D EVELOPM ENT O F O R A L LY A P P L IC AB L E N A N O PA R T I C L E D R U G D E L I V E RY SYS TEM FORLOC A L TREA TM ENT O F C O L O R E C TA L C AN C E R S
AUTHORS
Sedat ÜNAL, Doctoral Thesis (2020)
Hacettepe University - Institute of Health Sciences Pharmaceutical
Technology Program, Turkey

INTRODUCTION
Colorectal cancers start in the colon or rectum where they begin as a polypand turn into cancer over time. Drugs used in the treatment of colorectal
cancer have to be administered mostly parenterally due to limitations of their
physicochemical properties. Since oral administration is not possible during
treatment, parenteral administration implies low patient compliance, highcost of treatment, frequency of side effects and difficulty of repeatedadministration specific to chemotherapy. Those inconveniences havecreated the necessity to work on alternative routes of administration to theparenteral route. The oral pathway stands out as the most promising route inchronic treatments in terms of ease of administration, thus reducing theburden on health economics and patient compliance. Camptothecin (CPT),which is known to have strong anticancer activity against colon cancer cells,
remains limited in clinical practice due to solubility and stability problems inphysiological conditions. This situation requires a different formulation

approach such as the use of an oral nanoparticle drug delivery system (NPsDDS). NPs DDS can reduce or prevent side effects due to chemotherapy andincrease the stability of CPT and thus provide better quality of life to patients.

OBJECTIVE
This study aims to develop an oral anticancer drug model using Amphiphilic
cyclodextrin (CD)- based nanoparticles (Poly-β-CD-C6) carrying CPT, withspecific physico-chemical attributes chosen to favor structure integrity down
to the colon, accumulation to the target site and degradation by the colon
microflora.

MATERIAL & METHODS
A colon tumor mice model was created. For this purpose, 6-8 weeks old male
Balb/c orthotopic mice model were anesthetized, laparotomized, caecum
scratched, surgically stitched and inoculated with CT-26cells (100µL of2x106) into the cecum submucosa. The surgically created syngeneic micemodel of the colorectal cancer cell line CT-26 were divided into 4 groups:
Group1.Poly-β-CD-C6 nanoparticles (blank); Group 2. Poly-β-CD-C6nanoparticles (drug loaded) (containing 5 mg / kg CPT); Group 3. Suspensionof anticancer drug CPT in saline solution (1% DMSO) (5 mg / kg CPT) andGroup 4. Negative control (tumor induced and untreated group). In order tomonitor the localization and thus the extent of the anti-tumor activity of thedrug loaded amphiphilic CD nanoparticle in vivo, Nil Red (NR) fluorescent dye,was encapsulated in Poly-β-CD-C6 nanoparticle. The presence of tumors in
the colon and cecum region was surgically confirmed in one mousesacrificed for each group. The prepared NR loaded amphiphilic CD
nanoparticles and NR solution were then administered to mice by oral
gavage and the mice left for 24 hours. The mice were then euthanized withhigh dose anesthesia. Following this procedure, the GI tract were rapidly
surgically removed as a whole and the segments of the organ were used forex vivo visualization in the Newton 7.0 (Vilber Lourmat, France).

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RESULTS

Camptothecin (CPT) loaded (Poly-β-CD-C6) nanoparticles orallyadministered to mice bearing colorectal cancer revealed to be effective inthe course of this study. Imaging the extent to which the amphiphilic CD
nanoparticle formulation could carry the encapsulated drug 24hours post
injection in the gastrointestinal tract segments was made possible with theNewton 7.0 (Vilber Lourmat, France).

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NR çözeltisCONCLUSION

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NR-yüklü NPFigure 1. Gastrointestinal distribution of Nile red (NR) encapsulated Polyβ-CD-C6 nanoparticles. Ex vivo image of undisrupted GI tract 24hrs after
oral gavage of mice bearing colorectal tumors. A low fluorescence in thestomach and intestines has been detected, and no significant fluorescence
was observed in the colon area after the cecum.
Figure 2. Gastrointestinal distribution of NR solution and NR encapsulated
Poly-β-CD-C6 nanoparticles. Ex vivo imaging of the gastrointestinal tract
tissues removed from mice 24hrs following oral administration of NR
solution and NR encapsulated nanoparticles in mice bearing colorectaltumors. (NR çözeltisi =NR solution, NR yüklü NP = NR loaded particles,Tumor odagi = tumor focus). As a result of surgical opening of theabdominal region of sacrified mice, it was confirmed that specific andlocalized tumors were formed in the intestinal region, especially in the colon
where a high fluorescence is observed, starting from the cecum, which is thetumor inoculation site. The primary tumor, represented with highfluorescence in the cecum region, was due to the inoculation area and wasconsidered an expected and desired result. As a function of time after
inoculation of CT-26 cells, primary and secondary tumors were observed.
The amphiphilic CD nanoparticle formulation designed to target the column
proved to be effective in delivering the active substance to the cecum anddown to the colon.

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