A major obstacle for joint drug delivery is to penetrate the dense, negatively charged cartilage matrix. Previous studies have extensively investigated particle approaches to cartilage tissue uptake but have neglected to address potential interactions between the particles and the synovial fluid. Here, a NP panel with different PEGylation were incubated with synovial fluid from either rheumatoid or osteoarthritic patients, or FCS. Compared to non-protein covered NPs, we observed a prominent impact of the protein coronas on NP uptake into cartilage, chondrocytes, and monocytes. Utilizing a quantitative proteomics approach, we identified abundant proteins on all panel members irrespective of the NP modifications. Nonetheless, NP and protein condition-specific differences were also observed between the groups. Our study, therefore, suggests that the protein abundance dictates NP efficacy, emphasizing the importance of considering the biological milieu for translating drug delivery designs to the clinic.
A major obstacle for joint drug delivery is to penetrate the dense, negatively charged cartilage matrix. Previous studies have extensively investigated particle approaches to increase uptake efficiency into tissues but have neglected to address potential interactions with the synovial fluid. Here, we developed a nanoparticle (NP) panel with varying PEGylation and incubated them with synovial fluid from either osteoarthritic (OA) or rheumatoid arthritis (RA) patients, or fetal calf serum (FCS). Compared to nonprotein- covered NPs, the formed protein coronas majorly impacted NP uptake into cartilage tissue and dictated their uptake in chondrocytes and monocytes - a measure of targeting efficiency and clearance potential. Utilizing a quantitative proteomics approach, we identified certain families of proteins on all panel members irrespective of the NP modifications. Nonetheless, NP-, and protein-specific differences were also observed between the groups, and candidate proteins were identified that could account for the observed differences. This study is the first to demonstrate how protein coronas from different biological origins impact NP uptake into cartilage, emphasizing the importance of considering the several aspects of the biological microenvironment for successful translation of drug delivery vehicles into clinics.
A major obstacle for joint drug delivery is the penetration of a dense, negatively charged cartilage matrix. By adapting their size, charge, and surface chemistry to the tissue's native environment, nanoparticles (NP) can improve the transport and efficacy of novel and conventional drugs. Although previous studies have extensively considered the aspects of cartilage tissue uptake, they have neglected to address the potential interactions between the particles and the components of the synovial cavity.By varying the lengths of methoxy polyethylene glycol (mPEG) and consequently the surface chemistry of the nanoparticles, we synthesized a fluorescently labeled, dendrimeric polyamidoamine (PAMAM)based NP panel that was subjected to three different protein conditions including synovial fluid from RA or OA patients, as well as the conventional fetal calf serum (FCS). The effects of formed protein corona on the nanoparticles were evaluated in the cartilage and cellular uptake studies. Compared to non-protein covered NP, we observed a prominent impact of the origin of the protein coronas on the NP uptake into the cartilage, where the FCS derived coronas were taken up easier than the synovial fluid-derived coronas. Furthermore, we identified a candidate nanocarrier, NP5000, to be the most suitable for drug carrier applications in OA. Utilizing a quantitative proteomics approach, we identified similar profiles for RA and OA synovial fluid-derived protein coronas despite the distinction between the diseases. Proteins such as albumin, fibronectin, fibrinogen, various apolipoproteins, and others were present in high abundance on all panel members irrespective of the nanoparticle modifications.Nonetheless, nanoparticle and protein condition-specific differences were also observed between the groups. Our study, therefore, suggests that the biological protein abundance in the synovial fluid dictates the nanoparticle efficacy and uptake into the tissue, emphasizing the importance of biological milieu considerations for the joint drug delivery design and its translation into the clinics.
Background and Aims: An HPLC method with photodiode array detector on a chiral column was proposed for enantioselective determination of chlorpheniramine (CLP) enantiomers in dosage forms. Methods: The enantioselective determination was achieved on amylose tris(3,5-dimethylphenylcarbamate) column, using n-hexane-(propan-2-ol)-diethylamine (97.5:2.5:0.025, v/v/v) mobile phase. The peaks were detected at 258 nm. Diphenhydramine was used as an internal standard (IS). A new sample preparation procedure was developed to avoid the interference of the other ingredients present in the formulations. Results: Limit of quantification of the proposed method was 0.88 and 1.31 µg/mL for S-(+)-CLP and R-(-)-CLP, respectively. Conclusion: The method is linear, sensitive, specific and can be used for the enantioselective assay of CLP enantiomers in pharmaceutical formulations.
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