Biomedical Engineering Reference
In-Depth Information
cancer account for only 5% of cancer treatment in the U.S. annually.
3
Furthermore, these targeted approaches suffer from acquired resistance after
prolonged treatment.
In the past decades, nanomedicines, nanoscopic therapeutics consisting of
active pharmaceutical ingredients and delivery carriers, have shown great
potential to provide paradigm-shifting solutions to improve the outcome of
cancer diagnosis and therapy.
4-8
Compared to traditional small molecular
drugs, nanomedicine (10-200 nm in diameter) has the advantages of unique
pharmacological properties such as prolonged blood circulation time and
reduced systemic toxicity,
9
high payloads of anticancer drugs and diagnostic
agents, efficient cell uptake, and passive/active targeting to the tumor sites.
It is now widely accepted that nanomedicine can take advantage of the leaky
tumor vasculature also known as the enhanced permeability and retention
(EPR) effect to accumulate in the tumor tissues.
10,11
Compared to normal
tissues, the endothelium lining of blood vessel walls is not well organized in
tumors with numerous pores (200-1,200 nm) and high permeability to
nanoparticles.
12,13
In addition, tumor tissues lack lymphatic drainage, which
allows for the retention of nanoparticles.
14
In contrast, low molecular weight
anticancer drugs are not able to be retained in tumors because of their ability
to return to the circulation by diffusion. In multidrug-resistant (MDR) cancer
cells that overexpress certain membrane-embedded drug efflux pumps such as
P-glycoproteins (Pgp), the antitumor efficacy of nanomedicines is shown to be
beneficial over free drugs.
15
Nanomedicine can prevent the encapsulated drugs
from being recognized by efflux pumps.
16,17
Several drug-loaded nanomedi-
cines to treat multidrug-resistant tumors are now in clinical trials.
18,19
Despite the rapid progress, many technical and pharmacological challenges
still exist in the successful implementation of nanomedicines in clinics. Finding
the optimal physicochemical parameters that simultaneously confer molecular
targeting, immune evasion, and controlled drug release is the most important
challenge for successful clinical translation. The complex nanoparticle
properties, including size, shape, and surface properties (i.e., targeting ligand
type and density), pharmaceutical properties such as drug loading and release
kinetics, and in vivo physiological barriers to nanoparticle trafficking, have
great impact on the safety and efficacy of nanomedicines for solid tumor
treatment. This chapter will present current advances and discuss potential
problems in the development of targeted nanomedicines.
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2.2 Passive Targeting by Stealth Nanomedicines
Passive targeting (or physical targeting) describes that nanomedicines with
prolonged blood circulation times allow for selective tumor accumulation and
retention through the EPR effect. Although passive targeting approaches
achieved great success (e.g., clinical usage of stealth liposomes such as Doxil
1
),
many questions and concerns have recently been raised. First, the EPR effect is a
highly heterogeneous phenomenon, which varies from inside the same tumor
