Regulation of in vivo behavior of TAT-modified liposome by associated protein corona and avidity to tumor cells

Amin, M. and Bagheri, M. and Mansourian, M. and Jaafari, M. R. and 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. pp. 7441-7455.

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Regulation of in vivo behavior of TAT-modified liposome by associated protein corona and avidity to tumor cells.pdf

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Introduction: PEGylated liposomes are widely used and studied as carriers for chemothera-peutics. 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. © 2018 Amin et al.

Item Type: Article
Additional Information: Cited By :1 Export Date: 16 February 2020 Correspondence Address: Ten Hagen, T.L.M.; Laboratory of Experimental Surgical Oncology, Section of Surgical Oncology, Department of Surgery, Erasmus Medical Center, PO Box 2040, Netherlands; email:
Uncontrolled Keywords: Dysopsonization Ligand-modified liposomes PEGylated liposomal doxorubicin Protein corona TAT peptide doxorubicin liposome nanocarrier transactivator protein macrogol animal cell animal experiment animal model animal tissue antineoplastic activity Article colon carcinoma controlled study drug clearance drug distribution drug dosage form comparison drug efficacy drug stability endocytosis female in vitro study in vivo study melanoma mouse nonhuman opsonization pharmacokinetics regulatory mechanism single drug dose tumor cell analogs and derivatives animal Bagg albino mouse chemistry colloid human metabolism neoplasm particle size serum static electricity tissue distribution treatment outcome tumor cell line Animals Cell Line, Tumor Colloids Humans Mice, Inbred BALB C Neoplasms Polyethylene Glycols tat Gene Products, Human Immunodeficiency Virus
Subjects: QU Biochemistry
QZ pathology-neoplasms-Genetics
Divisions: Mashhad University of Medical Sciences
Depositing User: lib2 lib2 lib2
Date Deposited: 09 Jun 2020 06:09
Last Modified: 09 Jun 2020 06:09

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