Molecular Modeling of Block Copolymer Self‐Assembly and Micellar Drug Delivery

Kang, Myungshim; Lam, Dennis S.C.; Discher, Dennis E.; Loverde, Sharon M.

doi:10.1002/9781118573983.ch4

Cited by 7 publications

(8 citation statements)

References 140 publications

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“…UPSM displayed notable pH plateaus at pH 6.0, as previously observed, whereas the pH of NPSM decreased proportionally with the addition of HCl (Figure a), indicating that UPSM, but not NPSM, has a strong pH buffering effect. Since micellization of UPSM is critical for the pH buffering effect, , and the encapsulated hydrophobic drug may influence the self-assembly and dissociation of micelles, we further evaluated the impact of drug encapsulation on the pH buffering effect of these micelles. The pH titration results confirmed that drug encapsulation had a minimal impact on the pH buffering capabilities: T-NPSM had no obvious pH buffering effect (Figure b), whereas T-UPSM (polymer concentration 1 mg/mL) showed the same pH plateaus at pH 6.0 (Figure a,c).…”

Section: Resultsmentioning

confidence: 99%

Targeting the Oncogene KRAS Mutant Pancreatic Cancer by Synergistic Blocking of Lysosomal Acidification and Rapid Drug Release

et al. 2019

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Survival of KRAS mutant pancreatic cancer is critically dependent on reprogrammed metabolism including elevated macropinocytosis, autophagy, and lysosomal degradation of proteins. Lysosomal acidification is indispensable to protein catabolism, which makes it an exploitable metabolic target for KRAS mutant pancreatic cancer. Herein we investigated ultra-pH-sensitive micelles (UPSM) with pH-specific buffering of organelle pH and rapid drug release as a promising therapy against pancreatic cancer. UPSM undergo micelle–unimer phase transition at their apparent pK a, with dramatically increased buffer capacity in a narrow pH range (<0.3 pH). Cell studies including amino acid profiling showed that UPSM inhibited lysosomal catabolism more efficiently than conventional lysosomotropic agents (e.g., chloroquine) and induced cell apoptosis under starved condition. Moreover, pH-triggered rapid drug release from triptolide prodrug-loaded UPSM (T-UPSM) significantly enhanced cytotoxicity over non-pH-sensitive micelles (T-NPSM). Importantly, T-UPSM demonstrated superior safety and antitumor efficacy over triptolide and T-NPSM in KRAS mutant pancreatic cancer mouse models. Our findings suggest that the ultra-pH-sensitive nanoparticles are a promising therapeutic platform to treat KRAS mutant pancreatic cancer through simultaneous lysosomal pH buffering and rapid drug release.

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Section: Resultsmentioning

confidence: 99%

Targeting the Oncogene KRAS Mutant Pancreatic Cancer by Synergistic Blocking of Lysosomal Acidification and Rapid Drug Release

et al. 2019

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“…Each coarse-grained bead corresponds to several repeat units for polymer chains in experiments. 21 Block copolymers are modeled as a bead-spring sequence where the beads are connected by harmonic springs, F ij s = K(r ij − r 0 ) with K = 100 being the spring constant, r ij is the separation distance between two beads, and r 0 = 1 is the equilibrium bond length with all of the beads having an identical mass. 8 For a tadpole block copolymer, the first and eighth beads of the solvophilic B block are connected (using the same harmonic spring) into a ring structure, as shown in Figure 1b.…”

Section: Simulation Methodology and Detailsmentioning

confidence: 99%

“…Each tadpole and linear diblock copolymers contain N A = 5 solvophobic beads of type A and N B = 8 solvophilic beads of type B, i.e., A 5 B 8 . Each coarse-grained bead corresponds to several repeat units for polymer chains in experiments . Block copolymers are modeled as a bead-spring sequence where the beads are connected by harmonic springs, F ij s = K ( r ij – r 0 ) with K = 100 being the spring constant, r ij is the separation distance between two beads, and r 0 = 1 is the equilibrium bond length with all of the beads having an identical mass .…”

Section: Simulation Methodology and Detailsmentioning

confidence: 99%

Micelle Self-Assembly and Chain Exchange Kinetics of Tadpole Block Copolymers with a Cyclic Corona Block

