See references below for related reading.

8.1      Introduction
8.1.1    attachment strategies typically depend on core composition
8.1.2    but the attachment strategy should not drive the core choice
8.1.3    the choice of core should still depend on the desired overall “multifunctional” nanomedical device

8.2      “Surface chemistry” strategies for attachment of biomolecules to the core material
8.2.1    hydrophobic versus hydrophilic core materials
8.2.2    addition of biomolecules for biocompatibility
8.2.3    monofunctional versus bifunctional surface chemistry strategies
8.2.4    PEGylation as “stealth strategy” to minimize opsonification and increase circulation time
8.2.5    pay attention to overall zeta potential during the surface chemistry process!

8.3      Two main attachment strategies
8.3.1    covalent bonding strategies
         8.3.1.1 advantages
             8.3.1.1.2 very stable
             8.3.1.1.3 can control process of bond disruption for multilayering
         8.3.1.2 Disadvantages
             8.3.1.2.1 can be too stable and difficult to disassemble
             8.3.1.2.2 must be careful to avoid or minimize use of strong organic solvents that can be cytotoxic even at trace concentrations
8.3.2    non-covalent (primarily electrostatic) Bonding Strategies
         8.3.2.1 advantages
             8.3.2.1.1 can use very gentle chemistries for biocompatibility
             8.3.2.1.2 chemistry can be very simple layer-by-layer assemblies
             8.3.2.1.3 easier to disassemble multilayered structures
         8.3.2.2 disadvantages
             8.3.2.2.1 instability - different pH and ionic strength environments can cause layers to spontaneously disassemble at undesired times
             8.3.2.2.2 zeta potential can suddenly change as layers spontaneously strip off

8.4      Special considerations for the final attachment design
8.4.1    preparing the nanoparticle for addition of targeting and therapeutic molecules
8.4.2    what are the special requirements, if any, for these molecules?
         8.4.2.1 how to attach without changing function of molecule
         8.4.2.2 does this molecule need to stay attached, or not, to the nanoparticle in order to function
8.4.3    testing for targeting and therapeutic efficacy at the single cell level

8.5      Attaching different types of targeting molecules (some types and examples)
8.5.1    antibodies – which end to attach?
8.5.2    peptides – which end to attach, steric hindrance? Spacer arm needed?
8.5.3    aptamers - which end to attach, steric hindrance? Spacer arm needed?
8.5.4    small molecule ligands - which end to attach, steric hindrance? Spacer arm needed?

8.6      Testing the nanoparticle-targeting complex
8.6.1    ways of detecting this complex
8.6.2    ways of assessing targeting/mistargeting efficiency and costs of mistargeting
8.6.3    is the nanoparticle still attached to the targeting molecule?

8.7      Attaching/tethering different types of therapeutic molecules
8.7.1    antibody therapeutics - need to interact with the immune system to activate
8.7.2    peptides (e.g. apoptosis-inducing peptides)
8.7.3    therapeutic aptamers
8.7.4    transcribable sequences
8.7.5    small drugs

8.8      Testing the nanoparticle-therapeutic molecule complex
8.8.1    direct and indirect ways of detecting the therapeutic molecules
8.8.2    ways of assessing the therapeutic efficacy at single cell level
8.8.3    is the nanoparticle still attached to the therapeutic molecule? Is that important?

8.9      Nanomedical pharmacodynamics – the great unknown
8.9.1    little is known about complex nanoparticle pharmacodynamics
8.9.2    obtaining quantitative biodistribution data is extremely difficult!
8.9.3    some possible new approaches

Bagwe, R.P., Hilliard, L.R., Tan, W. “Surface Modification of Silica Nanoparticles to Reduce Aggregation and Nonspecific Binding” Langmuir 22: 4357-4362 (2006).

Derfus, A.M., Chen, A.A., Min, D-H, Ruoslahti, E., Bhati, S.N. “Targeted Quantum Dot Conjugates for siRNA Delivery” Bioconjugate Chem. 18: 1391-1396 (2007).

Hwu, J.R., Lin, Y.S., Josephrajan, T., Hsu,M-H, Cheng, F-Y, Yeh, C-S, Su, W-C, Shieh, D-B. “Targeted Paclitaxel by Conjugation to Iron Oxide and Gold Nanoparticles” Journal of the American Chemical Society 131, 66–68 (2009).

Kang, S.M., Choi, I.S., Lee, K-B, Kim, Y. “Bioconjugation of Poly(poly(ethylene glycol) methacrylate)-Coated Iron Oxide Magnetic Nanoparticles for Magnetic Capture of Target Proteins” Macromolecular Research, Vol. 17, No. 4, pp 259-264 (2009).

Kumar, C.S.S.R Biofunctionalization of Nanomaterials: Nanotechnologies for the Life Sciences Volume 1. Wiley-VCH Verlag GmbH & Co. Weinhaim, Germany. 2005.

Wang, A.Z., Bagalkot, V., Vasilliou, C.C., Gu, F., Alexis, F., Zhang, L., Shaikh, M., Yuet, K., Cima, M.J., Langer, R., Kantoff, P.W., Bander, N.H., Jon, S., Farokhzad, O.C. “Superparamagnetic Iron Oxide Nanoparticle–Aptamer Bioconjugates for Combined Prostate Cancer Imaging and Therapy”. ChemMedChem 3: 1311 – 1315 (2008).

Wang,Q., Liu, Y., Ke, Y., Yan, H. “Quantum Dot Bioconjugation during Core–Shell Synthesis” Angewandte Chemie International Edition 47: 316 –319 (2008).

Yu, W.W., Chang, E., Sayes, C.M., Drezek, R., Colvin, V.L. “Aqueous dispersion of monodisperse magnetic iron oxide nanocrystals through phase transfer”. Nanotechnology 17: 4483–4487 (2006).

Researchers should cite this work as follows:

• James Leary (2011), "BME 695L Lecture 8: Surface Chemistry: attaching nanomedical structures to the core," https://nanohub.org/resources/12181.

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1. antibiotics
2. biomedical engineering
3. cell targeting
4. course lecture
5. nanomedicine
6. nanoparticles