Recent advances of bioresponsive polymeric nanomedicine for cancer therapy

A bioresponsive polymeric nanocarrier for drug delivery is able to alter its physical and physicochemical properties in response to a variety of biological signals and pathological changes,and can exert its therapeutic efficacy within a confined space.These nanosystems can optimize the biodistribution and subcellular location of therapeutics by exploiting the differences in biochemical properties between tumors and normal tissues.Moreover,bioresponsive polymer-based nanosystems could be rationally designed as precision therapeutic platforms by optimizing the combination of responsive elements and therapeutic components according to the patient-specific disease type and stage.In this review,recent advances in smart bioresponsive polymeric nanosystems for cancer chemotherapy and immunotherapy will be summarized.We mainly discuss three categories,including acidity-sensitive,redox-responsive,and enzyme-triggered polymeric nanosystems.The important issues regarding clinical translation such as reproducibility,manufacture,and probable toxicity,are also commented.

LAT1 targeted brain delivery of temozolomide and sorafenib for effective glioma therapy

Glioma is the most common primary craniocerebral tumor caused by the cancerous growth of glial cells in the brain and spinal cord.Currently,standard treatment is the surgical resection followed by concurrent radiation and chemotherapy.However,the blood-brain barrier(BBB)prevents most antitumor drugs from entering the brain and reduces their efficacy,especially in lowgrade glioma.Since L-type amino acid transporter 1(LAT1)is highly expressed in glioma cells and mediates drug transport across the BBB,it is a promising target for drug delivery and treatment of glioma.Temozolomide(TMZ)is the first-line treatment for glioma,however,patients often exhibit drug resistance at advanced stage.A multikinase inhibitor and inducer of ferroptosis,sorafenib can improve the therapeutic effects of TMZ.Therefore,to optimize the glioma treatment and cross the BBB,we designed LAT1-targeting nanoparticles co-loaded with TMZ and sorafenib.Our results from both in vitro and in vivo studies confirmed that LAT1-targeting nanoparticles significantly increased the cellular uptake,cytotoxicity,accumulation at tumor site,and the anti-tumor efficacy compared to the non-target nanoparticles.Therefore,LAT1 can be used as a potential target for braintargeted drug delivery,and sorafenib-induced ferroptosis can aid the anti-glioma efficacy of TMZ.

NIR-II emissive dye based polymer nanoparticle targeting EGFR for oral cancer theranostics

Oral cancer is a common malignant tumor of the head and neck,and surgery combined with radiotherapy and chemotherapy is the primary treatment modality.However,a positive resection margin that may lead to recurrence after surgery has always been a critical issue to address.Furthermore,radiotherapy and chemotherapy also have shortcomings such as resistance to chemotherapy and radiation,lack of targeting,and severe side effects.Therefore,exploring new methods of tumor surgical navigation and tumor treatment is of great significance for oral cancer.Although,the emerging near-infrared II(NIR-II,1,000–1,700 nm)region fluorescent imaging has revolutionized surgical navigation,a high tumor-targeting fluorescent probe remains lacking.Furthermore,while emerging photothermal therapy(PTT)can overcome chemoradiotherapy’s shortcomings and achieve precise treatment of tumors,its clinical application is still limited by the lack of high photothermal conversion efficiency,high photothermal stability,and highly penetrating materials.Herein,a NIR-II dye SQ890 is developed for tumor imaging and PTT of oral cancer.By assembling into nanoparticles(NPs)and being modified with epithelial growth factor receptor(EGFR)-targeting peptides GE11,SQ890 NPs-Pep can specifically accumulate in tumor sites via active targeting,and realize photoacoustic/NIR-II fluorescence dual-modality imaging-guided PTT of oral cancer.

A prodrug nanoplatform via esterification of STING agonist and IDO inhibitor for synergistic cancer immunotherapy

Cancer immunotherapy has made significant progress in the last few decades,revolutionizing oncology.However,low patient response rates and potential immune-related adverse events continue to be major clinical challenges.Cancer nanomedicine,by virtue of its regulated delivery and modular flexibility,has shown the potential to strengthen antitumor immune responses and sensitize tumors to immunotherapy.In this study,we developed tumor microenvironment(TME)responsive nanomedicine to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner,while simultaneously reducing immune-related side effects.We synthesized the TME responsive prodrug by coupling MSA-2,a stimulator of interferon genes(STING)agonist,and NLG-919,an indoleamine 2,3 dioxygenase(IDO)inhibitor.The prodrug was assembled into nanoparticles to enhance the solubility and bioavailability.By synthesizing a TME responsive prodrug,we aim to explore the therapeutic efficacy of combined regimen(STING agonist and IDO inhibitor)for cancer,and reduce the unwanted side effects of STING agonism on normal tissues.Free prodrug and nanoparticles were characterized by mass spectrometry,dynamic light scattering(DLS),and transmission electron microscopy(TEM).Following that,we investigated the tumor accumulation,anti-tumor activity,and toxicity in vitro and in vivo.Prodrug nanoparticles demonstrated the ability to inhibit the tumor growth and activate antitumor immune response by modulating immune cells populations in tumor microenvironment.The TME responsive nanomedicine provided an effective tool for precise targeting,promoting antitumor immunity,and efficient tumor growth inhibition with safety.Outcomes of this study may have implications for future clinical trials.