Kenyelletso ea lithethefatsi tsa mRNA
Messenger RNA (mRNA) ke tatellano ea li-nucleotide tse kenyelletsang protheine, 'me ho cytoplasm e khona ho sebelisa organelles ho hlahisa protheine e kentsoeng. Lithethefatsi tsa mRNA li fetotsoe ka lik'hemik'hale ho latela khetho ea lipheo kapa li-antigens 'me li kenngoa cytoplasm ka mokhoa o itseng oa ho fana (mohlala, LNP), moo li hlahisang protheine e itseng (e lumellanang le morero oa moralo oa phetoho ea lik'hemik'hale),' me phello e etsahala ka intracellularly kapa ka mor'a ho kenngoa ka har'a karolo ea extracellular (Setšoantšo sa 1). Ho ea ka maikutlo a hore mRNA e ka fetoleloa ho protheine leha e le efe, 'me lithethefatsi leha e le life tse sebelisang liprotheine e le phekolo li ka nkeloa sebaka ke liphekolo tsa mRNA.
Setšoantšo sa 1. Likarolo tsa sebopeho sa lithethefatsi tsa mRNA le mokhoa oo li sebelisang matla a tsona ka ona.
Mekhoa ea lithuto tsa pharmacokinetic ea lithethefatsi tsa mRAN
Mabapi le thuto ea pele ea pharmacokinetic ea lithethefatsi tsa mRNA, e ka aroloa likarolo tse tharo tsa lithuto tse shebaneng le liente tsa mRNA, phekolo ea mRNA le li-excipients tsa meriana tse ncha. Ho latela ente-tataiso ea tekheniki e amanang le eona e fanoeng ke FDA le NMPA, hangata liente ha li hloke lithuto tsa ka mehla tsa pharmacokinetic, empa liente tse ling tse khethehileng li lokela ho ithutoa bakeng sa phepelo ea lintho tse phelang. Liente tsa mRNA ke tsa liente tse khethehileng, tse hlokang lithuto tsa biodistribution. 'Me thuto ea pharmacokinetic ea meriana ea phekolo ea mRNA e ka thusa ho utloisisa bongata-kamano ea phello ea lithethefatsi. Bakeng sa li-excipients tse ncha tsa meriana, tse kang cationic lipids kapa lisebelisoa tse ling tsa tsamaiso ea LNP ke li-excipients tse ncha tsa meriana, in vitro, in vivo le lithuto tsa ho sebelisana le lithethefatsi li hlokoa ho latela "Guidelines for Non-clinical Safety Evaluation of New Pharmaceutical Excipients".Boithuto ba in vitro bo na le botsitso ba metabolic le boits'oaro ba metabolite ea litsamaiso tse fapaneng, 'me boithuto ba in vivo bo na le lithuto tsa ho monya, kabo, metabolism le ho tsoa liphoofolong ho fumana ts'ebetso ea ADME ea motlatsi. Litšebelisano tsa lithethefatsi-lithethefatsi tsa lisebelisoa tse ncha lia hlahlojoa ho latela boemo ba kotsi.
Lihlahisoa tse Amanang le IPHASE
Messenger RNA (mRNA) ke tatellano ea li-nucleotide tse kenyelletsang protheine, 'me ho cytoplasm e khona ho sebelisa organelles ho hlahisa protheine e kentsoeng. Lithethefatsi tsa mRNA li fetotsoe ka lik'hemik'hale ho latela khetho ea lipheo kapa li-antigens 'me li kenngoa cytoplasm ka mokhoa o itseng oa ho fana (mohlala, LNP), moo li hlahisang protheine e itseng (e lumellanang le morero oa moralo oa phetoho ea lik'hemik'hale),' me phello e etsahala ka intracellularly kapa ka mor'a ho kenngoa ka har'a karolo ea extracellular (Setšoantšo sa 1). Ho ea ka maikutlo a hore mRNA e ka fetoleloa ho protheine leha e le efe, 'me lithethefatsi leha e le life tse sebelisang liprotheine e le phekolo li ka nkeloa sebaka ke liphekolo tsa mRNA.
Setšoantšo sa 1. Likarolo tsa sebopeho sa lithethefatsi tsa mRNA le mokhoa oo li sebelisang matla a tsona ka ona.
Mekhoa ea lithuto tsa pharmacokinetic ea lithethefatsi tsa mRAN
Mabapi le thuto ea pele ea pharmacokinetic ea lithethefatsi tsa mRNA, e ka aroloa likarolo tse tharo tsa lithuto tse shebaneng le liente tsa mRNA, phekolo ea mRNA le li-excipients tsa meriana tse ncha. Ho latela ente-tataiso ea tekheniki e amanang le eona e fanoeng ke FDA le NMPA, hangata liente ha li hloke lithuto tsa ka mehla tsa pharmacokinetic, empa liente tse ling tse khethehileng li lokela ho ithutoa bakeng sa phepelo ea lintho tse phelang. Liente tsa mRNA ke tsa liente tse khethehileng, tse hlokang lithuto tsa biodistribution. 'Me thuto ea pharmacokinetic ea meriana ea phekolo ea mRNA e ka thusa ho utloisisa bongata-kamano ea phello ea lithethefatsi. Bakeng sa li-excipients tse ncha tsa meriana, tse kang cationic lipids kapa lisebelisoa tse ling tsa tsamaiso ea LNP ke li-excipients tse ncha tsa meriana, in vitro, in vivo le lithuto tsa ho sebelisana le lithethefatsi li hlokoa ho latela "Guidelines for Non-clinical Safety Evaluation of New Pharmaceutical Excipients".Boithuto ba in vitro bo na le botsitso ba metabolic le boits'oaro ba metabolite ea litsamaiso tse fapaneng, 'me boithuto ba in vivo bo na le lithuto tsa ho monya, kabo, metabolism le ho tsoa liphoofolong ho fumana ts'ebetso ea ADME ea motlatsi. Litšebelisano tsa lithethefatsi-lithethefatsi tsa lisebelisoa tse ncha lia hlahlojoa ho latela boemo ba kotsi.
Lihlahisoa tse Amanang le IPHASE
| Lihlopha | Lihlopha |
| Karolo ea subcellular | sebete lysosome |
| Homogenate ea sebete e nang le asiti | |
| Sebete/ mala/diphio/matshwafo S9 | |
| Likokoana-hloko tsa sebete / mala / liphio / matšoafo | |
| Sebete / mala / renal / matšoafo cytoplasmic fluid | |
| Hepatocyte ea mantlha | Ho emisoa ha Hepatocyte |
| Likokoana-hloko tsa Hepatocyte | |
| Plasma e ikhethang | Botsitso ba plasma |
| Ho tlama protheine ea plasma | |
| Madi kaofela | Motho/Monkey/Canine/Rat/Muuse/Rabbit/Kolobe Madi A Feletseng |
Nako ea poso: 2024-08-25 19:54:01