| Immunotherapy has achieved encouraging efficacy in clinical and preclinical cancer therapy,especially the immune checkpoint blockade(ICB)therapies,whereas it efficacy is constrained by the limited objective response rates(ORRs)and severe immune related adverses(irAEs).To address these limitations,hydrogels loaded one or more species of drugs can be exploited as local platforms in combination tumor therapy.In this work,in situ formed injectable hydrogels based on poly amino acids are designed as platforms for locally sustained co-administration of chemotherapeutic drugs CDDP and ICB antibody anti PD-L1 to enhance antitumor properties.In addition,develop a new thermal-pH dual sensitive hydrogel as potential platforms for drug delivery because of the acidic tumor microenvironment.The conclusions are:1)In situ-forming hydrogels based on block copolymers mPEG-PELG was formed by ring opening polymerization of N-carboxyanhydride(NCA)monomers.We mix low-dose anti-tumor chemotherapy drug cisplatin CDDP and immunotherapeutic drug anti PD-L1 antibody with an aqueous polymer solution when the temperature is below body temperature,and inject it into B16F10 mouse melanoma tumor in situ for combined tumor treatment.The hydrophilic drug cisplatin is usually released from the gel at a faster rate.We prepared nanoparticles by complexing cisplatin with polyglutamic acid with side chain modified polyethylene glycol to slow the release of the small molecule drug cisplatin from the gel.The release rate of nano complexed cisplatin from the gel system is obviously slowed down.Hydrogels co-loaded CDDP and anti PD-L1 antibody system showed suppressive growth and extend survival in combination therapy of mice melanoma.It is noteworthy that initial rapid release of cisplatin locally can improve the efficacy of anti PD-L1.2)Solid tumors have inherent acidic microenvironment due to unique metabolism.We design thermo/pH dual sensitive hydrogel EG45(ExPDy)m based on low pH features of tumor microenvironment(TME).EG45(ExDk)m is synthesized by ring-opening polymerization of ELG-NCA and PLG-NCA initiated by mPEG-NH2,and piperidine(PD)is modified to EG45(ExDk)m by click-on reaction of azide and alkyne to obtain target product EG45(ExPDy)m.This polymer is protonated in an acidic environment,resulting in potential reversal,and has pH response and pH buffering capabilities.As the proportion of the pH-sensitive group PD increases,the pH buffering capacity increases.When the temperature rises,the hydration of the PEG segment is weakened,and the interaction of the polyaminoacid segment is enhanced,resulting in the formation of penetrating aggregates,and then the formation of a hydrogel.The gelation behavior respond pH stimulation.By adjusting the block composition,the gelation behavior can be regulated under different pH conditions.The polymer of EG45(E0.5PD0.5)16 can form hydrogels at physiological temperature in the environment of both pH 6.5 and pH 7.4,while the hydrogel formed in an acidic environment does not show obvious dehydration at high-temperature.Aqueous solution of the polymer can be quickly transformed into hydrogel in situ,and can be degraded in the body as time goes by,which allowing immune cell infiltration,and will not trigger a long-term inflammatory response.When use the hydrogel as a drug depot,the sustained release of the chemotherapeutic drug doxorubicin can realize in vitro.The physiologically responsive hydrogels showed biocompatibility in vivo and possess potential for drug delivery platform in local therapy of tumor. |
