Mesoporous Zirconium Phosphonates As Drug Carriers For Oral Colon-specific Delivery Of Biopharmaceutics

Mesoporous phosphonates possess not only typical features of mesoporous materials, butalso special functionalities, e.g. biocompatibility, pH-sensitivity etc., derived from functionalphosphonic acids. This endows mesoporous phosphonates with characters of drug carriers fororal colon-specific drug delivery system. In the thesis, the research focus on the applicationof functioanal mesoporous phosphonates as drug carriers in oral colon-specific delivery ofbiopharmaceutics, such as peptide and protein drugs as well as nucleic acid drugs.The pH-sensitive mesoporous zirconium diphosphonates as carriers in oralcolon-specific delivery of insulin, a model of peptide and protein drugs, was investigated indetails to provide a new method for oral colon-specific delivery of peptide and protein drugs.Based on the investigation of mechanism of insulin adsorbed onto and released frompH-sensitive mesoporous zirconium diphosphonate as drug carrier using ζ potential, a seriesof time-and pH-dependent oral colon-specific delivery systems have been developed bydip-coating lag-time films on tablet, which was formed through pressing core tablet of insulinloaded pH-sensitive mesoporous zirconium diphosphonate inserted into two thin picecs ofL-threonine containing absorption promoter of insulin, sodium cholate. The lag-time ofinsulin release can be controlled within7h through adjusting coating times, which makeinsulin could be released23.2%of gross released amount of insulin within7h (stomach:3h;small intestine:4h), and could be released76.8%of gross released amount of insulin in asustained-release method within the following47h (colon) in the simulated gastrointestinalfluid. Insulin can still retain it’s active conformation during the loading, pressing into tablet,coating lag-time films and release as evidenced by the results of FT-IR and CD. The time-and pH-dependent oral colon-specific drug delivery system based on pH-sensitivemesoporous zirconium diphosphonate ensures that orally administered insulin, as well asabsorption promoter, can be released specifically at colon. Furthermore, such system can bewidely used for oral colon-specific delivery of orther therapeutic peptides and proteins. Thus,pH-sensitive mesoporous zirconium diphosphonates as a novel drug carriers might bepotential application in oral colon-specific delivery of peptide and protein drugs.The bifunctional mesoporous zirconium phosphonates as carriers in oral colon-specificdelivery of salmon sperm DNA, a model of nucleic acid drugs, was systematicly studied topresent a novel idea for oral colon-specific delivery of nucleic acid drugs for therapy of colorectal cancer in the future. Comparing to the adsorption of salmon sperm DNA intopH-sensitive mesorporous zirconium diphophonate, a conclusion can be drawed that thespecial pore diameter of about5nm determines the adsorption behaviors of bifunctionalmesoporous zirconium phosphonates. Based on the pH-sensitivity of bifunctional mesoporouszirconium phosphonates with the addition of coating lag-time films, a series of time-andpH-controlled oral colon-specific delivery of nucleic acid to colon have been established.Through adjusting the coating times, the lag-time of7h can be controlled. Subsequently, theamount of released salmon sperm DNA can reach75%of gross released amount of salmonsperm DNA to realize that orally administered salmon sperm DNA can be releasedspecifically at colon. The CD spectra confirmed that the released salmon sperm DNA canwell retain its B-form conformation, indicating the effective protection of salmon sperm DNAmounted into nanometer mesopores (about5nm) of bifunctional mesoporous zirconiumphosphonates. Based on the functionalizability of of bifunctional mesoporous zirconiumphosphonates, a cell penetrating peptide, octaarginine (R8), can be coupled with salmonsperm DNA-loaded bifunctional mesoporous zirconium phosphonates through couplingmethod to enhance penetration capability through cytomembrane. The qualitative andquantitative analysis of R8linked with salmon sperm DNA-loaded bifunctional mesoporouszirconium phosphonates was conducted by fluorescence spetra. The result shows15.8g R8can be coupled with1mg salmon sperm DNA-loaded bifunctional mesoporous zirconiumphosphonates, which make bifunctional mesoporous zirconium phosphonates as carrier arefeasible in cell transfection and become a potential gene carriers.In a word, functional mesoporous zirconium phosphonates as drug carriers exhibitunique advantages in oral colon-specific delivery of peptide and protein drugs as well asnucleic acid drugs. The drug loading mechanism of these carriers and the method ofdeveloping time-and pH-controlled oral colon-specific drug delivery system are universal,indicating functional mesoporous zirconium phosphonates have potential applications in thefield of biopharmaceutics.