Apoptosis-inducing peptide loaded in PLGA nanoparticles induces anti-tumor effects in vivo.

Abstract

Induction of apoptosis in tumor cells specifically within the complex tumor microenvironment is highly desirable to kill them efficiently and to enhance the effects of chemotherapy. Second mitochondria-derived activator of caspase (Smac) is a key pro-apoptotic pathway which can be activated with a Smac mimetic peptide. However, in vivo application of peptides is hampered by several limitations such as poor pharmacokinetics, rapid elimination, enzymatic degradation, and insufficient intracellular delivery. In this study, we developed a nanosystem to deliver a Smac peptide to tumor by passive targeting. We first synthesized a chimeric peptide that consists of the 8-mer Smac peptide and a 14-mer cell penetrating peptide (CPP) and then encapsulated the Smac-CPP into polymeric nanoparticles (Smac-CPP-NPs). In vitro, Smac-CPP-NPs were rapidly internalized by 4T1 mammary tumor cells and subsequently released Smac-CPP into the cells, as shown with fluorescence microscopy. Furthermore, Smac-CPP-NPs induced apoptosis in tumor cells, as confirmed with cell viability and caspase 3/7 assays. Interestingly, combination of Smac-CPP-NPs with doxorubicin (dox), a clinically used cytostatic drug, showed combined effects in vitro in 4T1 cells. The effect was significantly better than that of SMAC-CPP-NPs alone as well as empty nanoparticles and dox. In vivo, co-treatment with Smac-CPP-NPs and free dox reduced the tumor growth to 85%. Furthermore, the combination of Smac-CPP-NPs and free dox showed reduced proliferating tumor cells (Ki-67 staining) and increased apoptotic cells (cleaved caspase-3 staining) in tumors. In conclusion, the present study demonstrates that the intracellular delivery of Smac-mimetic peptide using nanoparticle system can be an interesting strategy to attenuate the tumor growth and to potentiate the therapeutic efficacy of chemotherapy in vivo.

• Authors: Dwi L Priwitaningrum, Julian Jentsch, Ruchi Bansal, Sima Rahimian, Gert Storm, Wim E Hennink, Jai Prakash
• Journal: International journal of pharmaceutics (Int J Pharm) Vol. 585 Pg. 119535 (Jul 30 2020) ISSN: 1873-3476 [Electronic] Netherlands
• PMID: 32534162 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• Cell-Penetrating Peptides
• DIABLO protein, human
• Drug Carriers
• Mitochondrial Proteins
• Polylactic Acid-Polyglycolic Acid Copolymer
• Doxorubicin

Topics

• Animals
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (administration & dosage, pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell-Penetrating Peptides (administration & dosage, pharmacology)
• Doxorubicin (administration & dosage, pharmacology)
• Drug Carriers (administration & dosage, pharmacology)
• Hydrogen-Ion Concentration
• Mice
• Mitochondrial Proteins (administration & dosage, pharmacology)
• Nanoparticles (chemistry)
• Polylactic Acid-Polyglycolic Acid Copolymer (chemistry)