5.1.3. be targeted to specific tissues, lower the toxicity

5.1.3. Targeted delivery of small molecule

the DNA repair enzyme PNKP by small molecule inhibitors is a challenging
problem to normal tissue. We must preserve the DNA repair mechanism in normal
tissue, therefore the use of targeted delivery of PNKP small molecule
inhibitors is a priority. Nanoparticles, usually smaller than 100 nm, are
successfully used in several areas of drug delivery (39). Small molecule
inhibitors can be incorporated into nanoparticles to be targeted to specific
tissues, lower the toxicity of the free drug, prolong the circulation due to
reduced renal clearance, and provide enhanced therapeutic index (40). A recent study utilized
a system of self-assembled nanoparticles consisting of conjugates of aptide (high affinity peptide)
bound to SN38, the active metabolite of irinotecan, to achieve high drug
loading capacity, good solubility and effective tumor growth inhibition in a
pre-clinical investigation for SN38 delivery (41). Similarly, encapsulating
the newly found PNKP inhibitors, A12B4C50 and A83B4C63, in PEO-b-PCCL
and PEO-b-PBCL polymeric micelles,
respectively, resulted in high efficiency
loading, controlled release and effective sensitization of HCT116 cancer cells to radiation and
irinotecan. This raises the possibility of co-encapsulation of a PNKP inhibitor
with irinotecan or SN38 to improve targeted therapy. In addition, encapsulated
PNKP inhibitors can cause synthetic lethality in PTEN-deficient HCT116 cells
(Chapter 3).

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issue challenging the efficiency of small molecule inhibitors, is limited
penetration into tumor tissues due to the complex tumor microenvironment,
therefore, some regions of the tumor may receive lower concentrations of the
drug or no drug at all. Targeted nanoparticles with tumor-penetrating peptides
have been shown to specifically increase the accumulation of poorly penetrating
drugs or non-targeted carriers into tumors, as a result the efficacy of the drug is improved
43). Tumor-penetrating peptides facilitate internalization
of drugs to cancer cells by receptor-mediated endocytosis in comparison to the
non-targeted drug, which enters passively through the cell membrane (43).  iRGD is an example of a tumor-penetrating peptide
(44). A pre-clinical study showed that iRGD-conjugated
nanoparticles were able to reduce the level of metastasis of breast cancer in
the brain (45). GE11 peptide has a high affinity for EGFR (46), and several studies have confirmed the suitability of
using GE11 as a targeting moiety to achieve enhanced anticancer efficacy (47, 48). We functionalized our nanoparticles with GE11 to
target EGFR over-expressing HCT116 cancer cells. Dye-encapsulated GE11-conjugated polymeric micelles showed preferential
accumulation in EGFR-overexpressing HCT116 cells compared to minimal
internalization observed in SW620 cells, which express no EGFR on their
surface. Furthermore, uptake of the functionalized polymeric micelles in HCT116
cells was inhibited by saturation with free GE11 peptide. Together, these data
confirm successful internalization of GE11-conjugated polymeric micelles in
HCT116 cancer cells through the receptor-mediated process.