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.
Highlights
Targeting therapeutic agents to bone using bisphosphonates (BPs) is an attractive technology widely explored since the1990s to treat bone diseases, including osteoporosis, bone metastases, multiple myeloma, or osteosarcoma.[2]
This targeting methodology represents an intriguing solution to side effects and to the lack of selectivity associated with conventional therapies. This is especially relevant in the case of antineoplastic drugs for bone cancer and metastases
The design opportunities afforded by supramolecular chemistry have already been explored for BP-based osteotropic drug-delivery systems, giving rise to a panoply of architectures: hydrogels, liposomes, bioceramics, nanocapsules, and nanospheres, among others.[10−12]
Summary
1990s to treat bone diseases, including osteoporosis, bone metastases, multiple myeloma, or osteosarcoma.[2] This targeting methodology represents an intriguing solution to side effects and to the lack of selectivity associated with conventional therapies. This is especially relevant in the case of antineoplastic drugs for bone cancer and metastases. By virtue of their ability to bind to Ca2+, BPs behave as hydroxyapatite (HA) ligands[3] and drug-delivery systems incorporating conjugated BPs become osteotropic (bone-seeking) nanocarriers,[4] leading to an optimization of the therapeutic index. Associated to the well-defined bone-binding properties of BPs, their preferential uptake by osteoclasts, antiresorptive effects, and relative safety of BP therapies are the bases of multiple successful therapeutic applications.[5−7]
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