Abstract
The clinical use of 7-ethyl-10-hydroxy-camptothecin (SN-38), which is the active metabolite of irinotecan, has been hampered because of its practical water-insolubility. In this study, we successfully synthesized two self-associating SN-38-polymer drug conjugates to improve the water-solubility of SN-38, while retaining its anticancer activity. The polymeric micellar SN-38 conjugates were composed of either methoxy-poly(ethylene oxide)-block-poly(α-benzyl carboxylate-ε-caprolactone) conjugated to SN-38 at the PBCL end (mPEO-b-PBCL/SN-38) or mPEO-block-poly(α-carboxyl-ε-caprolactone) attached to SN-38 from the pendent-free carboxyl site (mPEO-b-PCCL/SN-38). The chemical structure of block copolymers was confirmed by 1H NMR. The physicochemical characterizations of their self-assembled structures including size, surface charge, polydispersity, critical micellar concentration, conjugation content and efficiency, morphology, kinetic stability, and in vitro release of SN-38 were compared between the two formulations. In vitro anticancer activities were evaluated by measuring cellular cytotoxicity and caspase activation by MTS and Caspase-Glo 3/7 assays, respectively. The hemolytic activity of both micellar structures against rat red blood cells was also measured. The results showed the formation of SN-38-polymeric micellar conjugates at diameters < 50 nm with a narrow size distribution and sustained release of SN-38 for both structures. The loading content of SN-38 in mPEO-b-PBCL and mPEO-b-PCCL were 11.47 ± 0.10 and 12.03 ± 0.17 (% w/w), respectively. The mPEO-b-PBCL/SN-38, end-capped micelles were kinetically more stable than mPEO-b-PCCL/SN-38. The self-assembled mPEO-b-PBCL/SN-38 and mPEO-b-PCCL/SN-38 micelles resulted in significantly higher cytotoxic effects than irinotecan against human colorectal cancer cell lines HCT116, HT-29, and SW20. The CRC cells were found to be 70-fold to 330-fold more sensitive to micellar SN-38 than irinotecan, on average. Both SN-38-incorporated micelles showed two-fold higher caspase-3/7 activation levels than irinotecan. The mPEO-b-PBCL/SN-38 micelles were not hemolytic, but mPEO-b-PCCL/SN-38 showed some hemolysis. The overall results from this study uphold mPEO-b-PBCL/SN-38 over mPEO-b-PCCL/SN-38 micellar formulation as an effective delivery system of SN-38 that warrants further preclinical investigation.
Highlights
IntroductionCancer-related mortality has increased by ~40% over the past 40 years and is anticipated to show a further 60% increase by 2030 [1]
The 1H NMR spectra for mPEO-b-PBCL/SN-38 and mPEO-b-PCCL/SN-38 and peak assignments are shown in Figure 2, while the 1H NMR spectra for free SN-38, mPEO-b-PBCL, and mPEO-b-PCCL are shown in Supplementary Figure S1, Figure S2, Figure S3 [24,28,29]
The mean zeta potential of the micelles formed from mPEO-b-PBCL and mPEO-b-PCCL were neutral at a range from 0.04–0.09 mV
Summary
Cancer-related mortality has increased by ~40% over the past 40 years and is anticipated to show a further 60% increase by 2030 [1]. For CRC patients with localized disease, surgery is a curative option. Despite improved screening practices, CRC is commonly diagnosed at advanced stages where metastasis to nearby or distant organs is seen. In CRC patients with metastatic disease, the curative benefit of first-line surgical interventions is limited. Patients with de novo metastatic disease or those showing relapse and advancement to metastatic stage after the first round of therapy make up more than 60% of CRC patients [3]. Chemotherapy and radiotherapy are the leading treatment strategies in these patients and are usually used either to control unresectable tumor growth and its further spread or reduce the size of locally metastasized cancer, making the patient a candidate for surgery and tumor removal at the metastatic site [4]
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