and time-dependent behavior of soft tissues under manipulations, an appropriate modeling of the interaction between the wireless camera capsule and abdominal tissues is essential for camera robot precise control. In this poster, we discuss an analytical model which is developed for the contact phenomena of a rigid cylinder capsule and viscoelastic tissue based on Kelvin-Voigt model. The model considers membrane tension forces, peritoneal fluid shear stress and deflected tissue pressure to derive Equations of motion for both translation and tilt rotation of camera capsule. The model is simulated analytically in MATLAB software. A Finite Element Analysis is conducted in order to simulate the interaction. Defining an accurate friction model at the contact point is the challenging part of simulation.

The Interaction Model Development and Simulation of Wireless Laparoscopic Camera and Abdominal Wall Tissue

Interaction Viscoelastic Model

The interaction is modeled by considering the membrane tension, Friction, and uneven contact during traverse of camera robot. the trailing edge (aft) loses contact with the capsule more quickly than in the elastic case due to the viscoelastic nature of the model (i.e. 𝜑 𝐹 > |𝜑 𝐴 |).

RezaFig. 1 .✓✓

 1 Fig. 1. (a) Conceptual illustration of the wireless capsule robot., (b) Single port invasive surgery with wireless camera Advantages: ✓ Unified design for anchoring, navigating, and rotating of a fully insertable camera by externally generated rotational magnetic field ✓ No Suturing ✓ No Internal Motors and wire Conflicts ✓ Steady image + Different view angles ✓ Better Surgical instruments dexterity ❖Drawbacks: ✓ Designing regardless of soft tissue mechanical properties ❖ Solution: Considering the Interaction to study the camera robot dynamics

Fig. 5 .

 5 Fig. 5. Magnetic force vs stator-rotor distance

Fig. 6 .Fully 2 .

 62 Fig. 6. finite element model simulated in order to study the contact

Fig. 3 .➢➢ConclusionFigure 4 .

 34 Figure 4. Horizontal Forces Acting on capsule