HPMA‐Based Nanocarriers for Effective Immune System Stimulation

Abstract

The selective activation of the immune system using nanoparticles as a drug delivery system is a promising field in cancer therapy. Block copolymers from HPMA and laurylmethacrylate‐co‐hymecromone‐methacrylate allow the preparation of multifunctionalized core‐crosslinked micelles of variable size. To activate dendritic cells (DCs) as antigen presenting cells, the carbohydrates mannose and trimannose are introduced into the hydrophilic corona as DC targeting units. To activate DCs, a lipophilic adjuvant (L18‐MDP) is incorporated into the core of the micelles. To elicit an immune response, a model antigen peptide (SIINFEKL) is attached to the polymeric nanoparticle—in addition—via a click reaction with the terminal azide. Thereafter, the differently functionalized micelles are chemically and biologically characterized. While the core‐crosslinked micelles without carbohydrate units are hardly bound by DCs, mannose and trimannose functionalization lead to a strong binding. Flow cytometric analysis and blocking studies employing mannan suggest the requirement of the mannose receptor and DC‐SIGN for effective micelle binding. It could be suppressed by blocking with mannan. Adjuvant‐loaded micelles functionalized with mannose and trimannose activate DCs, and DCs preincubated with antigen‐conjugated micelles induce proliferation of antigen‐specific CD8+ T cells.

Effect of Core‐Crosslinking on Protein Corona Formation on Polymeric Micelles

“…[ 13,45–48 ] In addition, the block copolymers used here are known to have very little unspecific cellular uptake [ 49 ] and they can be easily modified for immune cell activation. [ 50 ] Their properties have been summarized recently. [ 44 ] The CMC of block copolymers of similar composition was found to be in the low range of 10 −5 and 10 −4 mg mL −1 .…”

Design, synthesis and biological evaluation of immunostimulating mannosylated desmuramyl peptides

“…The attachment of mannose to the desmuramyl dipeptide may contribute to the recognition of the adjuvant compound by specific mannose receptors expressed at immune cells. Mannosylated drug delivery systems enhance uptake and activation of dendritic cells and increase T cell proliferation [24,27–28]. Mannosylation of the adamantylated desmuramyl peptides amplified the adjuvant activity in experiments in vivo [20–21].…”

RAFT Synthesis of Reactive Multifunctional Triblock‐Copolymers for Polyplex Formation

“…[ 47 ] and Kramer et al. [ 53 ] The included azide group is connected to a hydrophilic oligo ethylene oxide spacer to improve its presentation in the hydrophilic polymer shell. Thus, it is also possible to click highly polar targeting units to a preformed nanoparticle.…”