Akshay Be Day Poster
1
Introduction • Effective mitotic inhibitor for breast cancer, ovarian, and lung cancer cells • Cyclic aromatic components make it highly hydrophobic leads to solubility and toxicity problems Objective •To optimize the size and shape of a drug delivery system in order to enhance retention and uptake by tumor cell. •Computationally model PGGP on multiple scales from bond interactions to obtain desired physiochemical structures. •Model different permutations of drug loading and distribution to elucidate the optimal shape of the DDS. Polymeric drug delivery systems (DDS) Paclitaxel (PTX) Polyglutamyl-glutamate Paclitaxel (PGG Paclitaxel) • Hydrophilic 130-mer PGG • Variable amounts of PTX are loaded onto PGG on different locations Size and shape affects drug delivery Methods (ab initio methodology): Middle Ends •Using the above Boltzmann inversed curve, the force constants for the distances and angles (k ij and k ijk ), the equilibrium distance (r 0 ), equilibrium angle (θ 0 ), can be calculated. •Under the MARTINI force field parameters, the potential energies of the bond interactions can be calculated through the following: 0 ns 33 ns 66 ns 100 ns 0 ns 25 ns 50 ns 80 ns __ 50 nm Summary and Conclusion: References: 1. Seow WY et al. Biomaterials (2007). 2. Duncan R. Nature Rev (2006). 3. Ferrari et al. Nature (2008). 4. Marrink SJ et al. J Phys Chem B (2007). 5. Monticelli et al. J Chem Theory Comp (2008). 6. Tryslska J et al. Biophys J (2005). Elucidating Primary Structure of the Nanovector Poly (glutamyl – glutamate) Paclitaxel : a Coarse Grained Study Akshay S. Chaudhari †,§ , Vincent M. Wong †,§ , Lili X. Peng † and David Gough † †Department of Bioengineering, ‡Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0412, § Both authors contributed equally to the work. •Polymers are effective vehicles for chemotherapy because they are water-soluble, degradable in the body, and they minimize drug exposure to healthy tissue and metabolism by the body. Adhesion propertiesEntry into tumors Rate of endocytosis by tumor cells Ferrari et al., Nature 2008 •To coarse grain, around 4-5 atoms are grouped together to form a super atom. •The MARTINI force field dictates that the force field to account for the bead interactions is: E = E bonds + E angles + E torsions + E nonbonded The first three terms account for pseudo-bond, pseudo- angle and pseudo-dihedral interactions between the first two, three and four successive beads in each chain, respectively. • Circular Dichroism Spectroscopy on the PGG-PTX molecule did not find any secondary structures. So, the only values that are important for the force field are E bonds + E angles . • Calculating the energies is a four step process that involves : 1. Plot bond dist./angles against time. 2. Draw a probability distribution curve of the bond distances or angle. 3. Normalize the above generated probability distribution. 4. Apply the Boltzmann Inversion to calculate the mean potential energies. __ 50 nm Even Cluster s Random 0 ns 33 ns 66 ns 100 ns 0 ns 25 ns 50 ns 75 ns Atomistic simulations – PGG Paclitaxel (37%) Results Side 0 ns 25 ns 50 ns 80 ns 0 ns 40 ns 80 ns 120 ns •Traditional Method: Top-down wet lab trials deform existing polymers into desired shapes. •Computational Method: Bottom-up multi-scale computational modeling is more efficient in time and cost. •Using GROMACS, bond distances and angles between individual PGG monomers can be modeled. •Use MATLAB to analyze these bond interactions to find the equilibrium distances ,angles and with force constants of PGGP. •Using that data, a mesoscalic model can be created for the PGGP. Future Work: • Once the potential energies for bead interactions are known, a mesoscalic model of PGGP can be created. Due to the hydrophobic nature of the PGGP, multiple molecules form a micelle. • The precise shape of this micelle can be predicted by coarse graining. This is the final step that determines the optimal size and shape of PGGP. • In order to consolidate the findings, the PGGP molecule will be subject to Transmission Electron Microscopy (TEM), which has its own hurdles. • The highly hydrophobic nature of PGGP makes staining and viewing challenging since the molecule is constantly in motion. • One of the most pragmatic way of viewing the PGGP is probably through Cryo-TEM, where the PGGP would be subjected to low temperatures using liquid nitrogen so that the rigidity of the structure would be greatly reduced. Cryo-TEM would greatly assist in corroborating the multi-scale modeling approach with the true atomistic form of PGGP. (Derived from the Boltzmann inversion) • Multi scale modeling is an efficacious mechanism in order to test the effectiveness of a multitude of drug delivery systems. • Computational chemistry can deduce the optimal physiochemical properties of such DDS’ while minimizing time and costs and eliminating wet lab trials.
