Figure 9.

Composition and drug loading strategies of uPAR-targeted IONPs. (A) Most of the uPAR-targeted NPs developed up to date consist of magnetic IONPs coated with amphiphilic polymers. In addition to high stability, these polymers provide active functional carboxyl groups (COOH) on the particle surface for bioconjugation of targeting moieties, such as recombinant ATF (PDB accession number: 1URK) or other uPAR-peptide antagonists (not shown in the figure). (B) Different drug encapsulation methods can be utilized based on the physicochemical properties of the cargo, as well as drug-delivery strategies. Direct adsorption of the drug on the NP surface through non-covalent interaction increases the amount of drug encapsulated and efficiency of release into the targeted cells, compared to covalent linking [242]. Using this direct encapsulation method, doxorubicin and noscapine, two hydrophobic anticancer drugs, were physically adsorbed onto the amphiphilic polymer coating of ATF-IONPs via hydrophobic interactions (top) [236,237]. Similarly, the chemotherapeutic cisplatin (middle) was conjugated on the surface of ATF-PEG-IONPs via a coordinate bond between the positive charge of platinum (Pt⁺) with the negative charge of the coating polymer’s carboxylate groups (O=C-O-, Lewis base) [239]. In both cases, drug release is triggered at acidic pH values, typical of the hypoxic tumor milieu or intracellular lysosomes. Alternatively, more controlled drug release may be achieved via linker-mediated adsorption [242]. Using a pH-sensitive lysosomally cleavable peptide linker, gemcitabine, a hydrophilic drug, was covalently conjugated on the polymer surface of ATF-IONPs, achieving cathepsin B-mediated intracellular drug release (bottom) [236]. Created with BioRender.com.