CRISPR-Cas system permanently deletes any harmful gene-of-interest to combat cancer growth.Chitosan(CS)is a potential cancer therapeutic that mediates via PI3K/Akt/mTOR,MAPK and NF-kβsignaling pathway modulation.CS a...CRISPR-Cas system permanently deletes any harmful gene-of-interest to combat cancer growth.Chitosan(CS)is a potential cancer therapeutic that mediates via PI3K/Akt/mTOR,MAPK and NF-kβsignaling pathway modulation.CS and its covalent derivatives have been designed as nanocarrier of CRISPR-Cas9 alone(plasmid or ribonucleoprotein)or in combination with chemical drug for cancer treatment.The nanocarrier was functionalized with polyethylene glycol(PEG),targeting ligand,cell penetrating ligand and its inherent positive zeta potential to mitigate premature clearance and particulate aggregation,and promote cancer cell/nucleus targeting and permeabilization to enable CRISPR-Cas9 acting on the host DNA.Different physicochemical attributes are required for the CS-based nanocarrier to survive from the administration site,through the systemic circulation-extracellular matrix-mucus-mucosa axis,to the nucleus target.CRISPR-Cas9 delivery is met with heterogeneous uptake by the cancer cells.Choice of excipients such as targeting ligand and PEG may be inappropriate due to lacking overexpressed cancer receptor or availability of excessive metabolizing enzyme and immunoglobulin that defies the survival and action of these excipients rendering nanocarrier fails to reach the target site.Cancer omics analysis should be implied to select excipients which meet the pathophysiological needs,and chitosan nanocarrier with a“transformative physicochemical behavior”is essential to succeed CRISPR-Cas9 delivery.展开更多
Chitosan nanoparticles are exhalation prone and agglomerative to pulmonary inhalation.Blending nanoparticles with lactose microparticles(~5 μm) could mutually reduce their agglomeration through surface adsorption phe...Chitosan nanoparticles are exhalation prone and agglomerative to pulmonary inhalation.Blending nanoparticles with lactose microparticles(~5 μm) could mutually reduce their agglomeration through surface adsorption phenomenon. The chitosan nanoparticles of varying size, size distribution, zeta potential, crystallinity, shape and surface roughness were prepared by spray drying technique as a function of chitosan, surfactant and processing conditions. Lactose-polyethylene glycol 3000(PEG3000) microparticles were similarly prepared. The chitosan nanoparticles, physically blended with fine lactose-PEG3000 microparticles, exhibited a comparable inhalation performance with the commercial dry powder inhaler products(fine particle fraction between 20% and 30%). Cascade impactor analysis indicated that the aerosolization and inhalation performance of chitosan nanoparticles was promoted by their higher zeta potential and circularity, and larger size attributes of which led to reduced inter-nanoparticulate aggregation and favored nanoparticles interacting with lactose-PEG3000 micropaticles that aided their delivery into deep and peripheral lungs.展开更多
Virus-capsid mimicking mucus-permeable nanoparticles are promising oral insulin carriers which surmount intestinal mucus barrier.However,the impact of different viruscapsid mimicking structure remains unexplored.In th...Virus-capsid mimicking mucus-permeable nanoparticles are promising oral insulin carriers which surmount intestinal mucus barrier.However,the impact of different viruscapsid mimicking structure remains unexplored.In this study,utilizing biotin grafted chitosan as the main skeleton,virus-mimicking nanoparticles endowed with biologicshell(streptavidin coverage)and polymeric-shell(hyaluronic acid/alginate coating)were designed with insulin as a model drug by self-assembly processes.It was demonstrated that biologic-shell mimicking nanoparticles exhibited a higher intestinal trans-mucus(>80%,10 min)and transmucosal penetration efficiency(1.6–2.2-fold improvement)than polymeric-shell counterparts.Uptake mechanism studies revealed caveolae-mediated endocytosis was responsible for the absorption of biologic-shell mimicking nanoparticles whereas polymeric-shell mimicking nanoparticles were characterized by clathrin-mediated pathway with anticipated lysosomal insulin digestion.Further,in vivo hypoglycemic study indicated that the improved effect of regulating blood sugar levels was virus-capsid structure dependent out of which biologic-shell mimicking nanoparticles presented the best performance(5.1%).Although the findings of this study are encouraging,much more work is required to meet the standards of clinical translation.Taken together,we highlight the external structural dependence of virus-capsid mimicking nanoparticles on the mucopenetrating and uptake mechanism of enterocytes that in turn affecting their in vivo absorption,which should be pondered when engineering virus-mimicking nanoparticles for oral insulin delivery.展开更多