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Transcript of Akshay Be Day Poster
Introduction
• Effective mitotic inhibitor for breast cancer, ovarian, and lung cancer cells• Cyclic aromatic components make it highly hydrophobic leads to solubility and toxicity problems
Objective•To optimize the size and shape of a drug delivery system in order to enhance retention and uptake by tumor cell.•Computationally model PGGP on multiple scales from bond interactions to obtain desired physiochemical structures.•Model different permutations of drug loading and distribution to elucidate the optimal shape of the DDS.
Polymeric drug delivery systems (DDS)
Paclitaxel (PTX)
Polyglutamyl-glutamate Paclitaxel (PGG Paclitaxel)• Hydrophilic 130-mer PGG
• Variable amounts of PTX are loaded onto PGG on different locations
Size and shape affects drug delivery
Methods (ab initio methodology):
Middle
Ends
•Using the above Boltzmann inversed curve, the force constants for the distances and angles (kij and kijk), the equilibrium distance (r0), equilibrium angle (θ0), can be calculated.•Under the MARTINI force field parameters, the potential energies of the bond interactions can be calculated through the following:
0 ns 33 ns 66 ns 100 ns
0 ns 25 ns 50 ns 80 ns
__ 50 nm
Summary and Conclusion:
References:1. Seow WY et al. Biomaterials (2007). 2. Duncan R. Nature Rev (2006). 3. Ferrari et al. Nature (2008). 4. Marrink SJ et al. J Phys Chem B (2007). 5. Monticelli et al. J Chem Theory Comp (2008). 6. Tryslska J et al. Biophys J (2005).
Elucidating Primary Structure of the Nanovector Poly (glutamyl – glutamate) Paclitaxel : a Coarse Grained Study
Akshay S. Chaudhari †,§, Vincent M. Wong †,§, Lili X. Peng† and David Gough††Department of Bioengineering, ‡Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0412, § Both authors contributed equally to the
work.
•Polymers are effective vehicles for chemotherapy because they are water-soluble, degradable in the body, and they minimize drug exposure to healthy tissue and metabolism by the body.
Adhesion properties Entry into tumors Rate of endocytosis by tumor cells
Ferrari et al., Nature 2008
•To coarse grain, around 4-5 atoms are grouped together to form a super atom. •The MARTINI force field dictates that the force field to account for the bead interactions is: E = E bonds + E angles + E torsions + E nonbonded The first three terms account for pseudo-bond, pseudo-angle and pseudo-dihedral interactions between the first two, three and four successive beads in each chain, respectively.• Circular Dichroism Spectroscopy on the PGG-PTX molecule did not find any secondary structures. So, the only values that are important for the force field are E bonds + E angles . • Calculating the energies is a four step process that involves :
1. Plot bond dist./angles against time.
2. Draw a probability distribution curve of the bond distances or angle.
3. Normalize the above generated probability distribution.
4. Apply the Boltzmann Inversion to calculate the mean potential energies.
__ 50 nm
Even
Clusters
Random
0 ns 33 ns 66 ns 100 ns
0 ns 25 ns 50 ns 75 ns
Atomistic simulations – PGG Paclitaxel (37%)
Results
Side 0 ns 25 ns 50 ns 80 ns
0 ns 40 ns 80 ns 120 ns
•Traditional Method: Top-down wet lab trials deform existing polymers into desired shapes.•Computational Method: Bottom-up multi-scale computational modeling is more efficient in time and cost.•Using GROMACS, bond distances and angles between individual PGG monomers can be modeled.•Use MATLAB to analyze these bond interactions to find the equilibrium distances ,angles and with force constants of PGGP.•Using that data, a mesoscalic model can be created for the PGGP.
Future Work:• Once the potential energies for bead interactions are known,
a mesoscalic model of PGGP can be created. Due to the hydrophobic nature of the PGGP, multiple molecules form a micelle. • The precise shape of this micelle can be predicted by coarse graining. This is the final step that determines the optimal size and shape of PGGP.• In order to consolidate the findings, the PGGP molecule will be subject to Transmission Electron Microscopy (TEM), which has its own hurdles.• The highly hydrophobic nature of PGGP makes staining and viewing challenging since the molecule is constantly in motion.• One of the most pragmatic way of viewing the PGGP is probably through Cryo-TEM, where the PGGP would be subjected to low temperatures using liquid nitrogen so that the rigidity of the structure would be greatly reduced. Cryo-TEM would greatly assist in corroborating the multi-scale modeling approach with the true atomistic form of PGGP.
(Derived from the Boltzmann inversion)
• Multi scale modeling is an efficacious mechanism in order to test the effectiveness of a multitude of drug delivery systems.• Computational chemistry can deduce the optimal physiochemical properties of such DDS’ while minimizing time and costs and eliminating wet lab trials.
