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Active Targeting Strategies in Cancer with a Focus on Potential Nanotechnology Applications 23
Lipids such as phospholipids and cholesterol can be used to generate single- or multi-lamellar
spheres (liposomes) in the nanometer-size range. Liposome-based nanocapsules that can be loaded
with diagnostic or therapeutic agents for the targeted delivery to cancers 25 and enhancement
strategies for lipid-based nanoparticle-mediated tumor targeting have been reviewed. 26 Liposomes
were some of the first nanoparticle structures extensively evaluated for cancer targeting. Early
studies using liposomes highlighted issues associated with recognition and clearance by cells of the
reticuloendothelial system (RES) that remove particulates from the systemic circulation. 27 Methods
of masking liposomes from the RES such as modification with poly(ethylene glycol) (PEG) have
been successfully used to limit RES clearance and increase circulating half-lives in serum. 28
Solid lipid nanoparticles, nanostructure lipid carriers, and lipid–drug conjugate nanoparticles
have also been described for the drug delivery strategies that could be applied to cancer diagnosis
and/or therapy. 29 Lipid-based nanospheres can be sterically stabilized by the incorporation of
artificial lipid derivatives that can be cross-linked. Subsequently, stabilized lipid-based nanospheres
can be targeted to cancers using a conjugated antibody. 30 Such covalent modifications can improve
the stability of lipid-based nanoparticles but can also reduce the biocompatible natures of these
materials by modifying their clearance from the body. Apolipoprotein E-containing liposomes have
also been prepared as a carrier for a lipophilic prodrug of daunorubicin as a means of targeting
cancer cells that overexpress the receptor for low-density lipoproteins (LDL). 31
3.2.2 DERIVITIZATION
Because of their chemical and physical characteristics, nanoparticles exhibit inherent cellular
targeting and uptake characteristics. Size and surface charge seem to be the two prominent characteristics
that affect inherent nanoparticle targeting and cellular uptake. Because inherent targeting
mechanisms may not provide the targeting or delivery characteristics desired, methods to modify
nanoparticles with targeting agents can be critical. Although some nanoparticle materials are
composed of materials with functional groups useful for chemical coupling, others are not. Such
nanoparticle systems must be either modified to allow chemical coupling or doped with reagents
that can be used for this modification. A number of coupling strategies have also been worked out
that allow for efficient functionalization of nanomaterials through both reversible and irreversible
chemistries. 14,32 These modifications allow for the coupling of antibodies, receptor ligands, and
other potential targeting agents. Similar to the concerns associated with composition of the nanoparticle
itself, any modification through chemical derivitization must also be considered with regard
to generating materials with unacceptable toxicity or neutralization of the function of the nanoparticle
or its targeting element.
Nanoparticles have the advantage that they can be modified with multiple ligands to enhance
their targeting selectivity and/or allow for simultaneous delivery of diagnostic and therapeutic
agents. 33 It is important to appreciate the relative size of components used to construct and derivitize
nanoparticles. For example, a quantum dot may be only 10 nm in diameter. Targeting that
sized particle with an antibody might require the attachment of an IgG antibody that is roughly
equal in size. By comparison, a fluorescent material that might be useful for localization of a
targeted nanoparticle such as green fluorescent protein (GFP) is about 5 nm. Derivitization
strategies for the construction of targeted nanoparticles must incorporate a consideration of
potential steric conflicts for incorporation of targeting, detection, and therapeutic components.
Other chapters in this text will extensively examine derivitization technologies for nanoparticles.
3.2.3 DETECTION
Most, if not all, nanoparticle structures currently investigated for delivery of cancer therapeutics
also have the capacity to be detected or modified to contain a detectable agent that could be
simultaneously used for cancer diagnosis. For example, PAMAM folate-dendrimers that contain
q 2006 by Taylor & Francis Group, LLC