Nanoscale medicine confers passive and active targeting potential.The development of nanomedicine is however met with processing,handling and administration hurdles.Excessive solid nanoparticle aggregation and caking ...Nanoscale medicine confers passive and active targeting potential.The development of nanomedicine is however met with processing,handling and administration hurdles.Excessive solid nanoparticle aggregation and caking result in lowproduct yield,poor particle flowability and inefficient drug administration.These are overcome by converting the nanoparticles into a microscale dosage form via agglomeration or compaction techniques.Agglomeration and compaction nonetheless predispose the nanoparticles to risks of losing their nanogeometry,surface composition or chemistry being altered and negating biological performance.This study reviews risk factors faced during agglomeration and compaction that could result in these changes to nanoparticles.The potential risk factors pertain to materials choice in nanoparticle and microscale dosage form development,and their interplay effects with process temperature,physical forces and environmental stresses.To render the physicochemical and biological behaviour of the nanoparticles unaffected by agglomeration or compaction,modes to modulate the interplay effects of material and formulation with processing and environment variables are discussed.展开更多
Transdermal drug delivery is impeded by the natural barrier of epidermis known as stratum corneum.This limits the route to transport of drugs with a log octanol–water partition coefficient of 1 to 3,molecular weight ...Transdermal drug delivery is impeded by the natural barrier of epidermis known as stratum corneum.This limits the route to transport of drugs with a log octanol–water partition coefficient of 1 to 3,molecular weight of less than 500 Da and melting point of less than 200°C.Nanotechnology has received a widespread investigation as the nanocarriers are able to fluidize the stratum corneum as a function of size,shape,surface charges,and hydrophilicity–hydrophobicity balance,while delivering drugs across the skin barrier.展开更多
基金MOHE (FRGS/1/2023/STG05/UITM/01/3) for funding support
文摘CRISPR-Cas system permanently deletes any harmful gene-of-interest to combat cancer growth.Chitosan(CS)is a potential cancer therapeutic that mediates via PI3K/Akt/mTOR,MAPK and NF-kβsignaling pathway modulation.CS and its covalent derivatives have been designed as nanocarrier of CRISPR-Cas9 alone(plasmid or ribonucleoprotein)or in combination with chemical drug for cancer treatment.The nanocarrier was functionalized with polyethylene glycol(PEG),targeting ligand,cell penetrating ligand and its inherent positive zeta potential to mitigate premature clearance and particulate aggregation,and promote cancer cell/nucleus targeting and permeabilization to enable CRISPR-Cas9 acting on the host DNA.Different physicochemical attributes are required for the CS-based nanocarrier to survive from the administration site,through the systemic circulation-extracellular matrix-mucus-mucosa axis,to the nucleus target.CRISPR-Cas9 delivery is met with heterogeneous uptake by the cancer cells.Choice of excipients such as targeting ligand and PEG may be inappropriate due to lacking overexpressed cancer receptor or availability of excessive metabolizing enzyme and immunoglobulin that defies the survival and action of these excipients rendering nanocarrier fails to reach the target site.Cancer omics analysis should be implied to select excipients which meet the pathophysiological needs,and chitosan nanocarrier with a“transformative physicochemical behavior”is essential to succeed CRISPR-Cas9 delivery.
