Surface Modification of Nanoparticles

Nanoparticle surface modification may also be used to engineer their interaction with the surrounding tissue. These interactions could be positive (i.e., targeting molecules) or negative (i.e., nonadhesive coatings). The surface modification of nanoparticles is particularly important because intravenously applied nanoparticles may be captured by macrophages before ever reaching the target site. Therefore, surface modifying particles to render them invisible to macrophages is essential to making long-circulating nanoparticles.18,109 The ability to control the biodistribution of nanoparticles is particularly important for drug carrying nanoparticles because the delivery of drugs to the normal tissues can lead to toxicity.16,17

Hydrophilic polymers such as PEG,18,109 polysaccharides,110,111 and small molecules112 can be conjugated on the surface of nanoparticles to engineer particles with desirable biodistribution characteristics. For example, to enhance the rate of circulation within the blood and minimize uptake by nondesired cell types, nanoparticles may be coated with polymers such as PEG.18,109 Various molecular weights and types of PEG (linear or branched) have been used to coat nanoparticles.113 PEG coatings are also useful for minimizing nanoparticle aggregation and can be used to prevent clogging of small vasculature and improve size-based targeting. More recently, novel approaches aimed at conjugating small molecules on nanoparticles using high-throughput methods have yielded nanoparticle libraries that could be subsequently analyzed for targeted delivery.112 The use of similar high-throughput approaches has significant potential in optimizing nanoparticle properties for cancer therapy.

Surface modification of nanoparticles can be achieved in a multistep approach by first generating nanoparticles and subsequently modifying the surface of particles to achieve the desired characteristics. Alternatively, amphiphilic polymers may be covalently linked prior to generating nanoparticles to simultaneously control the surface chemistry as well as encapsulate drugs and

FIGURE 16.3 A schematic outlining a conjugation reaction between aptamers and polymer nanoparticles containing an encapsulated drug. Through incorporating a COOH-terminated, PEG-functionalized surface on the nanoparticle, NH2-modified aptamers can be easily conjugated using simple aqueous chemistry.

eliminate the need for subsequent chemical modifications once the particle has been synthesized. This method may provide a more stable coating and better nanoparticle protection in contact with blood. For example, PLA, poly(caprolactone), and poly(cyanoacrylate) polymers, have been chemically conjugated to PEG polymers.18,114,115 We have synthesized nanoparticles from amphiphilic copolymers composed of lipophilic PLGA and hydrophilic PEG (Figure 16.3) polymers where the PEG migrates to the surface of the nanoparticles in the presence of an aqueous solution.18 A similar approach has also been used to generate pegylated PLA nanoparticles using PLA-PEG block copolymers.23,108 These particles may be used to extend the nanoparticle residence times in circulation and enhance accumulation in tumor tissue through "passive targeting" and EPR effect.

In the case of engineering nanoparticles for active targeting, the polymer and its coating should have functional groups for the attachment of targeting moieties (which may be bound directly to the nanoparticle surface or though a spacer group). The targeting molecules can enhance the molecular interaction of the nanoparticles with a subset of cells or tissue.

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