Monovalent antibody-conjugated lipid-polymer nanohybrids for active targeting to desmoglein 3 of keratinocytes to attenuate psoriasiform inflammation

Abstract

To improve the treatment of psoriasiform inflammation, we developed actively targeted nanocarriers loaded with the phosphodiesterase 4 inhibitor AN2728. Methods: Phospholipid-poly(lactic- co -glycolic acid) nanohybrids were prepared and conjugated with monovalent anti-desmoglein 3 antibody to bind keratinocytes. Results: The actively targeted nanohybrids were 229 nm in mean size with a nearly neutral surface charge. Flow cytometry and confocal microscopy showed a 9-fold increase in keratinocyte uptake of targeted nanohybrids relative to non-targeted nanoparticles. The nanoparticles localized mainly in lysosomes after internalization. AN2728-loaded antibody-conjugated nanocarriers inhibited cytokine/chemokine overexpression in activated keratinocytes without affecting cell viability. The targeted nanohybrids also suppressed neutrophil migration by reducing CXCL1 and CXCL2 release from keratinocytes. Following subcutaneous administration in mice, the nanohybrids distributed to the epidermis and hair follicles. In a psoriasis-like skin mouse model, the actively targeted nanoparticles were superior to free drug and non-targeted nanoparticles in mitigating skin inflammation. Intervention with the targeted nanosystem reduced the epidermal thickness of the psoriasiform lesion from 191 to 42 µm, decreased the Psoriasis Area Severity Index by 74%, restored barrier function, and returned chemokine levels to baseline. Conclusions: Our developed nanosystem was safe and demonstrated efficient targeting properties for the treatment of cutaneous inflammation.

Targeting anti-inflammatory immunonanocarriers to human and murine neutrophils via the Ly6 antigen for psoriasiform dermatitis alleviation

“…28 We previously demonstrated the successful targeting of keratinocytes by monovalent antibody-conjugated nanoparticles. 29 Our examination of the nanoparticle size, FTIR, and protein level confirmed the antibody fragment conjugation with the nanocarriers. Unfortunately, the entrapment percentage of RFL was reduced by this linkage.…”

“…11,46 Moreover, nanoparticles containing a greater surface charge elevate the clearance by the immune cells. 29 The greater RES accumulation of the unfunctionalized nanoparticles compared to the functionalized nanoparticles in this study could be due to the lower polarity and higher negative zeta potential of the non-targeted nanosystem. From this perspective, the unfunctionalized nanocarriers had incomplete therapeutic potential for treating psoriasis.…”

Targeting and functional effects of biomaterials-based nanoagents for acute pancreatitis treatment

“…To overcome these limitations, biomaterials-based agents with active targeting properties should be considered; specific ligands or non-serum based-biomarkers can be applied to increase the treatment efficacy of AP. The nanoparticles modified with specific peptides can recognize and bind with corresponding receptors expressed in certain cells in the inflammatory sites, resulting in enhanced drug accumulation ( Da Silva-Candal et al, 2019 ; Lin et al, 2021 ). Hung et al (2021) selected five pancreatitis-specific peptides using a computational-guided in vivo phage display approach, demonstrating selectivity to different pancreatic cells.…”

The Antibiofilm Nanosystems for Improved Infection Inhibition of Microbes in Skin

“…It is possible to mix lipids and polymers to fabricate lipid-polymer nanohybrids. Lipid-polymer nanoparticles consisting of biocompatible lipids and polymers can act as ideal drug delivery carriers by combining the advantages of lipid-based and polymer-based nanosystems [112]. It has been reported that the use of lipid-polymer nanohybrids carrying linezolid can improve the treatment of MRSA infections inside bone cells and biofilms [113].…”