Directed Interactions of Block Copolypept(o)ides with Mannose-binding Receptors: PeptoMicelles Targeted to Cells of the Innate Immune System

Core-shell structures based on polypept(o)ides combine stealth-like properties of the corona material polysarcosine with adjustable functionalities of the polypeptidic core. Mannose-bearing block copolypept(o)ides (PSar-block-PGlu(OBn)) have been synthesized using 11-amino-3,6,9-trioxa-undecyl-2,3,4,6-tetra-O-acetyl-O-α-D-mannopyranoside as initiator in the sequential ring-opening polymerization of α-amino acid N-carboxyanhydrides. These amphiphilic block copolypept(o)ides self-assemble into multivalent PeptoMicelles and bind to mannose-binding receptors as expressed by dendritic cells. Mannosylated micelles showed enhanced cell uptake in DC 2.4 cells and in bone marrow-derived dendritic ce…

Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging.

Background In this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal-labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA-linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177. Results Short linkers and as low as 1.6% DOTA were enough to obtain labeling yields > 90%. Alkoxy linkers generally exhibited lower labeling yields than alkane analogues despite of similar chain length and DOTA incorporation rate. High sta…

A Deeper Insight into the Postpolymerization Modification of Polypenta Fluorophenyl Methacrylates to Poly(N -(2-Hydroxypropyl) Methacrylamide)

This work provides a detailed insight into the synthesis of N-(2-hydroxypropyl)methacrylamide (HPMA) polymers employing the activated ester approach. In this approach, polypenta fluorophenyl methacrylate (PFPMA)-activated ester polymers are synthesized by the reversible addition-fragmentation chain transfer (RAFT) polymerization and transferred into HPMA-based systems by the use of 2-hydroxypropylamine. To prove quantitative conversion in the absence of side reactions, special attention is devoted to investigate different reaction conditions by different analytical methods ((1) H, (19) F, inverse-gated (13) C NMR, and zeta potential measurements). Furthermore the influence of common solvent…

Polymeric Selectin Ligands Mimicking Complex Carbohydrates: From Selectin Binders to Modifiers of Macrophage Migration

Novel polymeric cell adhesion inhibitors were developed in which the selectin tetrasaccharide sialyl-LewisX (SLeX ) is multivalently presented on a biocompatible poly(2-hydroxypropyl)methacrylamide (PHPMA) backbone either alone (P1) or in combination with O-sulfated tyramine side chains (P2). For comparison, corresponding polymeric glycomimetics were prepared in which the crucial "single carbohydrate" substructures fucose, galactose, and sialic acid side chains were randomly linked to the PHPMA backbone (P3 or P4 (O-sulfated tyramine)). All polymers have an identical degree of polymerization, as they are derived from the same precursor polymer. Binding assays to selectins, to activated endo…

Targeting cells of the immune system: mannosylated HPMA–LMA block-copolymer micelles for targeting of dendritic cells

Background: Successful tumor immunotherapy depends on the induction of strong and sustained tumor antigen-specific immune responses by activated antigen-presenting cells (APCs) such as dendritic cells (DCs). Since nanoparticles have the potential to codeliver tumor-specific antigen and DC-stimulating adjuvant in a DC-targeting manner, we wanted to assess the suitability of mannosylated HPMA-LMA block polymers for immunotherapy. Materials & methods: Fluorescence-labeled block copolymer micelles derived from P(HPMA)-block-P(LMA) copolymers and according statistical copolymers were synthesized via RAFT polymerization, and loaded with the APC activator L18-MDP. Both types of copolymers wer…

Functionalization of Active Ester-Based Polymersomes for Enhanced Cell Uptake and Stimuli-Responsive Cargo Release

Poly(2,3-dihydroxypropyl methacrylamide) (P(DHPMA))-based amphiphilic block copolymers have recently proven to form polymer vesicles (polymersomes). In this work, we further expand their potential by incorporating (i) units for pH-dependent disintegration into the hydrophobic membrane and (ii) mannose as targeting unit into the hydrophilic block. This last step relies on the use of an active ester prepolymer. We confirm the stability of the polymersomes against detergents like Triton X-100 and their low cytotoxicity. The incorporation of 2-(2,2-dimethyl-1,3-dioxolane-4-yl)ethyl methacrylate into the hydrophobic block (lauryl methacrylate) allows a pH-responsive disintegration for cargo rele…

Back Cover: Macromol. Biosci. 1/2015

Targeting distinct myeloid cell populations in vivo using polymers, liposomes and microbubbles

Identifying intended or accidental cellular targets for drug delivery systems is highly relevant for evaluating therapeutic and toxic effects. However, limited knowledge exists on the distribution of nano- and micrometer-sized carrier systems at the cellular level in different organs. We hypothesized that clinically relevant carrier materials, differing in composition and size, are able to target distinct myeloid cell subsets that control inflammatory processes, such as macrophages, neutrophils, monocytes and dendritic cells. Therefore, we analyzed the biodistribution and in vivo cellular uptake of intravenously injected poly(N-(2-hydroxypropyl) methacrylamide) polymers, PEGylated liposomes…

PEGylation of HPMA-based block copolymers enhances tumor accumulation in vivo: a quantitative study using radiolabeling and positron emission tomography.

Abstract This paper reports the body distribution of block copolymers (made by controlled radical polymerization) with N-(2-hydroxypropyl)methacrylamide (HPMA) as hydrophilic block and lauryl methacrylate (LMA) as hydrophobic block. They form micellar aggregates in aqueous solution. For this study the hydrophilic/hydrophobic balance was varied by incorporation of differing amounts of poly(ethylene glycol) (PEG) side chains into the hydrophilic block, while keeping the degree of polymerization of both blocks constant. PEGylation reduced the size of the micellar aggregates (Rh = 113 to 38 nm) and led to a minimum size of 7% PEG side chains. Polymers were labeled with the positron emitter 18F,…

Polymere Selectinliganden als komplexe Glykomimetika: von Selectinbindung bis zur Modifizierung der Makrophagenmigration

Bei neuartigen polymeren Inhibitoren der Zelladhasion wird das Selectin-bindende Tetrasaccharid Sialyl-LewisX (SLeX) multivalent auf einem biokompatiblen Poly(2-hydroxypropyl)methacrylamid (PHPMA) entweder alleine (P1) oder in Kombination mit O-sulfatierten Tyramin-Seitenketten (P2) prasentiert. Zum Vergleich wurden entsprechende polymere Glykomimetika hergestellt, in denen die entscheidenden Fucose-, Galactose und Sialinsaure-Seitenketten statistisch verteilt im PHPMA-Ruckgrat (P3 oder P4 (O-sulfatiertes Tyramin) vorliegen. Alle Polymere haben den gleichen Polymerisationsgrad, da sie vom selben Ausgangspolymer abstammen. Assays fur die Bindung an Selectine, aktivierte Endothelzellen und Ma…