Layer-by-layer (LbL) assembly allows researchers to make hierarchical, multifunctional materials in a highly controlled manner. LbL works by the sequential absorption of oppositely charged materials, creating layers held together by electrostatic attraction. Modification of nanoscale drug-carriers allows incorporation of novel therapeutics, tuning of drug release and active targeting. Surface chemistry plays a major role in cancer-cell targeting and cellular uptake, and is easily modulated on LbL particles by choosing a particular terminal layer. In this work we focus on targeting ovarian cancer, which has seen little improvement in survival rates in the past thirty years. We aim to improve the delivery of therapeutic payloads by terminating LbL drug-carriers with novel layers composed of biocompatible polymers conjugated to active targeting moieties. Here we show preliminary data that demonstrates the benefits of modifying heparin sulfate by conjugating it to folate (heparin-folate). Heparin sulfate is strongly charged and native to the human body; using NHS addition chemistry, we modified it with folate, a B-vitamin whose receptors are over expressed in ovarian cancer. Flow cytometry determined nanoparticle association levels to treated cells and indicated that the heparin-folate outperformed unmodified heparin nanoparticles. Confocal microscopy showed that cancer cells were endocytosing heparin-folate nanoparticles, as indicated by co-localization with lysosomes. This promising data indicates potential for modulating nanoparticle-cell interactions by careful selection of the terminal layer on LbL nanoparticles. Continued exploration of modified native polymers can combine characteristic advantages of different biomolecules. In particular, future work will focus on the modification of linear polypeptides and polysaccharides with novel targeting moieties. LbL nanoparticle systems with synthetic terminal layers possess great potential in targeted drug delivery.

Generation of layer-by-layer nanoparticle library to selectively target ovarian cancer

251st National Meeting (2016)

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