Preparation And Anti-tumor Study Of Gelatin Composite Nanospheres With Tumor Microenvironmental Response

Cures of Cancer is a significant medical and pharmaceutical issue of greatly challenge.The medical workers or scientists have developed a lot of important therapeutic strategies of cancer treatment based on physics,chemistry or biology.Photothermal therapy,as a new phycically mini-invasive surgical surgery,has gained widespread attention recently.Although this therapy can be widely used in the future,it is an urgent problem to manufacture the material with high efficiency of light-to-heat conversion(LTHC)and favorable biocompatibility.Chemotherapy is one of the three classical weapons of killing tumors but has many defects such as evident toxicity,multidrug resistance(MDR)caused by excess chemotherapeutic drug and recurrence of tumor after treatment,which obviously pose a challenge to the development of the chemotherapy drug.Whereas the nano-drug carriers make the design of oncology drugs system controllable,flexible and high efficient to some degree and are able to implement targeting tumor,intelligently controlling the release of drug and less toxicity.The nano-drugs is going to the clinic step by step,but it possesses some drawbacks for example the toxcity of the nano-drug carrier itself,low anticancer effects and being difficult to be prepared on a large scale.The latest studies indicate preferable curative effect can be gained and drug resistance of tumor is capable of being prevented or delayed by combining multiple anti-cancer therapies together.In this subject,the complex and functional nanoparticles is prepared by packaging the chemotherapeutic and thermotherapeutic materials with gelatin to realize optimized treatment of tumor.In detail,on the thermotherapy,by modifying with polyacrylic acid(PAA)we compound the W18O49 nano-particle(WO-PAA)and find with PAA modification W18O49 acquires remarkably enhanced hydrophilicity,higher loading capability(580μg/mg)and outstanding LTHC coefficient(radiating for ten minutes with 1064nm near-infrared laser causes a temperature rise of about 30 °C).On the chemotherapy,we select a broad-spectrum anti-cancer drug doxorubicin(DOX),and observe that the amino of DOX can bind with the carboxyl of WO-PAA,rendering the loading capability of DOX increasing from 1.2μg/mg to 8.8 μg/mg.At last,adopting gelatin as carrier for the complex materials is able to advance the clinical value of this nano-particle.Moreover,in vitro cells experiment exhibits that the gelatin coat can suppress the toxicity of dissociative DOX and carry out slow release of drugs.Importantly,we have developed a new man-made approach to produce the gelatin coat which improves the conventional solvent-removal method,abandons the classical magnetic-stirring process and so the procedure of synthesis is simplified.Addition of Tween 20 upgrades the production,heightens the stability of the chemical reaction system and inhibits occurrence of flocculation;the solubility of gelatin microspheres can be substantially enhanced in water and the turnover of drug prolonged in vivo with PEG5000.This new technique is named with "the fast-solvent-removal method" by which the prepared gelatin nanoparticles take on uniform size and fine roundness.Finally,we explore the anti-cancer effect of the complex drug particle Gelatin-WO-PAA-DOX(GWD).Our results indicate gelatin can be hydrolyzed by matrix metalloproteinases(MMPs);GWD keeps stable in normal tissues and releases the encysted drug only when encountered with MMPs.In addition,is easily oxidized for which its efficiency of photothermal conversion can be repressed,whereas the gelatin coat can inhibit the contact of W18O49 with the oxidizing atmosphere so as to lengthen the time of effectively acting.Moreover,GWD is taken out to be used in cells photo-thermal experiments after stored for half a month,and the results of cellular life-death fluorescent staining reveal that the GWD still has a better thermotherapeutic effect.This project unites thermotherapy and chemotherapy and kills cancer at the fixed point to provide a new perspective for the design of anti-tumor drugs.A new synthetic approach is developed that we parcel drugs with gelatin to turn out nanoparticles and this way is easy to operate and high repeatability.Ultimately,the prepared complex nano-drugs can kill many types of cancer cells.