Think Beyond the Core: The Impact of the Hydrophilic Corona on the Drug Solubilization Using Polymer Micelles
Open accessPreprint — published as 10.1021/acsami.9b22495 · Paper page
Abstract
Polymeric micelles are typically characterized as core-shell structures. The hydrophobic inner core is considered as depot for hydrophobic molecules such as drugs or catalysts and the corona forming block acts as protective, stabilizing and solubilizing interface between the hydrophobic core and the external aqueous milieu. Tremendous efforts have been made to tune the hydrophobic block to increase the drug loading and stability of the micelles, while the role of hydrophilic blocks regarding drug loading and stability of micelles is rarely studied in detail. To do so, we investigated a small library of structurally similar A-B-A type amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s by varying the hydrophilic block A utilizing poly(2-methyl-2-oxazoline) (A) or poly(2-ethyl-2-oxazoline) (A*), both excellently water-soluble polymers that are able to provide beneficial stealth properties. Surprisingly, major differences in loading capacities from A-B-A > A*-B-A > A*-B-A* highlight the impact of the hydrophilic corona of the polymer micelles on drug loading and stability. 1H-NMR spectroscopy revealed that the hydrophilic pEtOx exhibits a stronger interaction with the cargo compared with its more hydrophilic counterpart pMeOx, reducing colloidal stability of the drug loaded micelles at lower drug loading. To gain more insights, formulations were also characterized by diffusion ordered and nuclear Overhauser effect NMR spectroscopy, dynamic light scattering and (micro) differential scanning calorimetry. Our findings suggest that the interaction between the hydrophilic block and the guest molecule should be considered an important but previously largely ignored factor for the rational design of polymeric micelles.
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As curcumin loading increased, SANS data suggest that curcumin initially located in the micelle core shifted to the periphery, forming an inner shell within the micelles.
“As the drug loading amount increased, the SANS data suggests that curcumin initially located in the micelle core shifted to the periphery forming an inner “shell” within the micelles.”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [46]
The Introduction (page not available) reports that, at higher loading, curcumin began to reside in the micelle’s shell-forming block. It does not identify SANS as the evidence or describe curcumin shifting from the core to form an inner shell. (LLM, conf=0.83)
Experimental — accuracy not yet measured1H-NMR revealed that PEtOx had a much greater propensity than PMeOx for interacting with curcumin at lower loadings.
“1H-NMR spectroscopy revealed that the latter displayed much greater propensity for interacting with the drug at the lower loadings, which is possibly reducing the colloidal stability of the drug loaded micelles by shrinking the shell.”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [46]
In the formulations discussion (page unavailable), the authors interpret their ¹H-NMR findings as indicating stronger interaction of pEtOx than pMeOx with curcumin. But their proposed micelle model says there is no major difference at no or very low drug loading; the stronger interaction emerges as loading increases. The claim’s qualification that the greater propensity occurs at lower loadings is therefore not supported as stated. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe greater propensity of PEtOx to interact with curcumin at lower loadings possibly reduces colloidal stability of drug-loaded micelles by shrinking the shell.
“1H-NMR spectroscopy revealed that the latter displayed much greater propensity for interacting with the drug at the lower loadings, which is possibly reducing the colloidal stability of the drug loaded micelles by shrinking the shell.”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [46]
The ¹H-NMR discussion reports that pEtOx loses mobility even at low curcumin loading and interacts more strongly with curcumin than pMeOx as loading increases. The paper links pEtOx-corona dehydration to agglomeration, but does not establish shell shrinkage or reduced colloidal stability at the lower loading: its DLS section reports no significant micelle-size differences at 2 g/L curcumin. (LLM, conf=0.80)
Experimental — accuracy not yet measuredIn SANS analysis of curcumin-loaded POx/POzi micelles, curcumin showed differential localization depending on its loading amount.
“Consistent with the NMR study discussed in the previous section, this drug revealed differential localization depending on its loading amount in the micelles.”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [46]
In the section on pPrOzi micelle formulations (page unavailable), the paper proposes a tentative loading-dependent model: as curcumin loading increases, the pEtOx corona interacts more strongly with the drug. That supports a loading-dependent change in the micelles, but the paper does not report SANS analysis or establish curcumin’s differential localization by that method; its relevant measurements include NMR. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDrug interactions with the hydrophilic block play a significant role in achieving extremely high drug loadings.
“This study suggests a significant role for drug interactions with the hydrophilic block in achieving extremely-high drug loadings.”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [46]
Micelles with a PMeOx shell were highly stable in solution.
“Such micelles were also highly stable in solution.”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [46]
Micelles with a mixed PEtOx and PMeOx shell displayed an intermediate result.
“The micelles with the mixed PEtOx and PMeOx shell displayed an intermediate result.”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [46]
PEtOx was much less efficient as a hydrophilic shell; the respective micelles did not solubilize as much curcumin and were less stable at higher loading.
“On the contrary, PEtOx was much less efficient as a hydrophilic shell and the respective micelles did not solubilize as much curcumin and were less stable at higher loading.”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [46]
Curcumin loading was extremely high when more hydrophilic PMeOx was used as the shell-forming block in the polymeric micelles.
“The drug (curcumin) loading was extremely high when more hydrophilic PMeOx was used as the shell forming block in the polymeric micelles.”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [46]
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Hwang, D., Ramsey, J. D., & Kabanov, A. V. (2020) · Advanced drug delivery reviews · doi:10.1016/j.addr.2020.09.009 · Cited by 699 · see citing works
- Authors
- Haider, M. S., Lübtow, M. M., Endres, S., Aseyev, V., Pöppler, A.-C., & Luxenhofer, R.
- Affiliations
- University of Würzburg (DE)
- University of Helsinki (FI)
- Corresponding author
- Luxenhofer, Robert
- Venue
- ACS Applied Materials & Interfaces
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-08-23
- Volume
- 12
- Issue
- 22
- Pages
- 24531-24543
- ISSN
- 1944-8244 (ISSN-L)
- OpenAlex
- W3021349866
- Cited by
- 100
- References
- 0
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 14 · 2023: 13 · 2022: 16 · 2021: 18 · 2020: 8
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- ACS Applied Materials & Interfaces (publishedVersion)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Royal College of Surgeons in Ireland (submittedVersion, cc-by-nc-nd)
- Funders
- Verband der Chemischen Industrie
- Evonik Stiftung
- Deutscher Akademischer Austauschdienst
- Deutsche Forschungsgemeinschaft (398461692)
- Higher Education Commission, Pakistan
- Higher Education Commision, Pakistan
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Chemistry › Organic Chemistry › Surfactants and Colloidal Systems
- Physical Sciences › Chemistry › Organic Chemistry › Advanced Polymer Synthesis and Characterization
- Keywords
- polymeric micelles, drug solubilization, amphiphilic block copolymers, poly(2-oxazoline), poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), drug loading capacity, curcumin, paclitaxel, core-shell micelles, micelle stability, drug-micelle interaction
- MeSH terms
- Curcumin, Drug Carriers, Drug Compounding, Micelles, Oxazoles, Polymers, Solubility, Surface-Active Agents, Molecular Structure, Paclitaxel, Small Molecule Libraries, Hydrophobic and Hydrophilic Interactions
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