基金Universiti Teknologi MARAMinistry of Higher Education of Malaysia for fund(0141903),LRGS-NanoMITe RU029-2014 and facility support。
文摘Chitosan nanoparticles are exhalation prone and agglomerative to pulmonary inhalation.Blending nanoparticles with lactose microparticles(~5 μm) could mutually reduce their agglomeration through surface adsorption phenomenon. The chitosan nanoparticles of varying size, size distribution, zeta potential, crystallinity, shape and surface roughness were prepared by spray drying technique as a function of chitosan, surfactant and processing conditions. Lactose-polyethylene glycol 3000(PEG3000) microparticles were similarly prepared. The chitosan nanoparticles, physically blended with fine lactose-PEG3000 microparticles, exhibited a comparable inhalation performance with the commercial dry powder inhaler products(fine particle fraction between 20% and 30%). Cascade impactor analysis indicated that the aerosolization and inhalation performance of chitosan nanoparticles was promoted by their higher zeta potential and circularity, and larger size attributes of which led to reduced inter-nanoparticulate aggregation and favored nanoparticles interacting with lactose-PEG3000 micropaticles that aided their delivery into deep and peripheral lungs.
基金financial support from National Natural Science Foundation of China(grant no.31870987)
文摘Virus-capsid mimicking mucus-permeable nanoparticles are promising oral insulin carriers which surmount intestinal mucus barrier.However,the impact of different viruscapsid mimicking structure remains unexplored.In this study,utilizing biotin grafted chitosan as the main skeleton,virus-mimicking nanoparticles endowed with biologicshell(streptavidin coverage)and polymeric-shell(hyaluronic acid/alginate coating)were designed with insulin as a model drug by self-assembly processes.It was demonstrated that biologic-shell mimicking nanoparticles exhibited a higher intestinal trans-mucus(>80%,10 min)and transmucosal penetration efficiency(1.6–2.2-fold improvement)than polymeric-shell counterparts.Uptake mechanism studies revealed caveolae-mediated endocytosis was responsible for the absorption of biologic-shell mimicking nanoparticles whereas polymeric-shell mimicking nanoparticles were characterized by clathrin-mediated pathway with anticipated lysosomal insulin digestion.Further,in vivo hypoglycemic study indicated that the improved effect of regulating blood sugar levels was virus-capsid structure dependent out of which biologic-shell mimicking nanoparticles presented the best performance(5.1%).Although the findings of this study are encouraging,much more work is required to meet the standards of clinical translation.Taken together,we highlight the external structural dependence of virus-capsid mimicking nanoparticles on the mucopenetrating and uptake mechanism of enterocytes that in turn affecting their in vivo absorption,which should be pondered when engineering virus-mimicking nanoparticles for oral insulin delivery.
文摘Nanoscale medicine confers passive and active targeting potential.The development of nanomedicine is however met with processing,handling and administration hurdles.Excessive solid nanoparticle aggregation and caking result in lowproduct yield,poor particle flowability and inefficient drug administration.These are overcome by converting the nanoparticles into a microscale dosage form via agglomeration or compaction techniques.Agglomeration and compaction nonetheless predispose the nanoparticles to risks of losing their nanogeometry,surface composition or chemistry being altered and negating biological performance.This study reviews risk factors faced during agglomeration and compaction that could result in these changes to nanoparticles.The potential risk factors pertain to materials choice in nanoparticle and microscale dosage form development,and their interplay effects with process temperature,physical forces and environmental stresses.To render the physicochemical and biological behaviour of the nanoparticles unaffected by agglomeration or compaction,modes to modulate the interplay effects of material and formulation with processing and environment variables are discussed.
文摘Transdermal drug delivery is impeded by the natural barrier of epidermis known as stratum corneum.This limits the route to transport of drugs with a log octanol–water partition coefficient of 1 to 3,molecular weight of less than 500 Da and melting point of less than 200°C.Nanotechnology has received a widespread investigation as the nanocarriers are able to fluidize the stratum corneum as a function of size,shape,surface charges,and hydrophilicity–hydrophobicity balance,while delivering drugs across the skin barrier.
