2.1 Introduction
Molecular imaging and the development of molecular agents aimed at the visualization of in vivo intracellular events without any molecular or cellular disturbance
can be excellent tools to study disease mechanisms as well as in vivo pharmacokinetics of targeted therapeutic and imaging probes. Nuclear medicine, including
nuclear imaging and treatment of diseases with radiolabeled tracers, has been
well-established in preclinical and clinical settings for decades [1]. Currently
available targeting strategies for cancer therapy and imaging usually rely on the use
of monoclonal antibodies and peptides, which are often limited by insufficient
delivery to tumor tissue, due to heterogeneous expression levels of tumor cells
receptors, as well as dose-limiting off-target side-effects. To ensure that toxicity
levels are low but the therapeutic effect remains maximized, it is essential to deliver
the desired agents to the correct site, at the appropriate concentration at the right
time [2].
Nanocarrier systems (NS) could serve as the platforms needed for enhancing the
delivery of imaging probes and therapeutics to the tumor sites, thus enhancing
imaging and therapeutic efficacy. Nanoparticles (NPs) are structures, nanometers in
size [3] and, as such, can extravasate from the endothelial cell layers to the tumor
site, while carrying large therapeutic and diagnostic cargos such as small molecule
drugs and radioisotopes [4]. Multifunctionality is the key advantage of nanoparticles
since nanomaterials, in contrast to traditional agents, have an extremely high
surface-to-volume ratio that provides chemically active sites and easily tailorable
surface bioengineering to achieve enhanced biological outcomes, such as increased
blood circulation time, target specificity, reticuloendothelial system (RES) evasion
and therapeutic delivery [5]. Also, NPs can be constructed to have tunable properties
(optical, electronic, magnetic, and biological), sizes, shapes and chemical compositions. By integrating a variety of functional components such as imaging agents,
targeting ligands and therapeutic compounds into the nanomaterials, they can be
precisely tailored for personalized targeted theranostics of diseases [6]. Thus, the
combination of an ideal size range with an ability to be conjugated with distinctive
targeting ligands makes nanosystems excellent candidates to break the physiological
barriers and access different diseased tissues in a controlled manner [7].
It is worth mentioning that a NS can accumulate at certain tissue sites through
two different targeting mechanisms: passive and active. Passive targeting relies on
enhanced permeability and retention (EPR) effect arising from the anatomical differences between healthy and non-healthy tissues. The EPR effect exploits (i) leaky
tumor vasculature for greater extravasation and accumulation of nanoparticles at the
tumor site, as well as (ii) inefficient lymphatic drainage at those sites to allow
prolonged retention of such molecules in the targeted tissue [7]. This type of
targeting enables non-specific accumulation of molecules and can occur in other
diseases besides cancer, such as infection and/or inflammation [8]. In contrast,
14
C. A. Ferreira et al.
Molecular imaging and the development of molecular agents aimed at the visualization of in vivo intracellular events without any molecular or cellular disturbance
can be excellent tools to study disease mechanisms as well as in vivo pharmacokinetics of targeted therapeutic and imaging probes. Nuclear medicine, including
nuclear imaging and treatment of diseases with radiolabeled tracers, has been
well-established in preclinical and clinical settings for decades [1]. Currently
available targeting strategies for cancer therapy and imaging usually rely on the use
of monoclonal antibodies and peptides, which are often limited by insufficient
delivery to tumor tissue, due to heterogeneous expression levels of tumor cells
receptors, as well as dose-limiting off-target side-effects. To ensure that toxicity
levels are low but the therapeutic effect remains maximized, it is essential to deliver
the desired agents to the correct site, at the appropriate concentration at the right
time [2].
Nanocarrier systems (NS) could serve as the platforms needed for enhancing the
delivery of imaging probes and therapeutics to the tumor sites, thus enhancing
imaging and therapeutic efficacy. Nanoparticles (NPs) are structures, nanometers in
size [3] and, as such, can extravasate from the endothelial cell layers to the tumor
site, while carrying large therapeutic and diagnostic cargos such as small molecule
drugs and radioisotopes [4]. Multifunctionality is the key advantage of nanoparticles
since nanomaterials, in contrast to traditional agents, have an extremely high
surface-to-volume ratio that provides chemically active sites and easily tailorable
surface bioengineering to achieve enhanced biological outcomes, such as increased
blood circulation time, target specificity, reticuloendothelial system (RES) evasion
and therapeutic delivery [5]. Also, NPs can be constructed to have tunable properties
(optical, electronic, magnetic, and biological), sizes, shapes and chemical compositions. By integrating a variety of functional components such as imaging agents,
targeting ligands and therapeutic compounds into the nanomaterials, they can be
precisely tailored for personalized targeted theranostics of diseases [6]. Thus, the
combination of an ideal size range with an ability to be conjugated with distinctive
targeting ligands makes nanosystems excellent candidates to break the physiological
barriers and access different diseased tissues in a controlled manner [7].
It is worth mentioning that a NS can accumulate at certain tissue sites through
two different targeting mechanisms: passive and active. Passive targeting relies on
enhanced permeability and retention (EPR) effect arising from the anatomical differences between healthy and non-healthy tissues. The EPR effect exploits (i) leaky
tumor vasculature for greater extravasation and accumulation of nanoparticles at the
tumor site, as well as (ii) inefficient lymphatic drainage at those sites to allow
prolonged retention of such molecules in the targeted tissue [7]. This type of
targeting enables non-specific accumulation of molecules and can occur in other
diseases besides cancer, such as infection and/or inflammation [8]. In contrast,
14
C. A. Ferreira et al.