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Several liposome products have been approved for the treatment of cancer. In all of them, the active agents are encapsulated in the liposome water phase passively or by transmembrane ion gradients. An alternative approach in liposomal drug delivery consists of chemically modifying drugs to form lipophilic prodrugs with strong association to the liposomal bilayer. Based on this approach, we synthesized a mitomycin c-derived lipidic prodrug (MLP) which is entrapped in the bilayer of PEGylated liposomes (PL-MLP, Promitil®), and activated by thiolytic cleavage. PL-MLP is stable in plasma with thiolytic activation of MLP occurring exclusively in tissues and is more effective and less toxic than conventional chemotherapy in various tumor models. PL-MLP has completed phase I clinical development where it has shown a favorable safety profile and a 3-fold reduction in toxicity as compared to free mitomycin c. Clinical and pharmacokinetic studies in patients with advanced colo-rectal carcinoma have indicated a significant rate of disease stabilization (39%) in this chemo-refractory population and significant prolongation of median survival in patients attaining stable disease (13.9 months) versus progressive disease patients (6.35 months). The pharmacokinetics of MLP was typically stealth with long T½ (~1 day), slow clearance and small volume of distribution. Interestingly, a longer T½, and slower clearance were both correlated with disease stabilization and longer survival. This association of pharmacokinetic parameters with patient outcome suggests that arrest of tumor growth is related to the enhanced tumor localization of long-circulating liposomes and highlights the importance of personalized pharmacokinetic evaluation in the clinical use of nanomedicines. Another important area where PL-MLP may have an added value is in chemoradiotherapy, where it has shown a strong radiosensitizing effect in animal models based on a unique mechanism of enhanced prodrug activation and encouraging results in early human testing. Unlabelled Image [ABSTRACT FROM AUTHOR]

[Display omitted] • Protein corona interferes with the intended function of nanoparticles, such as target-specific interactions. • Previous efforts have focused on avoiding protein corona formation or overriding the effect of the protein corona. • Specific proteins in the blood, such as albumin or apolipoproteins, can enhance nanoparticle delivery to particular organs. • To exploit the functions of protein corona, nanoparticles are functionalized with the proteins or designed to attract them. • Remaining challenges include interpatient variability in serum proteins and poor understanding of non-protein corona. For systemically delivered nanoparticles to reach target tissues, they must first circulate long enough to reach the target and extravasate there. A challenge is that the particles end up engaging with serum proteins and undergo immune cell recognition and premature clearance. The serum protein binding, also known as protein corona formation, is difficult to prevent, even with artificial protection via "stealth" coating. Protein corona may be problematic as it can interfere with the interaction of targeting ligands with tissue-specific receptors and abrogate the so-called active targeting process, hence, the efficiency of drug delivery. However, recent studies show that serum protein binding to circulating nanoparticles may be actively exploited to enhance their downstream delivery. This review summarizes known issues of protein corona and traditional strategies to control the corona, such as avoiding or overriding its formation, as well as emerging efforts to enhance drug delivery to target organs via nanoparticles. It concludes with a discussion of prevailing challenges in exploiting protein corona for nanoparticle development. [ABSTRACT FROM AUTHOR]