Glutathione-depleted cyclodextrin pseudo-polyrotaxane nanoparticles for anti-inflammatory oxaliplatin(Ⅳ) prodrug delivery and enhanced colorectal cancer therapy

Oxaliplatin(Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer(CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2(COX-2) and prostaglandin E2(PGE2), which can promote tumor metastasis. Moreover,high glutathione(GSH) levels in CRC cells significantly reduce Oxa sensitivity and seriously restrict the clinical application of Oxa. Herein, an Oxa(Ⅳ) prodrug with anti-inflammatory properties(desmethyl naproxe, DN) and GSH-depleting cyclodextrin pseudo-polyrotaxane carriers were prepared and further self-assembled into micellar nanoparticles(designated DNPt@PPRI). The relesae of DN from DNPt@PPRI can reduce the level of PGE2 to inhibit inflammation and tumor metastasis by decreasing COX-2 protein,and also synergize with Oxa to inhibit tumor. More importantly, GSH depletion can reduce the detoxification of Oxa and further enhance chemotherapy-induced apoptosis. DNPt@PPRI have a good GSH depletion ability to enhance the sensitivity of Oxa, indicating a potential in the synergistic chemotherapy and chemo-sensitization of colorectal cancer.

Dual inhibition of glucose uptake and energy supply synergistically restrains the growth and metastasis of breast cancer

Metastatic breast cancer(MBC) is one of the most common and knotty diseases in female population which could place them in a life-threatening condition. For malignant proliferation and migration, cancer cells require a large amount of glucose and energy to meet the demand of rapid metabolism. Hence,efficiently diminishing the utilization of energy substances by cancer cells is emerging as validated therapeutic strategies for cancer therapy. Herein, a nanoplatform with dual-inhibition of glucose uptake and oxidative phosphorylation(OXPHOS) was designed, which consisted of albendazole(ABZ) and atovaquone(ATO) by simple carrier-free self-assembling. The introduction of ABZ could evidently decrease glucose uptake to reduce the main “energy fuel” of cancer cells. Meanwhile, as a blocker of OXPHOS, ATO would reduce adenosine triphosphate(ATP) production and ameliorate hypoxia microenvironment by suppressing mitochondrial respiratory chain. Under such dual inhibition of energy metabolism, AA NPs exerted synergistic energy exhaustion effect and outstanding hypoxia improvement function, efficiently inhibiting tumor growth and metastasis. This research not only illustrates the feasibility of energy metabolism therapy by co-inhibiting glucose uptake and OXPHOS, but also provides an ingenious tactic to diminish metastasis during MBC treatment.

Recent progress in tumor photodynamic immunotherapy

Photodynamic therapy(PDT)is a promising alternative approach for effective cancer treatment,which can directly destroy local tumor cells due to the generation of cytotoxic singlet oxygen and reactive oxygen species(ROS)in the tumor cells.Intriguingly,PDT-mediated cell death is also associated with anti-tumor immune response.Howeve r,immunosuppre s sion of tumor microe nvironment is able to limit the immune response induced by PDT,it is therefore necessary to combine with immunocheckpoint inhibitor and immunoadjuvant for synergistic treatment of tumors.Herein,the recent advances of PDT,immunotherapy,and photodynamic immunotherapy are reviewed.

Breaking-then-curing strategy for efficient cystic echinococcosis therapy

Cystic echinococcosis(CE)is one of the most harmful and life-threatening helminths.As the essential therapeutics,chemotherapy is always difficult to achieve desired anti-echinococcal effect due to the problems that the echinococcus granulosus cyst laminated layer makes the drug difficult to infiltrate and the poor solubility of drugs.In this study,we established a“breaking-then-curing”anti-echinococcal treatment strategy for efficient CE therapy.The photodynamic therapy(PDT)was used as a breaker to produce toxic reactive oxygen species(ROS)and damage the laminated layer of protoscolices(PSCs),leading to enhanced infiltration of albendazole sulfoxide nanoparticles(ABZSO NPs).Then,ABZSO NP was worked as curer for efficient anti-echinococcal treatment.As a result,the breaking-then-curing treatment strategy could generate more intracellular ROS in PSCs induced by plenty of ABZSO NPs,greatly increasing the mortality rate of PSCs in a shorter time than using ABZSO NPs alone,leading to the attenuation of laminated layer and finally disintegrating PSCs.We believe the“breaking-then-curing”strategy will suggest great potential in the treatment of CE and provide a new sight for anti-echinococcal treatment.