Combining Core Cross-Linking and π–π-Interactions in Polymer Micelles Based on Polypept(o)ide AB3 Miktoarm Star Polymers

Macromolecules, vol. 58, pp. 4225–4237

Abstract

High Resolution Image Download MS PowerPoint Slide The lack of stability in nanocarriers, premature release of drugs in the bloodstream, and the resulting adverse effects have greatly hindered the advancement of nanomedicines by comprising their therapeutic effectiveness. In order to surpass these limitations and fully exploit the potential of polymeric micelles for targeted drug delivery, various physical and chemical strategies have been devised to improve micellar blood circulation time and improve drug retention. In this regard, the improved polymer density at the hydrophilic/hydrophobic interface in miktoarm star polymers based micelles is highly appealing and sets them apart from conventional linear block copolymers. Nonetheless, the often complex synthesis of asymmetric architectures hinders a broader application in the field of nanomedicine. In this study, we have designed novel dual-stabilizable PeptoMiktoStars by optimizing the orthogonal group strategy, introducing core cross-linkability and π–π-interactions. These polypept(o)ide miktoarm star polymers unify the polypeptide blocks of poly( S -ethylsulfonyl- l -cysteine) (pCys(SO 2 Et))/poly( S -ethylsulfonyl- l -homocysteine) (pHcy(SO 2 Et)) and poly(γ-benzyl- l -glutamate (pGlu(OBn))) with multiple arms of the polypeptoid polysarcosine (pSar) in an AB 3 architecture. By utilizing 1 H NMR, 1 H DOSY, and GPC, the formation of well-defined star polymers was confirmed. The obtained results showcased star structures with narrow molecular weight distributions, low dispersities ( Đ = 1.16–1.18), and accurate control over the degree of polymerization. After successful core cross-linking and drug encapsulation, uniform micelles with hydrodynamic diameters ranging from 60 to 68 nm were observed by dynamic laser light scattering (DLS) and transmission electron microscopy (TEM), making these structures suitable for controlled intracellular drug release upon local or systemic administration.

Authors 3

1. David Schwiertz Aachen Biotherapeutics Division Leiden Academic Centre for Drug Research

   Leiden University · Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Biotherapeutics Division, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands

   Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz (JGU), Obere Zahlbacher Straße 63, 55131 Mainz, Germany

2. Gabriela Giannina Schäfer Aachen Biotherapeutics Division Leiden Academic Centre for Drug Research

   Leiden University · Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Biotherapeutics Division, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands

   Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz (JGU), Obere Zahlbacher Straße 63, 55131 Mainz, Germany

3. Matthias Barz corresponding Aachen Biotherapeutics Division Leiden Academic Centre for Drug Research

   Leiden University · Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

   Affiliation as printed

   Biotherapeutics Division, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands

   Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz (JGU), Obere Zahlbacher Straße 63, 55131 Mainz, Germany