Multiscale Approach to Investigate Self-Assembly of Telodendrimer Based Nanocarriers for Anticancer Drug Delivery

Abstract

Delivery of poorly soluble anticancer drugs can be achieved by employing polymeric drug delivery systems, capable of forming stable self-assembled nanocarriers with drug encapsulated within their hydrophobic cores. Computational investigations can aid the design of efficient drug-delivery platforms; however, simulations of nanocarrier self-assembly process are challenging due to high computational cost associated with the large system sizes (millions of atoms) and long time scales required for equilibration. In this work, we overcome this challenge by employing a multiscale computational approach in conjunction with experiments to analyze the role of the individual building blocks in the self-assembly of a highly tunable linear poly(ethylene glycol)-b-dendritic oligo(cholic acid) block copolymer called telodendrimer. The multiscale approach involved developing a coarse grained description of the telodendrimer, performing simulations over several microseconds to capture the self-assembly process, followed by reverse mapping of the coarse grained system to atomistic representation for structural analysis. Overcoming the computational bottleneck allowed us to run multiple self-assembly simulations and determine average size, drug-telodendrimer micellar stoichiometry, optimal drug loading capacity, and atomistic details such hydrogen-bonding and solvent accessible area of the nanocarrier. Computed results are in agreement with the experimental data, highlighting the success of the multiscale approach applied here.

A drug-specific nanocarrier design for efficient anticancer therapy

“… 23 We have demonstrated that the hydrophilic hydroxyl-rich surface of CA faces towards the aqueous PEG layer on the core-shell interface of PEG 5k CA 8 micelles to minimize the surface tension, therefore stabilizing the nanocarriers. 33 With this in mind, we developed another two versions of telodendrimers with the rational architecture design: i.e. the second generation (G2) of hybrid telodendrimers and the third generation (G3) of functional-segregated telodendrimers ( Figure 2B ) using CA as co-building blocks.…”

Investigating the Influence of Aromatic Moieties on the Formulation of Hydrophobic Natural Products and Drugs in Poly(2-oxazoline)-Based Amphiphiles

“…In particular, Luo, Nangia and co-workers backed the synthetic work with extensive modeling and achieved very high drug loadings paired with excellent therapeutic efficacy. [49][50][51] Börner and co-workers employed a high-throughput screening to find an improved drug loading for different cargo. [52][53][54] The driving forces considered relevant for drug incorporation are hydrophobic and electrostatic interactions, hydrogen bonding, π-π stacking and van der Waals forces.…”

Design of Nanoparticle-Based Carriers for Targeted Drug Delivery

“…Their models were validated with experimental synthesis and evaluations of nanocarrier library. Jiang, et al 94 employed multiscale modeling together with experiments to understand the building blocks’ role in telodendrimer self-assembly process. Recently, microchip device development has become another direction to simulate a tumor's microenvironment and test the effectiveness of NPs for targeted drug delivery 95,90 .…”