Polyethylenimine–Bisphosphonate–Cyclodextrin Ternary Conjugates: Supramolecular Systems for the Delivery of Antineoplastic Drugs

Abstract

Bisphosphonates (BPs) are bone-binding molecules that provide targeting capabilities to bone cancer cells when conjugated with drug-carrying polymers. This work reports the design, synthesis, and biological evaluation of polyethyleneimine–BP–cyclodextrin (PEI-BP-CD) ternary conjugates with supramolecular capabilities for the loading of antineoplastic drugs. A straightforward, modular, and versatile strategy based on the click aza-Michael addition reaction of vinyl sulfones (VSs) allows the grafting of BPs targeting ligands and βCD carrier appendages to the PEI polymeric scaffold. The in vitro evaluation (cytotoxicity, cellular uptake, internalization routes, and subcellular distribution) for the ternary conjugates and their doxorubicin inclusion complexes in different bone-related cancer cell lines (MC3T3-E1 osteoblasts, MG-63 sarcoma cells, and MDA-MB-231 breast cancer cells) confirmed specificity, mitochondrial targeting, and overall capability to mediate a targeted drug transport to those cells. The in vivo evaluation using xenografts of MG-63 and MDA-MB-231 cells on mice also confirmed the targeting of the conjugates.

Cyclodextrin Polymers as Delivery Systems for Targeted Anti-Cancer Chemotherapy

“…In the literature, there are many studies on Dox nanoformulation based on CyDs and few studies on Oxa [ 7 , 27 ]. Some formulations are based on self-aggregates exploiting triggering behavior but, in many cases, critical stability [ 7 , 27 , 46 , 47 ].…”

“…Although the reason of selectivity is not well clarified, the most important result is the increase of the antiproliferative activity of Dox and Oxa in the presence of CyD polymers as compared to the free drugs. This result is quite remarkable since the encapsulation of the drug in nanoparticles often produces a decrease in cytotoxicity in vitro compared to the free drug [ 7 , 27 , 46 ] and only in vivo experiments can show the advantage of the nanoformulations [ 7 , 37 , 46 ].…”

Divinylanthracene-Containing Tetracationic Organic Cyclophane with Near-Infrared Photoluminescence

“…The divinylanthracene-containing cyclophane VAnBox ·4Cl is, therefore, an excellent probe for live-cell imaging. On account of its NIR emission, biocompatibility, and cyclic structure, we envision that VAnBox ·4Cl is a good candidate for biomedical applications, such as drug delivery and oxygen transport as endoperoxides for photoactivated therapy …”

Current and Emerging Approaches for Spine Tumor Treatment

“…Alternatively, Plesselova et al [ 65 ] have created a polyethyleneimine scaffold conjugated with bisphosphonates as targeting ligands and cyclodextrins as supramolecular drug carriers. The authors tested this nanovehicle for the delivery of doxorubicin to three different bone-related cancer cell lines (i.e., MC3T3-E1 osteoblasts, MG-63 sarcoma cells, and MDA-MB-231 breast cancer cells).…”