Since the introduction of Doxil® on the market nearly 20years ago, a number of nanomedicines have become part of treatment regimens in the clinic. With the exception of antibody-drug conjugates, these nanomedicines are all devoid of targeting ligands and rely solely on their physicochemical properties and the (patho)physiological processes in the body for their biodistribution and targeting capability. At the same time, many preclinical studies have reported on nanomedicines exposing targeting ligands, or ligand-targeted nanomedicines, yet none of these have been approved at this moment. In the present review, we provide a concise overview of 13 ligand-targeted particulate nanomedicines (ligand-targeted PNMs) that have progressed into clinical trials. The progress of each ligand-targeted PNM is discussed based on available (pre)clinical data. Main conclusions of these analyses are that (a) ligand-targeted PNMs have proven to be safe and efficacious in preclinical models; (b) the vast majority of ligand-targeted PNMs is generated for the treatment of cancer; (c) contribution of targeting ligands to the PNM efficacy is not unambiguously proven; and (d) targeting ligands do not cause localization of the PNM within the target tissue, but rather provide benefits in terms of target cell internalization and target tissue retention once the PNM has arrived at the target site. Increased understanding of the in vivo fate and interactions of the ligand-targeted PNMs with proteins and cells in the human body is mandatory to rationally advance the clinical translation of ligand-targeted PNMs. Future perspectives for ligand-targeted PNM approaches include the delivery of drugs that are unable or inefficient in passing cellular membranes, treatment of drug resistant tumors, targeting of the tumor blood supply, the generation of targeted vaccines and nanomedicines that are able to cross the blood-brain barrier.
Keywords: ACUPA; AD-PEG; ADC; APC; BBB; Bacterial-derived minicell; CDP; CNS; CTL; Clinical translation; DC; DC-SIGN; DLT; DOX; DTXL; EGFR; EPR; GSH; IFN-γ; ILs; L-OHP; LPS; Liposome; M2 subunit of ribonucleotide reductase; MDR; MPS; MTD; N-glutaryl-phosphatidylethanolamine; NGPE; Nanomedicines; PAC; PEG; PEGylated liposomal doxorubicin; PK; PLA; PLD; PLGA; PNM; PSMA; Particulate nanocarrier; Polymeric nanoparticle; RRM2; Retroviral vector; S,S-2-[3-[5-amino-1-carboxypentyl]-ureido]-pentanedioic acid; Targeting ligand; Tf; Tf-AD-PEG; adamantane-conjugated polyethylene glycol; antibody–drug conjugate; antigen-presenting cell; blood-brain barrier; central nervous system; cyclodextrin-containing polymer; cytotoxic T cell; dendritic cell; dendritic cell-specific intracellular adhesion molecule 3-grabbing non-integrin; docetaxel; dose-limiting toxicit; doxorubicin; enhanced permeability and retention; epidermal growth factor receptor; glutathione; immunoliposomes; interferon-gamma; lipopolysaccharide; maximum tolerated dose; mononuclear phagocyte system; multi drug resistance; oxaliplatin; paclitaxel; particulate nanomedicine; pharmacokinetic; poly(d,l-lactide); poly(lactic-co-glycolic acid); polyethylene glycol; prostate-specific membrane antigen; scFv; shRNA; short hairpin RNA; single-chain antibody fragment; transferrin; transferrin-conjugated adamantane-conjugated polyethylene glycol.
© 2013.