Structural Features Facilitating Tumor Cell Targeting and Internalization by Bleomycin and Its Disaccharide

Abstract

We have shown previously that the bleomycin (BLM) carbohydrate moiety can recapitulate the tumor cell targeting effects of the entire BLM molecule, that BLM itself is modular in nature consisting of a DNA-cleaving aglycone which is delivered selectively to the interior of tumor cells by its carbohydrate moiety, and that there are disaccharides structurally related to the BLM disaccharide which are more efficient than the natural disaccharide at tumor cell targeting/uptake. Because BLM sugars can deliver molecular cargoes selectively to tumor cells, and thus potentially form the basis for a novel antitumor strategy, it seemed important to consider additional structural features capable of affecting the efficiency of tumor cell recognition and delivery. These included the effects of sugar polyvalency and net charge (at physiological pH) on tumor cell recognition, internalization, and trafficking. Since these parameters have been shown to affect cell surface recognition, internalization, and distribution in other contexts, this study has sought to define the effects of these structural features on tumor cell recognition by bleomycin and its disaccharide. We demonstrate that both can have a significant effect on tumor cell binding/internalization, and present data which suggests that the metal ions normally bound by bleomycin following clinical administration may significantly contribute to the efficiency of tumor cell uptake, in addition to their characterized function in DNA cleavage. A BLM disaccharide-Cy5** conjugate incorporating the positively charged dipeptide d-Lys-d-Lys was found to associate with both the mitochondria and the nuclear envelope of DU145 cells, suggesting possible cellular targets for BLM disaccharide–cytotoxin conjugates.

Electrospun Nanofibrous P(DLLA–CL) Balloons as Calcium Phosphate Cement Filled Containers for Bone Repair: in Vitro and in Vivo Studies

“…However, although systematic comparisons between the in vitro and in vivo behaviors of ENPBs are important before they are evaluated in the clinic, such comparisons were not made in our previous work Polymer materials have been widely used as biomedical materials. [27][28][29][30][31] Many synthetic polymer biomaterials similar to P(DLLA-CL), such as PDLLA, [32][33][34][35] PLGA, 36-37 P(LLA-CL), 38 and PCL, [39][40] have been assessed in vivo to determine their behaviors in the bone microenvironments of sheep, [32][33][35][36] rabbit, 34,37 and pig. [38][39][40] However, there have been no reports evaluating the in vivo behaviors of P(DLLA-CL) biomaterials in bone microenvironments thus far.…”

Immune activity and biodistribution of polypeptide K237 and folic acid conjugated amphiphilic PEG-PLGA copolymer nanoparticles radiolabeled with 99mTc

“…The resulting emulsion was rotated and evaporated under 0.5 MPa and 37 ° C. After 30 min, the emulsion was stirred gently at room temperature to evaporate the left organic solvent. Finally, the NPs were isolated by centrifugation at 15000 rpm, at 4 ° C for 30 min, and the pelleted NPs were freeze dried [32, 33]. …”

A Magnetic and pH-Sensitive Composite Nanoparticle for Drug Delivery

“…Targeting drug delivery system is proven to be effective methods for precise location [16,17]. Magnetic response property was another frequently used method to design and prepare a passive targeting nanocarrier system, which can aggregate objective tissue under the action of the magnetic field.…”