Prhashanna

Dormidontova

2020

Macromolecules

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Micelle self-assembly and chain exchange kinetics play an important role in technological applications such as biomedicine, cosmetics, etc. and remain an active area of research. In this work, using dissipative particle dynamics, we study the self-assembly and chain exchange kinetics of micelles formed by diblock copolymers with a cyclic hydrophilic block (“tadpole polymer”) in comparison with that for micelles of linear diblock copolymers with the same hydrophobic block and the overall composition. We found that tadpole diblock copolymers form micelles of smaller sizes and aggregation numbers and exhibit quicker chain exchange compared to linear diblock copolymers. These changes are attributed to higher crowding of the hydrophilic cyclic block near the core–corona interface. This effect can be described within a simple scaling model, which predicts the micelle size and aggregation number decrease and area per chain increase for tadpole micelles in excellent quantitative agreement with the simulation results. Even the presence of a small fraction (20%) of cyclic hydrophilic blocks in the corona of mixed linear/tadpole micelles results in a micelle size decrease and alters the chain exchange kinetics. We observe that the chain exchange of individual components in mixed micelles exhibits synergy: exchange of tadpole chains slows down, while the linear chains speed up compared to the corresponding pure micelles, which correlates with the change in the area per chain. In contrast, mixed micelles containing linear chains of different hydrophilic block lengths do not show such a synergy and do not exhibit noticeable changes in the area per chain, indicating that the origin of the phenomenon is the cyclic corona chain architecture.

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“…To model tadpole and linear diblock copolymers, we employed dissipative particle dynamics (DPD) simulations, , which are well-suited to study the thermodynamics and kinetics of large-scale diblock copolymer assembly. ,,,, We model A 5 B 6 diblock copolymers, where A and B are respectively hydrophobic and hydrophilic beads with the subscript representing the number of coarse-grained units. We note that each coarse-grained unit represents a group of several atoms and in general is larger than a polymer repeat unit . For the tadpole block copolymer, the first and fifth bead of A block are connected (using the same harmonic spring as for a regular chemical bond) into a ring structure, as shown in Figure .…”

Section: Simulation Methodology and Detailsmentioning

confidence: 99%

“…We note that each coarsegrained unit represents a group of several atoms and in general is larger than a polymer repeat unit. 42 For the tadpole block copolymer, the first and fifth bead of A block are connected (using the same harmonic spring as for a regular chemical bond) into a ring structure, as shown in Figure 1. Chemical bonds between beads are modeled as harmonic springs, F ij s = K(r ij − r 0 ) with K = 100 being the spring constant, r ij is the separation distance between two beads, and r 0 = 1 is the equilibrium bond length with all the beads having an identical mass.…”

Section: ■ Simulation Methodology and Detailsmentioning

confidence: 99%

Tadpole and Mixed Linear/Tadpole Micelles of Diblock Copolymers: Thermodynamics and Chain Exchange Kinetics

Prhashanna

Dormidontova

2017

Macromolecules

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Chain architecture is known to control macromolecular self-assembly and furthermore affect in a more complex way nanostructure stability. Equilibrium properties and chain exchange kinetics between micelles formed by tadpole-shaped diblock copolymers containing a loop-shaped hydrophobic block and a linear hydrophilic block are investigated using dissipative particle dynamics simulations. We found that tadpoles form micelles of smaller size and aggregation number than the corresponding linear diblock copolymers and have faster chain exchange kinetics, demonstrating that chain architecture can alter its effective hydrophobicity. Similar observations are made for linear diblock copolymer with a less hydrophobic core block indicating that the more compact conformation of tadpole coreforming block makes it "less hydrophobic". We show that tadpole and linear block copolymers form mixed micelles with tadpoles (or less hydrophobic chains) located on the periphery of the micelle core. The chain exchange kinetics between mixed micelles is found to be quicker than in linear diblock copolymer micelles and slower than in tadpole micelles. Tadpole escape or less hydrophobic chain exchange between mixed micelles occurs slower (in part due to the shielding role that these chains play) than in the corresponding pure micelles, while linear more hydrophobic chain exchange only slightly changes, suggesting that the exchange kinetics of the individual components can be affected differently by mixing.

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Molecular Modeling of Block Copolymer Self‐Assembly and Micellar Drug Delivery

Cited by 7 publications

References 140 publications

Targeting the Oncogene KRAS Mutant Pancreatic Cancer by Synergistic Blocking of Lysosomal Acidification and Rapid Drug Release

Targeting the Oncogene KRAS Mutant Pancreatic Cancer by Synergistic Blocking of Lysosomal Acidification and Rapid Drug Release

Micelle Self-Assembly and Chain Exchange Kinetics of Tadpole Block Copolymers with a Cyclic Corona Block

Tadpole and Mixed Linear/Tadpole Micelles of Diblock Copolymers: Thermodynamics and Chain Exchange Kinetics

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