Enzyme-cleavable polymeric micelles for the intracellular delivery of proapoptotic peptides
Open accessAbstract
Peptides derived from the third Bcl-2 homology domain (BH3) renormalize apoptotic signaling by antagonizing prosurvival Bcl-2 family members. These potential peptide drugs exhibit therapeutic activities but are limited by barriers including short circulation half-lives and poor penetration into cells. A diblock polymeric micelle carrier for the BIM BH3 peptide was recently described that demonstrated antitumor activity in a B-cell lymphoma xenograft model [Berguig et al., Mol. Ther. 2015, 23, 907–917]. However, the disulfide linkage used to conjugate the BIM peptide was shown to have nonoptimal blood stability. Here we describe a peptide macromonomer composed of BIM capped with a four amino acid cathepsin B substrate (FKFL) that possesses high blood stability and is cleaved to release the drug inside of target cells. Employing RAFT polymerization, the peptide macromonomer was directly integrated into a multifunctional diblock copolymer tailored for peptide delivery. The first polymer block was made as a macro-chain transfer agent (CTA) and composed of a pH-responsive endosomolytic formulation of N, N -diethylaminoethyl methacrylate (DEAEMA) and butyl methacrylate (BMA). The second polymer block was a copolymer of the peptide and polyethylene glycol methacrylate (PEGMA). PEGMA monomers of two sizes were investigated (300 Da and 950 Da). Protein gel analysis, high performance liquid chromatography, and coupled mass spectrometry (MS) showed that incubation with cathepsin B specifically cleaved the FKFL linker and released active BIM peptide with PEGMA 300 but not with PEGMA 950 . MALDI-TOF MS showed that incubation of the peptide monomers alone in human serum resulted in partial cleavage at the FKFL linker after 12 h. However, formulation of the peptides into polymers protected against serum-mediated peptide degradation. Dynamic light scattering (DLS) demonstrated pH-dependent micelle disassembly (25 nm polymer micelles at pH 7.4 versus 6 nm unimers at pH 6.6), and a red blood cell lysis assay showed a corresponding increase in membrane destabilizing activity (<1% lysis at pH 7.4 versus 95% lysis at pH 6.6). The full carrier–drug system successfully induced apoptosis in SKOV3 ovarian cancer cells in a dose-dependent manner, in comparison to a control polymer containing a scrambled BIM peptide sequence. Mechanistic analysis verified target-dependent activation of caspase 3/7 activity (8.1-fold increase), and positive annexin V staining (72% increase). The increased blood stability of this enzyme-cleavable peptide polymer design, together with the direct polymerization approach that eliminated postsynthetic conjugation steps, suggests that this new carrier design could provide important benefits for intracellular peptide drug delivery.
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DLS showed its usefulness in defining micelles structural modifications in response to temperature, pH, enzymes, and light.
“Concerning stimuli-responsive micelles, DLS showed its usefulness in defining micelles structural modifications in response to temperature [141][142][143], pH [143,144], enzymes [145,146] and light [141,147].”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [143]
The Results section, “Micelle Sizing and pH-Responsive Membrane Destabilizing Activity” (page not provided), reports that DLS detected micelle disassembly as pH decreased. This paper is cited for the enzyme-response part of the sentence, but its “Cathepsin B Cleavage Assay” section describes measuring enzymatic cleavage by RP-HPLC, mass spectrometry, and SDS–PAGE—not using DLS to detect enzyme-induced structural changes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDLS showed its usefulness in defining micelles structural modifications in response to temperature, pH, enzymes, and light.
“Concerning stimuli-responsive micelles, DLS showed its usefulness in defining micelles structural modifications in response to temperature [141][142][143], pH [143,144], enzymes [145,146] and light [141,147].”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [144]
This citation is attached to the enzyme-response part of the sentence. The Results section on micelle sizing uses DLS to show changes with pH, while the Results and Experimental sections on cathepsin B assess enzyme cleavage using RP-HPLC, mass spectrometry, and gels. Our copy does not show DLS defining micelle structural changes in response to enzymes. (LLM, conf=0.76)
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- [34]Berguig GY Convertine AJ Frayo S Kern HB Procko E Roy D Srinivasan S Margineantu DH Booth G Palanca-Wessels MC Baker D Hockenbery D Press OW Stayton PS Intracellular delivery system for antibody-peptide drug conjugates Mol Ther 2015 23 907 17 25669432 PMC4427876
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- Authors
- Kern, H. B., Srinivasan, S., Convertine, A. J., Hockenbery, D., Press, O. W., & Stayton, P. S.
- Affiliations
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Corresponding author
- Stayton, Patrick S.
- Venue
- Molecular Pharmaceutics
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-03-30
- Volume
- 14
- Issue
- 5
- Pages
- 1450-1459
- ISSN
- 1543-8384 (ISSN-L)
- 1543-8392
- PMC
- PMC5823688
- OpenAlex
- W2594451304
- Cited by
- 63
- References
- 59
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 10 · 2023: 12 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 5 · 2018: 10 · 2017: 4
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Pharmaceutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (F30 CA183263, R01 CA076287, R01 CA109663, R01 CA154897, R01 CA158921-04)
- National Institute of Biomedical Imaging and Bioengineering (R21 EB014572)
- National Institute of General Medical Sciences (T32 GM0072666)
- Giuliani/Press Endowed Chair in Cancer Research
- David and Patricia Giuliani Family Foundation
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- polymeric micelles, proapoptotic peptide, cathepsin B, RAFT polymerization, pH-responsive micelles, poly(ethylene glycol) methacrylate, intracellular drug delivery, B-cell lymphoma, serum stability, micelle disassembly
- MeSH terms
- Cathepsin B, Drug Carriers, Humans, Hydrogen-Ion Concentration, Methacrylates, Micelles, Peptides, Polyethylene Glycols, Polymers, Drug Delivery Systems, Cell Line, Tumor
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