Polymeric Micelle Having Upper Critical Solution Temperature For Anti-tumor Targeting Therapy

The sustained drug delivery systems are designed to deliver anti-tumor drugs directly to tumors avoiding a non-specific distribution,thus reducing the side effects and they can improve the pharmacokinetics of the anti-tumor drugs.The DDSs always release the drug in a constant and slow rate resulting in a low drug concentration at the target sites over a long period.This may result in a in-efficient drug concentration inside the cancer cells which induces the development of drug resistance.Also,cancer cells are more sensitive to the short-term,high-concentration of the cytotoxic agents than to low concentration over longer periods.One way to integrate the selective drug delivery and controlled drug release is the stimuli-responsive drug delivery system which may include light-,temperature-,pH-and glutathione-sensitive systems.Among all these stimuli-responsive drug delivery systems,the temperature-sensitive drug delivery system has gained more popularity.Since the temperature change in tumor can not only trigger the drug release from the DDSs leading to the improved chemotherapy efficiency but also result in a hyperthermia therapy.A series of poly(acrylamide-co-acrylonitrile)s(p(AAm-co-AN)s)with variable UCSTs are first synthesized to study the UCST thermal-sensitive behavior:as the AN content in the polymer increases from 10.7 up to 24.4%mol,the UCST of polymers varies from 28 to 56 ?;when the molecular weight of the polymer drops from 51.3 to 14.6 kDa,the UCST of the polymer decreases from 83 to 30 ?.Further,poly(ethylene glycol)s(PEGs)with different chain lengths and graft densities are grafted to p(AAm-co-AN)and the graft of PEG shows no influence on the thermal-sensitive behavior of the p(AAm-co-AN)-g-PEG.However,as the increase of the chain length of PEG from 33 to 167,the critical assemble concentration(CAC)of p(AAm-co-AN)-g-PEG first decreases from 128.8 to 30.2 ?g/ml and then increases dramatically to 420.8 ?g/ml.While,when the PEG graft density is at 4.8,5.0 and 7.2 per polymer(mol/mol),the CAC is at 30.2,71.7 and 365.9 p.g/ml,respectively.In principle,this research provides a universal way to synthesize polymers with different UCST and assembly behavior in water for wide applications.Then a drug delivery system composed of a poly(acrylamide-co-acrylonitrile)-g-polyethylene glycol(poly(AAm-co-AN)-g-PEG)micelle that exhibites an upper critical solution temperature(UCST)of 43 ?.The micelles could load hydrophobic anti-tumor drug,and the fabricated drug delivery system could passively accumulate in tumor tissues and be internalized into tumor cells.The drug was released from the micelles in a sustained manner under physiological conditions.However,the drug could realize a burst and complete release from the micelles in tumor cells assisted by microwave hyperthermia,resulting in a higher free drug concentration,which not only improves the inhibition of tumor cells but also achieves a deep tumor penetration.A dramatically improved anti-tumor efficiency(IC50 decreases from 4.9 to 1.6 ?g/mL,tumor inhibiton rate increases from 55.6%to 92.8%)is observed.These results suggest the UCST drug delivery we fabricated can be an alternative to the thermal-sensitive DDS for an enhanced anti-tumor efficiency.The development of combinational anti-tumor therapy is of great of value.Here,the thermal-sensitive and hepatic tumor cell targeting peptide-A54 modified polymer,A54-poly(ethylene glycol)-g-poly(acrylamide-co-acrylonittile)(A54-PEG-g-p(AAm-co-AN))can self-assembly into a 80 nm-sized micelle which shows a thermal-sensitive behavior with an upper critical solution temperature(UCST)of 43 ?.This self-assemble and targeted A54-PEG-g-p(AAm-co-AN)micelle can co-encapsulate anti-tumor drug doxorubicin(DOX)and magnetic nanoparticles(MNPs)taking advantage of the hydrophobic core of the core-shell micellar structure,when the temperature is lower than 43 ?.A much higher accumulation of the MNPs@A54-PEG-g-p(AAm-co-AN)to the tumor navigated by the A54 targeting peptide is achieved.Due to the thermal-agent effect of the accumulated MNPs in tumor,the mild microwave(8 W)applied afterwards specifically elevates the local tumor temperature by 10 ? in 15 min compared to 6 ? in 20 min without MNPs accumulation.The greater temperature rise resulted from the thermal-agent effect of MNPs doesn't just activate a complete drug release inside tumor cells,but also an augmented hyperthermia.A mild microwave activated,chemo-thermal combinational tumor therapy is thus developed.