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and/or distant, may occur in up to approximately 50% of patients, but 5-year survival if curative re-
[7,8]
resection or R0 metastasectomy is achieved, may still be from 22%-49% . In primary CRC survival is
very much stage dependent and varies from 90% 5-year survival rate in stage I rectal cancer to less than
[6,9]
10% of people diagnosed with distant metastatic cancer . Lymph-node (LN) metastases are the most
powerful predictor of survival and need for adjuvant treatment in all solid cancer and almost always follow
[10]
a well-defined tumour-draining lymph node basin . Due to their small size and poor vascularisation,
LN metastases are difficult to detect with certainty using conventional imaging modalities. Given that
chemotherapy and radiation in the (neo-) adjuvant setting have their specific adverse effects and limited
efficacy profile, it is imperative to increase the diagnostic accuracy of LN metastases in the pre-operative
[11]
setting . Nanomedicine may offer an alternative and potentially may be more effective in diagnostics.
In combination with therapeutics, it may offer a less toxic theranostic pathway [12-20] . The present paper
highlights the current understanding of nanomedicine and its role in the management of CRC, and rectal
cancer in particular. Nanomedicine is in its adolescence and is slowly transitioning from cell and animal
studies towards human trials. To develop appropriate first-in-human trials it is important for clinicians
to understand the variety of nano-platforms and particles currently available along with their specific
features.

NANOMEDICINE
The ability to explore the structure and characteristics of materials at the nanoscale has made a
great change in many fields of science such as medicine. In the comparison of nanoparticles to their
bulk systems, the main properties of nanoparticles that make them fundamentally different in their
behaviour are surface-related characteristics and quantum characteristics [21-25] . Efficient drug and medical
radioisotopes loading (due to the highly reactive surfaces of nanoparticles) in combination with unique
physical (e.g., magnetic) properties of nanoparticles have led to rapidly growing interest in nanoparticles
for medical applications such as drug delivery and imaging [26-33] . Particles or molecules with 10-100 atoms
(at least in one dimension) are normally regarded as nanoparticles [34-37] [Figure 1]. Generally, nanoparticles
are sized between 1-100 nanometers. Nanoparticles compared to their bulk system (e.g., microparticles)
have high surface area-to-volume ratio. Therefore in a nanoparticle, the number of atoms at the surface is
greater than those within their internal core and consequently they have a high number of interaction sites
[38]
available at the surface which makes them chemically more reactive . Moreover, at nano-scale where the
size of particles (e.g., nanocrystal) is comparable to the de Broglie wavelength of an electron, the change
in electronic energy levels become discretely discrete, a condition known as the quantum confinement of
[39]
the electron wave function . This effect is responsible for some of the unique behaviour (e.g., optical) of
nanoparticles such as quantum dots. These unique properties (e.g., optical, magnetic, active surface) give
nanoparticles the potential to be used as a diagnostic agent or carrier for delivering therapy and thus to be
an ideal platform for developing theranostic nano-agents in medicine.

NANO-PLATFORMS FOR DRUG DELIVERY
Tumour tissues of different cancer types such as colon, breast, prostate and lung cancer are permeable
to nano-molecules and nanoparticles [40-42] . This is due to their distinctive structural characteristics such
as the hyper-permeable vasculature and impaired lymphatic drainage [40,43,44] . Nanoparticle and nano-
molecule drug delivery mechanisms can be classified into active and passive targeting. Active targeting
highly depends on the interaction between the target cell receptors and nanoparticles whereas passive
targeting relies on a number of factors such as longer biological half-life, long-circulating time at tumour
locations and the flow rate of nanoparticles to the impaired lymphatic system [45-49] . Moreover, the enhanced
permeability and retention effects and nanoparticle clearance by the mononuclear phagocyte system
play an important role in determining the effectiveness of the nano-platform drug delivery system [44,50] .
The reticuloendothelial system (RES) effect is one of the most common problems among all different