Construction And Properties Of Supramolecular Drug Delivery Systems For Cervical Cancer Therapy

Cervical cancer is one of the most common gynecological malignancies,which seriously threatens the physical and mental health of women worldwide.With the development of chemotherapeutic drugs,chemotherapy gradually plays an important role in the treatment of cervical cancer.However,the drug availability of systemic chemotherapy is very low due to the small volume of cervical tissue.Traditional small molecular chemotherapeutic drugs have many limitations in the treatment of cervical cancer because of their short circulation time in the blood,poor selectivity and severe side effects.Therefore,how to improve the drug utilization of cervical cancer chemotherapy and reduce its side effects is still a challenge so far.In recent years,drug delivery systems formed by supramolecular assembly has been widely used in the biomedical field due to its unique and tunable advantages.Supramolecular self-assembly after loading drugs through chemical grafting or physical embedding can effectively improve the solubility and stability of chemotherapeutic drugs.The nanostructures with suitable size through supramolecular assembly can reduce the filtration and removal of kidneys,thereby prolonging the half-life of drugs in the blood.At the same time,it can also passively target tumor cells,thereby reducing systemic toxicity.In this way,the utilization of drugs can be improved and the toxicity of chemotherapy drugs can be reduced to a certain extent.Nevertheless,considering the small size of cervical tissue,the concentration of drugs that reach the tumor site is difficult to meet the needs of cervical cancer treatment.On this basis,it is necessary to construct a drug delivery system with a long retention effect at the tumor sites to further improve the drug utilization.Based on supramolecular assembly,this thesis provides several strategies to prolong the retention time at the tumor sites for efficient and safe chemotherapy in cervical cancer:(1)a nanomedicine to improve the circulation time in the blood;(2)a nanogel to improve the mucosal adhesion ability for local drug delivery;(3)a strategy to prolong the sustained release time of drugs.First,we chose polyethylene glycol(PEG)with a long circulation effect to construct a degradable nanomedicine,which greatly prolonged the residence time of drugs in the blood.In that way,drugs can accumulate at the tumor site to achieve effective treatments.Moreover,its degradability also reduces the side effects of carriers accumulated in the tissue.In addition,compared with systemic chemotherapy,local chemotherapy can avoid the first-pass effect of the liver and provide higher drug utilization,so we used mucoadhesive polyacrylic acid to construct a nanogel for local chemotherapy of cervical cancer,significantly enhancing the efficacy.Finally,since the carriers that the previous two works used are foreign substances with potential side effects,we designed a self-delivery drug hydrogel to minimize the side effects of carriers.When delivered as a nanofibrous hydrogel,this system can realize the long-term sustained release of drugs.As a result,the residence time of drugs at the tumor site is prolonged and the antitumor efficacy is effectively increased.The specific research contents and conclusions of this dissertation are summarized as follows:1.Amphiphilic polyprodrug based on platinum(IV)compound for systemic chemotherapy of cervical cancerPolymeric drug delivery systems have attracted much attention in biotechnology and medicine due to the versatile and tunable chemistry.Among them,PEG with long circulation effect can be used to effectively improve the utilization of drugs for cervical cancer treatment.However,the biosafety issue of PEG is increasing and limits the application in cervical cancer treatments.Long treatment with nonbiodegradable highmolecular-weight PEG causes side effects such as inflammation and hypersensitivity reactions.To solve this,here we proposed a safer,simpler and more efficient polymeric drug delivery system(DDS).The DDS is formed by the polymerization of a hydrophobic platinum(IV)prodrug and low-molecular-weight PEG with p H-responsive acylhydrazine bonds in the polymeric backbone,the amphiphile then self-assembles into nanoparticles in water by hydrophobic effects.It also associates with tunable structure and drug loading efficiency,contributed by the drug-polymer hybrid.This system maintains high-molecular-weight PEG's advantage to improve pharmacokinetics of small molecular drugs for high drug accumulation and long residence time in tumor tissues,effectively improving the therapeutic effect of cervical cancer.At the same time,this system is degraded into lowmolecular-weight PEG under acidic conditions with glutathione after entering the cancer cells,thereby promoting renal excretion and reducing the side effects of PEG.2.A mucoadhesive nanogel with host-guest inclusions for local chemotherapy of cervical cancerCervical cancer treatment is subjected to limited drug access to local lesions and inevitable systemic toxicity,thus it is essential to develop a local drug delivery system to overcome the problems premised on guaranteeing its drug efficacy.With this goal in mind,a host-guest inclusions-based mucoadhesive nanogel for vaginal delivery is proposed.Briefly,the nanogel is constructed with mucoadhesive poly(acrylic acid)as the backbone and multiple inclusions between ?-cyclodextrin and paclitaxel as the crosslinking points,providing good stability.In the presence of esterase,the nanogel is degraded,so as to realize the continuous and controlled release of paclitaxel.The in vitro cell proliferation experiments demonstrate that nanogel exerts high cytotoxicity to cancer cells and effectively reverses paclitaxel resistance in tumor cells.According to the results of mucin adsorption and permeability experiment,this nanogel successfully strengthens mucosal adhesion and promotes the permeation of drugs,enabling the delivery of drugs through the vagina to achieve local treatment,thereby improving the drug availability and reducing side effects.More to the point,as proved in in vivo experiments,the retention time in the vagina is prolonged and the tumor growth is effectively suppressed by nanogel in the orthotopic cervical cancer model.As mentioned above,this novel mucoadhesive nanogel is believed to supply a useful tool of designing drug delivery systems for cervical cancer treatment.3.A raltitrexed hydrogel based on hydrogen bonds and ?-? stacking for the prevention of postoperative recurrence in cervical cancerIn recent years,local drug delivery systems,especially hydrogels,show superior strengths in the prevention of postoperative recurrence in cervical cancer.Despite great advances,clinical translation of these hydrogels has been largely restricted as these drug delivery systems generally require additional chemical modification or carrier molecules,which results in side effects correlative with local inflammation and systemic toxicity.Here,we developed a carrier-free anticancer drug gel that reduced post-surgical tumor recurrence.The macroscopic molecular pure nanofibrous hydrogel is generated via ultrasonication of anticancer drug raltitrexed in aqueous solution,which is facile without involving chemical synthesis.The results of molecular dynamics simulations confirm that raltitrexed selfassembles into a hydrogel through hydrogen bonds and ?-? interactions.Delivered as a hydrogel,raltitrexed can achieve the long-term sustained release of drugs and retain long time at the tumor sites,thus promoting the inhibition of tumor growth in vivo and effectively decreasing tumor recurrence rate.This raltitrexed self-delivery hydrogel has the potential to serve as a powerful auxiliary implement for preventing postoperative local cervical cancer recurrence.