Biomedical Engineering Reference
In-Depth Information
signals (e.g., epidermal growth factor, EGF) or nutrient uptake for DNA or
protein syntheses (e.g., folic acid) are overexpressed. These receptors
potentially provide useful cancer-specific molecular targets for targeted drug
delivery. A variety of ligands such as monoclonal antibodies, peptides, or small
molecules have been developed, with many of them used as therapeutics
directly (e.g., Erbitux
1
, a monoclonal antibody that targets the EGF
receptor). The availability of these targeting ligands prompted an intensive
research effort to develop nanoparticles conjugated with the ligands for tumor-
targeted delivery. Active targeting nanomedicines have the potential to directly
recognize cancer-specific receptors on the tumor cell surface, followed by
receptor-mediated endocytosis to deliver drug payloads inside cancer cells. As
a result, active targeting nanomedicines hold considerable promise to increase
tumor selectivity with a potential decrease of adverse side effects in healthy
tissues.
39-41
Despite the therapeutic promise, active targeting nanomedicines must
overcome numerous obstacles and physiological barriers before they can
achieve the optimal targeting efficacy. First, before nanomedicines reach the
cancer cells, they need to accumulate inside tumor tissues. In this case, passive
targeting via the EPR effect may play a predominant role. Limitations such as
fast RES clearance from blood, limited nanoparticle penetration, nanoparticle
instability in blood, and heterogeneous tumor vasculature, as described in the
passive targeting section (Section 2.2), all have great impact on the active
targeting efficiency.
42,43
Second, introduction of targeting ligands can increase
the clearance rates and affect other pharmacokinetic profiles of nanoparticles.
The added complexity in surface functionalization may also be a limiting
factor that increases the cost in commercial scale-up.
44,45
Recently, several
research papers have reported that active targeting primarily increases
intracellular uptake of nanomedicines and does not increase tumor accumula-
tion as advocated by ''magic bullets'', whereas other reports indicate that
tumor localization is dependent on the active targeting.
46-48
In the ensuring
sections, we will review some of the above issues in more detail and discuss
their importance in the design of active targeting nanomedicines.
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2.3.1 Cancer Specificity of Active Targeting Nanomedicines
The basic principle of active targeting nanomedicines is the molecular
recognition of cancer-specific receptors by ligand-encoded nanoparticles to
increase the delivery of anticancer drugs. Ideally, the receptors should be
uniquely expressed on the surface of cancer cells. However, in reality, receptor
expression profiles are never black-and-white between cancer cells vs. normal
cells, as most of the receptors are also expressed on the normal cell surface at a
lower level compared to cancer cells. As such, even for antibodies, which
provide the broadest opportunities in the diversity of targets and high
specificity of interactions, their encoded nanoparticles still show moderate
binding to normal cells and can cause nonspecific toxicity and side effects.
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