Lung most cancers is a serious world well being concern, rating among the many most prevalent and deadliest types of most cancers worldwide [1]. The arrival of immunotherapy, which makes use of the sufferers’ personal immune system to determine and remove most cancers cells, has opened up new prospects for the therapy of lung most cancers [2]. Among the many varied varieties of immunotherapies, immune checkpoint inhibitors (ICIs) corresponding to pembrolizumab, nivolumab, and atezolizumab have gained approval for treating lung most cancers and have proven enhanced outcomes in particular affected person teams [3], [4], [5]. ICIs are antibodies that work by obstructing the interplay between immune checkpoint proteins, corresponding to programmed cell demise protein 1 (PD-1) on T cells and programmed death-ligand 1 (PD-L1) on most cancers cells [6], [7]. This disruption unleashes the immune system’s potential to acknowledge and assault most cancers cells. Presently, ICIs are administered systemically and distributed all through the physique. Nonetheless, whereas these immune checkpoint proteins are upregulated in most cancers cells, they’re additionally expressed in regular cells [8]. This lack of tumor specificity necessitates excessive doses of ICIs to realize efficacy, which may result in immune-related antagonistic occasions (IRAEs) [9]. Due to this fact, the focused supply of ICIs to lung tumors is a promising technique to enhance efficacy and scale back the negative effects.
Pulmonary administration permits the direct supply of therapeutics into the lungs and is taken into account essentially the most easy method for lung-targeted supply [10], [11]. Pulmonary administration provides a number of benefits over intravenous injections, together with elevated drug concentrations within the lungs, decreased systemic negative effects, and improved affected person compliance [12], [13]. Nonetheless, the dense and viscoelastic nature of the airway mucus layer, mixed with its negatively charged parts corresponding to glycoproteins and surfactants, creates a bodily and electrostatic barrier that restricts the penetration of antibodies to the lungs [14], [15]. Moreover, free ICIs are topic to degradation or aggregation within the mucus, which additional hampers their therapeutic efficacy [16].
To beat these challenges, varied nanoparticle-based supply autos had been developed to facilitate the transport of biologics throughout the mucus layer [17], [18]. For instance, chitosan-based nanoparticles that carry optimistic fees might adhere to the mucus layer and extend the retention time of encapsulated antibodies [19], [20]. Nonetheless, these mucus-adhesion particles nonetheless face sure obstacles, together with the instability of antibodies throughout the mucus and the potential danger of extreme accumulation [21], [22]. Then again, nanoparticles coated with polyethylene glycol (PEG) have demonstrated the power to passively diffuse throughout the mucus layer [23], [24], [25]. That is attributed to the hydrophilicity, impartial cost, and non-fouling properties of PEG. These mucus-penetrating nanoparticles sometimes have hydrophobic or cationic polymers as their cores, which sadly leads to restricted encapsulation of antibodies and potential cytotoxicity [26], [27]. Due to this fact, PEG nanogels composed totally of crosslinked PEG are promising candidates for the pulmonary supply of ICIs. PEG nanogels supply a number of advantageous properties, together with excessive loading capability, hydrophilicity, stability, and biocompatibility [28], [29], [30], [31]. Moreover, they are often simply modified with stimuli-responsive moieties corresponding to disulfide bonds or acetals, enabling managed launch of ICIs on the goal web site [32], [33]. We hypothesize that PEG nanogel might effectively penetrate the mucus barrier attributable to its excessive water content material and low protein adsorptions. Earlier research have reported the synthesis of PEG nanogels utilizing copper catalyzed click on chemistry, photocatalyzed thiol-end reactions, or radical polymerization of acrylate-modified PEG [34], [35], [36], [37]. Nonetheless, the usage of steel catalysts, thiols, and radicals might negatively have an effect on the organic exercise of antibodies [38]. Due to this fact, cautious consideration is required when deciding on the suitable synthesis methodology. Furthermore, the appliance of nanogels composed totally of covalently crosslinked PEG for the pulmonary supply of ICIs has not but been completely explored.
Herein, we developed a responsive PEG nanogel that may successfully encapsulate and transport anti-PD-1 antibody (aPD1) throughout the mucus barrier (Fig. 1). The synthesis of the PEG nanogel and the in situ encapsulation of aPD1 had been achieved in a single step by crosslinking 4-arm PEG by copper-free click on chemistry. The PEG nanogel consists totally of biocompatible PEG and doesn’t require coupling reagents or catalysts throughout synthesis. We demonstrated that PEG nanogel maintained its colloidal stability throughout nebulization and considerably improved the buildup of aPD1 within the lungs after pulmonary supply. Upon getting into the tumors, the PEG nanogel underwent dissolution triggered by the overexpressed matrix metalloproteinase-9 (MMP-9) within the tumor microenvironment, resulting in the discharge of encapsulated aPD1. This improved mucus-penetrating potential of the PEG nanogel leads to a outstanding enhancement of therapeutic efficacy in a metastatic lung most cancers mouse mannequin. These findings spotlight the potential of the PEG nanogel as a promising platform for the efficient, protected, and handy supply of ICIs for the therapy of lung metastasis.