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    • br Problem of cellular retention not only affects the

    2021-11-29


    Problem of cellular retention not only affects the cellular activity of the nanoparticles and nanocomplexes but can also have ramifications in their in vivo applications. While inorganic nanoparticles are being developed extensively for detection as well as treatment of different human diseases, including new advances in cell specific targeting, there are several issues that plague efficient development. One of the problems is the balance between extended circulation stability and the toxicity due to non-clearance. Circulation in the bloodstream results in formation of protein corona on the nanoparticle surfaces through interaction with the opsonin protein. It has been shown that large amounts of nanoparticles are cleared by the mononuclear phagocytic system (MPS), e.g. the Kupffer LDC000067 of the liver and the red pulp macrophages of the spleen where these nanoparticles are processed and degraded and eventually cleared. This results in limited amount of nanoparticles being available to reach the target sites. On the other hand, depending upon the nature of the nanoparticles, they can be taken up by the MPS cells and can be trapped in the lysosomes resulting in chronic toxicity via inflammation or immunological response. Therefore it is important to study the retention and excretion of nanoparticles from macrophages to understand the possible effects of these nanoparticles on systemic clearance and toxicity. Many of the studies discussed earlier in this text therefore have been on this cell type. The changes in the nature of the nanoparticles while they are in systemic circulation can alter their cellular retention profiles in different ways. This makes it difficult to extrapolate parameters standardised in cell culture studies to in vivo conditions. For example, the nature of the protein corona formed around a nanoparticle when treated with serum in vitro vis-a-vis that formed in vivo can be quite different [85]. Such situations create obvious complications in experimental design. One needs to therefore take into account retention at the target-site as well for the subsequent cellular processing to take place. Poor retention and low bio-availability at the tumour site has been reported as the main limiting factor of nano-structured biotherapeutics in multiple in vivo studies. Dual-functional gold nanoparticles (comprising two functional particles: 2-cyano-6-amino-benzothiazole and R8-RGD-comodified AuNPs (AuNP-CABT-R) and Ala-Ala-Asn-Cys-Asp (AK) and R8-RGD-comodified AuNPs (AuNP-AK-R)) were synthesised for successfully improving site specific retention in Glioblastoma(GBM) [86]. There have been studies on the role of tumour micro-environment and its effect on nanoparticle aggregation in regards to improving retention of drug bearing nanoparticles at tumour site. Controlled aggregation of nanoparticles at the tumour site was emphasised as an important strategy to improve retention [87]. Legumain induced aggregation of gold nanoparticles (AuNPs) was successfully explored as a strategy to improve retention of these particles in glioma cells and brain tumors. Gold nanoparticles were surface modified with Ala-Ala-Asn-Cys-Lys (AuNPs-AK) and 2-cyano-6-aminobenzothiazole AuNPs-CABT) respectively, before treatment. Legumain hydrolyzed peptide modified AuNPs underwent cycloaddition on contiguous cyano group present on AuNPs-AK, resulting into aggregation [55]. Peptide-modified novel multifunctional drug delivery systems have been used to overcome blood-brain tumour barrier, enhance homing to glioma cells and allow efficient binding to fibrin-flibronectin complexes expressed in the tumour microenvironment in order to effectively retain nanoparticles in case of GBM [88]. Similarly, a combination of human serum albumin with ellagic acid and thermoresponsive liposomes have been able to improve blood retention, delivery at desired site and effective action through tumour accumulation and matrix penetration in case of PDA. Thus, alterations and smart multicomponent designs can ensure that the carriers effectively overcome in vivo retention problems and can be effective in the cellular context [89].