Regulation of in vivo behavior of TAT-modified liposome by associated protein corona and avidity to tumor cells
Introduction: PEGylated liposomes are widely used and studied as carriers for chemotherapeutics. While pharmacokinetics of the encapsulated drug is drastically altered resulting in favorable circulation time, improved tumor accumulation, and better manageable or reduced side effects, therapeutic efficacy has been disappointing. Major drawbacks are a failure to reach the tumor cell, limited penetration depth, and impaired uptake by tumor cells. Materials and methods: Here, we study the implication of HIV-1 transactivator of transcription (TAT)-derived peptides inserted on PEGylated liposomal doxorubicin (PLD) and followed in vitro and in vivo fate. PLDs were installed with 25-400 TAT peptides per liposome without an effect on PLD stability. Results: While TAT peptides facilitate active endocytosis of the carriers, we observed that these peptides did not promote endosomal escape or enhanced intracellular availability of doxorubicin. Interestingly, incorporation of TAT peptides did not change pharmacokinetics or biodistribution, which we found to result from a dysopsonization of the TAT-modified liposomes by serum proteins. A protein corona (PC) on TAT peptide-modified PLDs shields the active moieties and effectively reduces clearance of the TAT peptide containing nanoparticles. However, intratumoral activity was influenced by the number of TAT peptides present. The best antitumor efficacy was observed with a TAT peptide density of 100, while lower amounts showed results comparable to unmodified PLDs. At 200 TAT peptides, the preparation appeared to be least effective, which likely results from augmented interaction with tumor cells directly upon extravasation. Conclusion: We conclude that by optimizing TAT-modified PLDs, the occurring PC balances pharmacokinetics and tumor penetration through interference with avidity.
|Keywords||dysopsonization, ligand-modified liposomes, PEGylated liposomal doxorubicin, protein corona, TAT peptide|
|Persistent URL||dx.doi.org/10.2147/IJN.S170274, hdl.handle.net/1765/113381|
|Journal||International journal of nanomedicine|
Amin, M, Bagheri, M. (Mahsa), Mansourian, M, Jaafari, M.R, & ten Hagen, T.L.M. (2018). Regulation of in vivo behavior of TAT-modified liposome by associated protein corona and avidity to tumor cells. International journal of nanomedicine, 13, 7441–7455. doi:10.2147/IJN.S170274