Intelligent self-assembly prodrug micelles loading doxorubicin in response to tumor microenvironment for targeted tumors therapy

Compared with physical drug-loaded nanocarriers,polymeric prodrug micelles have many advantages such as high drug loading and enhanced stability in blood,so they have great potential in cancer therapy.However,these micelles have a big disadvantage,which cannot achieve long-term circulation in vivo and high absorption of tumor cells simultaneously,resulting in low administration efficiency and poor therapeutic effect on cancer.To solve problems of traditional polymeric prodrug micelles,novel polymeric micelles with tumor microenvironment response were designed in this work.The prodrug formed by covalently linking D-α-tocopherol polyethylene glycol succinate(TPGS_(3350)),peptide(Pep),and doxorubicin(DOX)(TPGS_(3350)-Pep-DOX)was self-assembled into micelles by encapsulating DOX physically.When the micelles entered the tumor tissue,the long-chain polyethylene glycol(PEG)was sensitively cut by the matrix metalloproteinase 2/9(MMP2/9)enzyme,exposing the targeting molecule folate,then it entered the cell through the endocytic pathway mediated by the folate receptor.The drug loading content,encapsulation efficiency,critical micelle concentration,and invitro release of the micelles invented in this study were measured to characterize their properties.The particle size and zeta potential of micelles were characterized by dynamic light scattering.Images were scanned by transmission electron microscopes.In vitro cytotoxicity,cellular uptake,and in vivo antitumor effect evaluation experiments were measured to show that smart micelles have made much progress in material chemistry and drug delivery,making it possible to apply a stimulus-response carrier drug delivery system in clinical application.

Light-activated arginine-rich peptide-modified nanoparticles for deep-penetrating chemo-photo-immunotherapy of solid tumor

Poor permeation of drugs and“immune-cold”tumor microenvironment in solid tumors are the two major challenges which lead to the inefficient therapeutic efficacy for cancer treatment.Here,light-activated penetrable nanoparticles(PEGVAL&DOX&ICG@RNPs)for co-delivery of the chemotherapeutic drug doxorubicin(DOX),the photosensitizer agent indocyanine green(ICG),and the angiotensin II receptor blockers valsartan(VAL)were developed to achieve deep drug penetration and synergistic photo-chemo-immunotherapy of solid tumor.Studies showed that under the first-wave of laser irradiation,the polyethylene glycol(PEG)hydrophilic layer as an“inert”surface could detach from the nanoparticles,release VAL and expose the arginine-rich peptide modified-cores that can facilitate deep drug penetration via a transcytosis pathway.When exposed to the second-wave of laser irradiation,the synergistic chemo-photo-immunotherapy can be achieved.As expected,in 4T1 tumorbearing mice,PEG-VAL&DOX&ICG@RNPs treatment could effectively inhibit the growth of tumors,down-regulateα-smooth muscle actin expression level of cancer-associated fibroblasts cells in tumors,induce dendritic cells(DCs)maturation,and promote intratumoral infiltration of cytotoxic T lymphocytes.Moreover,combination therapy by PEG-VAL&DOX&ICG@RNPs and anti-PD-1 monoclonal antibody can elicit memory T cell response for preventing tumor recurrence and metastasis in vivo.This work provides a promising delivery strategy to overcome the current limitations of nanomedicine for achieving more effective therapeutic index of“immune-cold”solid tumor treatment.