Selective Tumor Cell Targeting by the Disaccharide Moiety of Bleomycin

Abstract

In a recent study, the well documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been derivatized with multiple copies of BLM. It was shown that BLM selectively targeted MCF-7 human breast carcinoma cells, but not the “normal” breast cell line MCF-10A. Further, the BLM analogue deglycobleomycin, which lacks the disaccharide moiety of BLM, was found not to target either cell line, indicating that the BLM disaccharide moiety is necessary for tumor selectivity. Not resolved in the earlier study was the issue of whether the BLM disaccharide moiety alone is sufficient for tumor cell targeting, as well as the possible cellular uptake of the disaccharide. In the present study, we have conjugated BLM, deglycoBLM and BLM disaccharide to the cyanine dye Cy5**. It was found that the BLM and BLM disaccharide conjugates, but not the deglycoBLM conjugate, bound selectively to MCF-7 cells, and were internalized. The same was also true for the prostate cancer cell line DU-145 (but not for normal PZ-HPV-7 prostate cells) and for the pancreas cancer cell line BxPC-3 (but not for normal SVR A221a pancreas cells). The targeting efficiency of the disaccharide was only slightly less than that of BLM in MCF-7 and DU-145 cells, and comparable to BLM in BxPC-3 cells. These results establish that the BLM disaccharide is both necessary and sufficient for tumor cell targeting, a finding with obvious implications for the design of novel tumor imaging and therapeutic agents.

Nanoparticles inhibit cancer cell invasion and enhance antitumor efficiency by targeted drug delivery via cell surface-related GRP78

“…Recently, researchers have found that some specific molecules used as targeting agents, such as carbohydrate, 10 folic acid, 11,12 transferrin, 13,14 and some peptides, 15,16 could be modified onto the surface of NPs and achieve active targeting therapy with high specificity, selectivity, and affinity through coupling targeting molecules with their specific receptor expressed on the cell surface.…”

Molecular-Matched Materials for Anticancer Drug Delivery And Imaging

“…Other common issues with nanocarriers are uncontrolled cargo release or rapid pharmacokinetic (PK) clearance. Great efforts have been made to remedy these problems; however, no carrier has effectively managed all these issues [1][2][3][4][5]. While many different formulations have been applied to PTX, there has been very little success thus earning it the description 'brickdust' [6].…”

“…The lipid dispersion was then sonicated for 2 min (probe sonicator, output power 10 W, Fisher Scientific). 3 H-labeled nanoformulations were prepared by mixing a trace amount of 3 H-PTX, 3 H-PTX-VE or 3 H-PTX-LA in the mixtures as preliminary treatment.…”

“…At predetermined time intervals (0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 32 h), 100 μl of medium was withdrawn and fresh medium was complemented. 3 H-labeled PTX and VE-PTX were quantified on a liquid scintillation analyzer (TRI-CARB, Packard Bioscience Company, MA, USA). In vitro DSPE-PEG2000-CF release from the NEs was determined using a similar method.…”

Inhibitory effect of (−)-epigallocatechin-3-gallate and bleomycin on human pancreatic cancer MIA Paca-2 cell growth

“…Bleomycin (BLM) is a glycopeptid drug originally isolated from Streptomyces verticillus [19,20] is clinically used for cancer therapy [20,21]. The bleomycins are a family of glycopeptide-derived antitumor antibiotics used clinically for the treatment of squamous cell carcinomas and malignant lymphomas [22][23][24]. Their antitumor activity is due to selective oxidative cleavage of 5′-GC-3′ and 5′-GT-3′ sequences in DNA, and possibly also to RNA oxidative degradation [25][26][27][28][29][30][31].…”