The classic compatibility/solubility theories and molecular simulations have been applied to predict the drug loading properties of polymeric nanoconstructs. However, the success of these approaches to guide nanocarrier design is still limited. At the same time, it is challenging to synthesize a variety of nanocarriers as predicted with the precise control on structure, molecular weight and functional diversity via the conventional polymer chemistry, which further limits the systematic validation and experimental evaluation of the theoretical design. The current development of nanocarriers, especially for polymeric micelle and nanoparticles, is often a trial-error process with numerous attempts on a small subset of polymers, which frequently yield nanoparticles with less optimized drug loading properties and limited opportunity for further optimization. Inspired by the well- defined structure-activity relationship in peptide chemistry, we have developed a PEG-b-dendritic oligomer system (named telodendrimer) using stepwise peptide chemistry, which assembles into micellar nanocarrier for drug delivery. A new version of telodendrimer possesses a function-segregated structure, e.g. a hydrophilic PEG shell, a facial amphiphilic oligo-cholic acid intermediate layer o shelter the interior hydrophobic drug- binding interior core. These telodendrimers inherit the features of peptide, e.g. well-defined highly engineer- able structure, therefore providing a blueprint for both computational design and the combinatorial synthesis of the nanocarriers for systematic optimization. Our hypothesis is that engineering of the core structure of nanocarriers with the introduction of drug binding moieties will be able to optimize drug loading properties within the nanocarrier. It will be tested via the following steps: (1) A training dataset will be ued to validate the computational approach in identifying drug-binding molecules (DBMs), such as, scoring function, criteria for DBM selection, experimental validation of docking energy, etc.; (2) A enhanced natural compound library will be virtually screened against three important anticancer drugs with distinct structures, e.g. cabazitaxel, SN-38 and doxorubicin. Subsequently, the rationally designed nanocarriers will be synthesized combinatorially and characterized; (3) Drug loading properties, in vitro anticancer effects and the in vivo tumor-targeted drug delivery will be characterized to validate the computational predictions. At the end of study, we expect to elucidate the structure-property relationship (SPR) of telodendrimer nanocarriers in drug delivery and several optimized nanocarriers for SN-38, cabazitaxel and doxorubicin delivery will be developed, respectively, for the further in vivo anticancer evaluation Success in this effort is able to create a paradigm shift in the field of drug delivery. It can als benefit the pharmaceutical industry potentially by providing a reliable and predictable path for nanomedicine design and development.

Public Health Relevance

The lack of quantitative structure-property relationship (SPR) in the self-assembly of polymer system limits the theoretical and computer-aided nanocarrier design for drug delivery. We have developed a well-defined highly engineer-able amphiphilic telodendrimer system, which enables us to introduce drug-binding molecules (DBMs) in a combinatorial manner to optimize the drug loading properties of nanocarriers. We further propose to apply computational approaches in virtual screening of a natural compound library to identify suitable DBMs for nanocarrier library synthesis, which allows for the methodology validation and systematic evaluation to improve anticancer effects of nanotherapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB019607-02
Application #
9119009
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Rampulla, David
Project Start
2015-08-01
Project End
2017-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Upstate Medical University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
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Wang, Lili; Shi, Changying; Wright, Forrest A et al. (2017) Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment. Cancer Res 77:3293-3305
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