Transient Lymph Node Immune Activation by Hydrolysable Polycarbonate Nanogels

Abstract

The development of controlled biodegradable materials is of fundamental importance in immunodrug delivery to spatiotemporally controlled immune stimulation but avoid systemic inflammatory side effects. Based on this, polycarbonate nanogels are developed as degradable micellar carriers for transient immunoactivation of lymph nodes. An imidazoquinoline-type TLR7/8 agonist is covalently conjugated via reactive ester chemistry to these nanocarriers. The nanogels not only provide access to complete disintegration by the hydrolysable polymer backbone, but also demonstrate a gradual disintegration within several days at physiological conditions (PBS, pH 6.4-7.4, 37 °C). These intrinsic properties limit the lifetime of the carriers but their payload can still be successfully leveraged for immunological studies in vitro on primary immune cells as well as in vitro. For the latter, a spatiotemporal control of immune cell activation in the draining lymph node is found after subcutaneous injection. Overall, these features render polycarbonate nanogels a promising delivery system for transient activation of the immune system in lymph nodes and may consequently become very attractive for further development toward vaccination or cancer immunotherapy. Due to the intrinsic biodegradability combined with the high chemical control during the manufacturing process, these polycarbonate-based nanogels may also be of great importance for clinical translation.

Efficient Self-Immolative RAFT End Group Modification for Macromolecular Immunodrug Delivery

“…However, polymer–drug conjugation is assumed to be superior during actual in vivo setups by improving the pharmacokinetic profile through prolonged blood circulation instead of rapid renal excretion. Moreover, like many other potent immunomodulators, IMDQ tends to exhibit severe systemic distribution, which can be overcome by conjugation to a macromolecular carrier. − …”

Peptide‐Decorated Artificial Erythrocyte Microvesicles Endowed with Lymph Node Targeting Function for Drug Delivery

“…Recent years have witnessed the wide exploration of nanoparticles as instructive delivery vehicles to achieve drug accumulation in LNs. [8][9][10] Various physical and chemical properties (such as size, composition, and surface charge) of nanoparticles can also be tailored to target the LNs for drug delivery, among which size is the most important determinant of whether nanoparticles can enter lymphatic capillaries and subsequently accumulate in LNs. [11] Generally, nanoparticles larger than 100 nm cannot efficiently penetrate lymphatic capillaries because of reduced diffusion and convection through the interstitium, while those less than 10 nm basically enter blood capillaries.…”

Nontoxic N-Heterocyclic Olefin Catalyst Systems for Well-Defined Polymerization of Biocompatible Aliphatic Polycarbonates

“…Especially for biological applications, functional polymers are needed to manufacture tailor-made materials. , Thus, tuning polymer functionalization provides the ability (a) to anchor or encapsulate therapeutic molecules, , (b) to enable a (triggered/stimuli-responsive) release, , and (c) to fine-tune polymer degradation. , Aliphatic polycarbonates are a promising material class in this regard due to their functionalizability by side chain introduction, biodegradability, and favorable toxicological profiles. ,,, Polycarbonate-based block copolymers were self-assembled into nanoparticular carriers and used for a variety of therapeutic applications. − An important motif for functional polycarbonates are six-membered monomers derived from 2,2-bis­(hydroxymethyl)­propionic acid (bis-MPA) with a carboxy side chain substituent which, through esterification, can comprise a wide range of different functional groups. , An important monomer within this group is the hydrophobic 5-methyl-5-benzyloxycarbonyl-1,3-dioxan-2-one (MTC-OBn) that fosters block copolymer self-assembly into micellar nanoparticles and the encapsulation of hydrophobic (aromatic) compounds (supported by π–π stacking). , Alternatively, the development and polymerization of 5-methyl-5-pentafluorophenyloxycarbonyl-1,3-dioxane-2-one (MTC-PFP), a six-membered carbonate monomer with an active ester side chain motif, by Hedrick and co-workers enlarged the polycarbonate toolbox. , However, previously ROP of MTC-PFP was only achieved by using an acidic catalyst (e.g., trifluoromethanesulfonic acid) which, however, provided polymers of only moderate definition . Starting from poly­(MTC-PFP) postpolymerization, modification reactions access various materials by amine conjugation. , Polymeric materials accessed from both monomers were shown to be highly tolerable in vitro and even in vivo, and they can therefore be considered as biocompatible.…”

“…37 Starting from poly(MTC-PFP) postpolymerization, modification reactions access various materials by amine conjugation. 38,39 Polymeric materials accessed from both monomers were shown to be highly tolerable in vitro 33 and even in vivo, 40 and they can therefore be considered as biocompatible. By selecting the functional carbonate monomers MTC-OBn and MTC-PFP for our study, we aimed to investigate the influence of ester side chain motifs on the polymerization process under NHO catalysis.…”

“… 37 Starting from poly(MTC-PFP) postpolymerization, modification reactions access various materials by amine conjugation. 38 , 39 Polymeric materials accessed from both monomers were shown to be highly tolerable in vitro 33 and even in vivo, 40 and they can therefore be considered as biocompatible.…”