Environment-responsive Nanomaterials Assisted Prostate Cancer Chemohormonal Therapy

Background:Prostate cancer(PCa)is one of the most important maligancies in male urinary system.With the development of the aging population in our country and changes in people's lifestyles,the incidence of PCa is increasing year by year.Clinically,the main treatment methods for PCa are: surgical treatment,radiation therapy,endocrine therapy and chemotherapy.Androgen deprivation therapy(ADT is the first choice for PCa patients.The currently clinical drugs used for ADT are mainly Gonadotropin releasing hormone(GnRH)analogues,which can regulate the production of androgens in hypothalamic-pituitary-testosterone pathway.GnRH can reduce the body's androgen level.which can cause transient increase of androgen and achieve long-term androgen suppression.However,the clinically hormone-sensitive prostate cancer often turns into castration resistant prostate cancer(CRPC)and develops resistance to ADT.When the PCa progresses to CRPC,ADT was unable to obtain effective outcomes for PCa patients.Then,chemotherapy begins to play an important role in the treatment of CRPC.Paclitaxel drugs such as docetaxel(DTX),anthracyclines such as Mitoxantrone(MTO)and Doxorubicin(DOX)are commonly used in clinical chemotherapy for PCa.However,chemotherapy drugs have many side effects,such as myelosuppression,reproductive system toxicity,and damages to organs.In recent years,the combinations of ADT and chemotherapy have been researched clinically.For patients with high-burdern androgen-sensitive PCa,chemotherapy drugs and ADT drugs are combined at the beginning of treatment.The chemohormonal therapy can significantly prolong the survival of PCa patients,and slow the progression and metastasis of PCa.Based on the concept of this chemohormonal therapy,how to more effectively combine the advantages of the two treatment,improve the drug's sustained release,enhance the targeting effects,and reduce the side effects of this treatment will be the key in future research.The biodegradable nanomaterial delivery drug system has been widely studied recently due to its good control of slow release effect,intelligent targeting of tumor tissues,and reduction of side effects of chemotherapy drugs.Therefore,the combination of biodegradable nanomaterials and chemohormonal therapy is the basic idea of this topic.ObjectiveInvestigate the anti-PCa effect by environment-responsive nanocarriers assisted chemohormonal therapy.MethodsFirst,we designed an acid-responsive mPEG-b-PLG nanomicelle(PM),which was loaded with MTO to form a PM/MTO micelle drug and combined with ENT to treat PCa.We performed material characterization(proton nuclear magnetic resonance spectroscopy,FT-IR spectroscopy,particle size distribution,and in vitro release),cytotoxicity experiments,endocytosis,drug biodistribution,and pharmacokinetics of PM/MTO,Then,we performed in vivo anti-PCa experiments by PM/MTO and ENT.Subsequently,we designed a mPEG-PLALa thermo-responsive gel loaded leuprolide(LEU)to replace the ENT.At the same time,we also synthesized reduced-sensitive PEG-Cys-Phe NGs containing Doxorubicin(DOX)and Bicalutamide(BCL).We characterized these two nanogels by material characterization(proton nuclear magnetic resonance spectroscopy,FT-IR spectroscopy,particle size detection,and drug releasing experiment),cell experiments(reduction-responsive cytotoxicity and endocytosis),and animal studies(thermal-sensitive gel degradation test,pharmacokinetics detection,drug biodistribution detection,combined application of temperature-sensitive gel and reduction-sensitive nano-gel in vivo PCa inhibition test).ResultsIn the first part,we combined pH-sensitive nanomicelles with commercial LEU microspheres.These pH-sensitive nanomicelles can increase the sustained release of MTO drugs in the blood and increase the drug concentration in tumor tissues.And significant reduce the side effects.In the second part,we designed and synthesized two kinds of nanogels,PEG-b-ALA thermo-sensitive gel and PEG-Cys-Phe reduction-sensitive NGs.Thermal-sensitive gel can release LEU drugs in vivo,and reduce androgen levels.The reduction-sensitive NGs can effectively carry DOX and BCL drugs,and inhibit the progression of PCa by cellular cytotoxicity and androgen receptor antagonism.This systemetic nanomaterial-assisted chemohormonal therapy can significantly inhibit tumor growth and decrease androgen levels in PCa tumor allografted mice models.Conclusion 1.The environment-responsive polymer nano materials has a significant effect on the improvement of prostate cancer chemohormonal therapy.2.This therapeutic idea of using polymer nanomaterials to combine chemotherapy with hormone therapy will provide more strategies for PCa's treatment of chemohormonal therapy in the future.