Challenges In Integrating Multiple Functionalities And Future Directions

Although remotely actuated nanoparticle cores such as iron-oxide and metal nanoshells naturally lend themselves to dual-imaging and therapeutic applications, the combination of imaging and other functionalities using other nanoparticle cores can be challenging. There are inherent trade-offs when combining many functional groups into one nanoparticle. In many cases, a limited number of attachment sites are available on the particle surface, making it difficult to couple several functional groups in sufficient concentration for each to function. Moreover, some groups may interact to sterically shield or alter the activity of one another when combined in close proximity. Multiple functional moieties on a nanoparticle may also reduce colloidal stability or adversely affect its in vivo pharmacokinetics. With significant characterization and fine tuning, dendrimers that combine targeting, imaging, and therapeutic moieties on their surface have been synthesized successfully.4 Similar efforts will be necessary to achieve other multifunctional nanoparticles with decorated-surface moieties.

An alternative strategy to consolidate multiple functionalities onto a single particle is to use core-shell architecture. In this case, an outer shell with one functionality, such as targeting, may be unveiled to reveal an inner core that performs a secondary function such as endosomal escape or drug release. This has been demonstrated with the conjugation of targeting moieties or protective PEG groups on the surface of dendrimers or polymers via acid-labile chemistries that degrade in the lower pH of the endosome and unveil endosomal escape mechanisms on the particle core.109,110 This has also been demonstrated with protease-cleavable linkers that release protective polymers on the surface of complementary nanoparticles to initiate their self-assembly.73

The synthesis of nanoparticles with polar domains is another strategy that could be used to incorporate multiple functionalities on a single particle. Janus nanoparticles—named for Janus, the Roman God of doorways typically depicted with faces on the front and back of his head—have been engineered with two chemically distinct hemispheres or surfaces. These nanoparticles may be spherical (with opposing faces of unique composition), dumbbell-shaped (with two equal-sized spheres linked together), snowman-shaped, and may have other morphologies as well.95,111 The creation of nanoparticles with spatially separated chemical domains is a step towards replicating the controlled polarity exhibited in nature across many length scales. Separate hemispheres may be used to isolate and organize functional domains on nanoparticles such that they may simultaneously carry targeting molecules, endosomal escape domains, sensing moieties, hydrophilic and hydro-phobic therapeutics, or contrast agents that otherwise might be mutually inhibitory if randomly incorporated. Moreover, there may be specific applications for which the polarity and anisotropy of Janus nanoparticles have benefit, such as real-time detection of oriented binding events, targeted bridging of multiple components at a tumor cell, directed drug delivery, or guided self-assembly.

Although there have been many exciting advances in the application of nanoparticles for cancer imaging and treatment, the true power of these materials will be in their ability to interact with disease processes intelligently. The modular design of functionalities that target, sense, signal, and treat and the ongoing efforts to consolidate these into single nanoparticle platforms is one way in which such 'smart' materials are being developed. The further elucidation of complex biological processes in tumorogenesis, the discovery of nanomaterials with other novel properties, and the consolidation of biological and synthetic machinery in these materials in new and elegant ways are key factors that will determine their future success in cancer therapy.

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