Construction Of CaP Drug Delivery System Based On The Biomolecules Regulation

Drug administration by oral route is the most ideal choice owing to its simplicity and convenience.Oral medication greatly alleviates patients'pain,especially for chronic therapy(e.g.ulcerative colitis,UC).Macromolecular drugs such as protein,enzyme,nucleic acid show superiority for Cancer,Cardiovascular disease(CVD)and AIDS due to their stronger targeting.Due to the pH variatios in digestive system and enzymes which digest and degrade external compounds,oral delivery of macromolecules remains many challenges.Drug delivery systems(DDS)are defined as an approach by which drugs are specifically delivered to desired tissues,organs,cells and subcellular with minimal side effects,and augment theruapeutic efficacy.Calcium phosphate(Ca P)have been widely applied in various biomedical fields including tissue engineering,bone defect repairation,drug delivery and bioimaging,owing to their excellent biocompatibility and biodegradability.Neverthless,the systhesis of Cap drug carrier with high drug loading capacity and sustained release property remians challenges.Meanwhile,since the Ca P is liable to decomposion in the stomach,the application of Ca P in oral drug delivery system is restricted.To address the above-mentioned issues,in this work,the Ca P carriers were synthesized by biomolecules regulation and applied to the construction of oral colon pH-responsive Ca P macromolecular drug delivery system(Ca P-MDDS).Moreover,the carriers growth mechanism,drug loading and release mechanisms as well as the coating thechnology and cytotoxicity of Ca P-MDDS were systematically and detaily investigated to excavate the theoretical core of the pH-responsive Ca P-MDDS.Primarily,the Yok-shell structured amorphous calcium phosphate(ACP)carrier and hierarchical mesoporous structured hollow hydroxypatie(HAp)carrier were successfully prepared by using the biomolecules containing phosphorous(adenosine 5'-triphosphate diso-dium salt,ATP;creatine phosphate disodium,CP)and biomolecules containing calcium(calcium L-lactate pentahydrate,CL;calcium gluconate monohydrate,CG)as phosporous and calcium source,respectively.The results suggest that Ca P carriers possesss larger specific surface area in comparison with other Ca P carriers.In detail,the specific surface area of Yolk-shell structured carrier(ATP-CG)and the hollow hierarchical mesoporous structured HAp carrier(CP-CL)is 143 m²g^-1 and 113 m²g^-1,respectively.The mechanism suggest that the biomolecules not only providing Ca²⁺and PO₄^3-,but also can act as a regulator to control the nucleation,growth and self-assembly of crystal,which fully exhibits the dual fuction and synergistic regulation of biomolecules in the synthesis of Cap carriers.In addition,the inherent properties of biomolecules and hydrothermal conditions also play a vital role in the carrier synthesis.Furthermore,the HEL was utilized a macromolecular drug model to explory the potential application of Cap carriers in the drug delivery and the corresponding mechanism.The drug loading capacity gradually increases with prolonged time and increasing initial drug concentration.Additionally,the loading capacity is tightly correlated with the medium environment.All carriers show a relatively high drug loading capacity.Detailly,the drug loading capacity of ATP-CG,ATP-CL and CP-CL carriers is 176 mg/g,332 mg/g and 260mg/g,respectively.Moreover,it is find that the adsorption of HEL onto ATP-CG is driven by electrostatic force,and the specific surface area derived from low crystallinity plays a central role in the drug loading capacity.Nevertheless,the adsorption of HEL on CP-CL is driven by electrostatic force and hydrogen bond,and the drug loading capacity is affected by the hierarchical mesopores structure.Additionally,the release of HEL from Ca P carriers with different morphology is dominated by ion exchange.Moreover,the structure and morphology of carrier and release environment have important influence on the HEL release.Overall,the loading and release are regulated by the interaction among carrier,drug,and medium environment.Meanwhile,the difference in structure,morphology,particle size,specific surface area and pore size based on the biomolecules ragulation have significant influence on the drug loading and release.Finally,the pH-responsive Ca P-MDDS(Eu@ATP-CG/HEL)was constructed by integrating the pH sensitive material into the ATP-CG carrier.By optimizing process parameters,the optimal coating conditions are obtained as follows:oil/water ratio=16:1,core/shell ratio=1:10,emulsifying time=3h,rotational speed=1000 rpm,emulsifier concentration=1.5%and polymer concentration=2%.It is notable that the surface potential and thermostability of the Eu@ATP-CG/HEL is dramatically improved after coating.The drug relese was carried out in simulated gastric and colon fluids.In simulated gastric fluids.the accumulative release amount of incorporated HELis less than 8%.However,the Eu@ATP-CG/HEL displays a sustained release behavior in simulated colon fluid and the cumulative amount of released HEL reaches a plateau of 81%after 48 h.The above results reveal that the release is depentent on the pH value.The release dynamics kinetics display that the drug release is controlled by polymer swelling and diffusion.Also,the Eu@ATP-CG/HEL has no appreciable cytotoxicity,which is expected to show great potential for in vivo application.In the work,for the first time,the Ca P-MDDS with the advantage of large specific surface area,high drug loading capacity and the excellent pH-reponsive release performance was successfully constructed,addressing a key problem of the application of macromolecular drugs and Ca P in OCDDS,and provding a novel strategy for preparing the OCDDS.