Design And Synergistic Antitumor Study Of Small Molecule Cisplatin Nanoprecursors

Chemotherapy as a systemic treatment has been widely used in the treatment of clinical tumors,however,many disadvantages also limit it achieve better therapeutic effect.Nanocarrier drug delivery systems(NDDSs)are considered as a promising strategy due to their stability,targeting,stimulus responsiveness and synergistic tumor suppression.However,the toxicity and immunogenicity arising from carrier heterogeneity and the complexity of the design and synthesis process have greatly reduced their clinical application.Carrier-free nanodrug delivery systems are formed by the self-assembly of drugs under the action of intermolecular forces.It retains many advantages of NDDSs,but discards the carriers,simplifies the drug molecular structure,has higher drug loading capacity,and is simpler to design and prepare.Currently,the most widely studied carrier-free nanomedicine systems are drug nanocrystals,antibody-drug conjugates(ADCs),prodrug self-assembled nanoparticles and drug-drug conjugated nanoparticles(DDC).Amphiphilic drug-drug coupled nanoparticles(ADDCs),as a special kind of DDC,consist of hydrophilic and hydrophobic drugs connected by sensitive bonds,which can be easily prepared into nanoparticles by hydrophobic forces.In particular,the different therapeutic mechanisms of the two drugs and their precise ratios are extremely valuable for research to address tumor heterogeneity,drug toxicities and drug resistance during treatment.Based on the above research background and the unique microenvironment of tumors,two reduction-sensitive amphiphilic drug-drug coupled nanoparticles(ADDC)were designed based on the antitumor drug cisplatin coupled with different chemotherapeutic drugs or functional molecules,with precise drug ratios and 100%drug loading,in order to reduce the toxic side effects of chemotherapy drugs and achieve a synergistic tumor suppression effect.The design ideas and main findings are as follows.(1)The amphiphilic drug-drug coupling CP-DDA,synthesized from cisplatin(CP)and dasatinib(DAS),it can self-assemble into nanoparticles CP-DDA NPs by hydrophobic forces of small molecules in aqueous solution.CP-DDA NPs maintain their nanostructures stably in a neutral environment,while can degrade rapidly under reducing conditions,releasing CP and DAS.Cellular experiments demonstrated that CP-DDA NPs can be degraded in the tumor microenvironment after being taken up by cells,releasing active drugs and promoting apoptosis.The results of scratch experiments and Transwell migration experiments showed that CP and DAS released from CP-DDA NPs could synergistically control the proliferation and migration of tumor cells.In vitro inhibition experiments of HepG2 MCs validated the good in vitro antitumor activity of CP-DDA NPs.Finally,in vivo anti-tumor experiments and organ tissue section analysis in mice further demonstrated the low toxicity and good synergistic anti-tumor effects of CP-DDA NPs.(2)The amphiphilic drug-drug coupling LNP,synthesized from cisplatin and clonidine(LND),it can be self-assembled into nanoparticles LNP-NPs in aqueous solution,which can maintain their nanostructures stably in a neutral environment and rapidly degrade and release CP and LND under reducing conditions,exerting the drug activity of LND and inhibiting the energy metabolism of the glycolytic pathway in tumor cells.Drug uptake experiments showed that LNP-NPs could be effectively taken up by both MCF-7 and EMT6 cells.MTT experiments showed that LNP-NPs of cellular uptake could rapidly degrade under reductive conditions in tumor cells,releasing active drugs and synergistically inhibiting tumor and promoting apoptosis.The changes in the amount of ATP in tumor cells and lactate(LD)in the culture medium demonstrated that LND released from LNP-NPs could effectively inhibit the energy metabolism of cancer cells.The growth inhibition experiments of MCs showed that LNP-NPs had the same tumor suppressive effect as the free drug in vitro.