Algorithm for Designing Nanoscale Supramolecular Therapeutics with Increased Anticancer Efficacy

Abstract

In the chemical world, evolution is mirrored in the origin of nanoscale supramolecular structures from molecular subunits. The complexity of function acquired in a supramolecular system over a molecular subunit can be harnessed in the treatment of cancer. However, the design of supramolecular nanostructures is hindered by a limited atomistic level understanding of interactions between building blocks. Here, we report the development of a computational algorithm, which we term Volvox after the first multicellular organism, that sequentially integrates quantum mechanical energy-state- and force-field-based models with large-scale all-atomistic explicit water molecular dynamics simulations to design stable nanoscale lipidic supramolecular structures. In one example, we demonstrate that Volvox enables the design of a nanoscale taxane supramolecular therapeutic. In another example, we demonstrate that Volvox can be extended to optimizing the ratio of excipients to form a stable nanoscale supramolecular therapeutic. The nanoscale taxane supramolecular therapeutic exerts greater antitumor efficacy than a clinically used taxane in vivo. Volvox can emerge as a powerful tool in the design of nanoscale supramolecular therapeutics for effective treatment of cancer.

Materials for Immunotherapy

“…The authors also included antibodies against CD47, which is “self‐marker” often expressed on cancer cells to escape immunosurveillance. Their liposome‐like nanoparticles are distinct from traditional liposomes, as they are made from the supramolecular assembly of a novel molecular subunit that engenders weaker intermolecular interactions, enabling higher loading capabilities compared to traditional shell‐encapsulating liposomes . Finally, ISCOMATRIX is a type of lipid‐based nanocage similar to liposomes that has been used an adjuvant for prophylactic and therapeutic vaccines against infectious diseases .…”

A designer self-assembled supramolecule amplifies macrophage immune responses against aggressive cancer

“…As the first step, we designed an amphiphilic molecular subunit that could assemble into a supramolecular structure via hydrophobic-hydrophilic interactions. In a recent study, we have described an algorithm based on quantum mechanical-all atomistic simulations to design these amphiphiles, starting from a known chemical backbone that blocked the molecular target 18,19 . The quantum mechanical energy minimized structure of an amphiphile with a CSF-1R-inhibiting pharmacophore is shown in Fig.1c.…”

“…The quantum mechanical energy minimized structure of an amphiphile with a CSF-1R-inhibiting pharmacophore is shown in Fig.1c. Our previous studies have revealed that such amphiphiles form bilayers with co-lipids, resulting in a supramolecular structure in the nanoscale 18 . Unlike nanoparticles or liposomes, where the drug is loaded in a carrier matrix and are rarely stable beyond 5 mol% drug, the supramolecular assembly means that we could achieve excellent stability of the structures at >20 mol % of the amphiphile 18,19 .…”

“…Similar concepts have been used to inspire the design of bifunctional antibodies or antibody drug conjugates, where different parts of the construct have distinct functions 16,17 . In a recent study, we have demonstrated an alternative strategy, where two distinct molecular building blocks are designed to assemble into a single structure via supramolecular interactions 18 (Fig.1b). We proposed that such a supramolecule could utilize the SIRPα-targeting component for binding to macrophages and block the ‘eat me not’ signal, while enabling a sustained shutdown of CSF-1R-signaling pathway, which could skew the TAM M1/M2 ratio towards a M1 phenotype (Fig.1b).…”

Characterization of the interaction forces in a drug carrier complex of doxorubicin with a drug‐binding peptide

“…Getting greater insight of the non‐covalent interactions of small‐molecule drugs with peptides, proteins, or nanocarriers is essential for designing better drug transporters. Theoretical calculations have played an important role in this regard, as they have revealed molecular details of the interaction between pharmacologically active substances and their carrier or with biomolecules . Molecular dynamics (MD) computations can be utilized to optimize drug delivery agents and to study the properties of the materials, such as their structure, stability, diffusion, and interactions in biological milieu .…”