Abstract
Inhibition of the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) increases the sensitivity of cancer cells to DNA damage by ionizing radiation (IR). We have developed a novel inhibitor of PNKP, i.e., A83B4C63, as a potential radio-sensitizer for the treatment of solid tumors. Systemic delivery of A83B4C63, however, may sensitize both cancer and normal cells to DNA damaging therapeutics. Preferential delivery of A83B4C63 to solid tumors by nanoparticles (NP) was proposed to reduce potential side effects of this PNKP inhibitor to normal tissue, particularly when combined with DNA damaging therapies. Here, we investigated the radio-sensitizing activity of A83B4C63 encapsulated in NPs (NP/A83) based on methoxy poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (mPEO-b-PBCL) or solubilized with the aid of Cremophor EL: Ethanol (CE/A83) in human HCT116 colorectal cancer (CRC) models. Levels of γ-H2AX were measured and the biodistribution of CE/A83 and NP/A83 administered intravenously was determined in subcutaneous HCT116 CRC xenografts. The radio-sensitization effect of A83B4C63 was measured following fractionated tumor irradiation using an image-guided Small Animal Radiation Research Platform (SARRP), with 24 h pre-administration of CE/A83 and NP/A83 to Luc+/HCT116 bearing mice. Therapeutic effects were analyzed by monitoring tumor growth and functional imaging using Positron Emission Tomography (PET) and [18F]-fluoro-3’-deoxy-3’-L:-fluorothymidine ([18F]FLT) as a radiotracer for cell proliferation. The results showed an increased persistence of DNA damage in cells treated with a combination of CE/A83 or NP/A83 and IR compared to those only exposed to IR. Significantly higher tumor growth delay in mice treated with a combination of IR and NP/A83 than those treated with IR plus CE/A83 was observed. [18F]FLT PET displayed significant functional changes for tumor proliferation for the drug-loaded NP. This observation was attributed to the higher A83B4C63 levels in the tumors for NP/A83-treated mice compared to those treated with CE/A83. Overall, the results demonstrated a potential for A83B4C63-loaded NP as a novel radio-sensitizer for the treatment of CRC.
Highlights
Colorectal cancer (CRC) is the second most common cause of cancer death globally [1] and its incidence is expected to increase by 33% by 2028 [2]
To overcome the limitation of poor water-solubility, and at the same time reduce the access and radio/chemo-sensitizing effects of A83B4C63 in normal tissues, we have developed NP formulations of this compound, which were based on methoxy poly(ethylene oxide)-poly(a-benzyl carboxylate-e;-caprolactone)
We have shown that polymeric micellar NPs (PMNPs), formed through self-assembly of poly(ethylene oxide)-blockpoly(abenzyl carboxylate-ε-caprolactone) (PEO-b-PBCL) containing methoxy-PEO or acetal-PEO, and radiolabeled with 64Cu resulted in a 3-fold increased measurable accumulation into subcutaneous HCT116 tumors versus muscle tissue as determined with Positron Emission Tomography (PET) [49]
Summary
Colorectal cancer (CRC) is the second most common cause of cancer death globally [1] and its incidence is expected to increase by 33% by 2028 [2]. IR is not a preferred option to treat colon cancer, it is fairly common in Abbreviations: AUC, area under the curve; CDCl3, deuterated chloroform; CE, cremophor EL: ethanol; CE/A83, A83B4C63-solubilized cremophor EL: ethanol formulation; Cmax, peak plasma concentration; CRC, colorectal cancer; DLS, dynamic light scattering; DMEM/F12, dulbecco’s modified eagle medium and F12; DNA, deoxy ribonucleic acid; HLB, hydrophilic-lipophilic balance; IR, ionizing radiation; IV, intravenous; IVIS®, in vivo imaging systems; Kp, tissue to plasma ratio; MAP, maximum a posteriori; mPEO, methoxy polyethylene oxide; mPEO-b-PBCL, methoxy poly(ethylene oxide)-b-poly(a-benzyl carboxylate-ε-caprolactone); MRT, mean residence time; MW, molecular weight; NP, nanoparticle; NP/A83, A83B4C63-encapsulated mPEO-b-PBCL nanoparticle; PARP, poly (ADP-ribose) polymerase; PDI, polydispersity index; PET, positron emission tomography; PNKP, polynucleotide kinase/phosphatase; PTEN, phosphatase and TENsin homolog deleted on chromosome 10; ROI, regions of interest; SARRP, small animal radiation research platform; SUV, standardized uptake values; TEM, transmission electron microscopy; Tmax, peak plasma concentration time; TV, tumor volume
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