Nanodrug Delivery System:a Promising Targeting Strategy for Treatment of Pancreatic Ductal Adenocarcinoma
Pancreatic ductal adenocarcinoma(PDAC)is a highly malignant solid tumor of the digestive system,characterized by rapid progression and difficulties of early diagnosis.Five-year survival rate of the patients is less than 9％.With the acceleration of global population aging and lifestyle change,the incidence of PDAC has been increasing annually.Currently,surgical treatment and chemotherapy remain the standard treatment options for PDAC patients.Early symptoms of PDAC are so undetectable that most patients miss the optimal opportunity for radical surgical resection.Even among those who undergo surgery,the high recurrence rate remains a major problem.PDAC is known for its unique tumor microenvironment.The cellular and non-cellular components in the tumor microenvironment account for as much as 90％of the tumor stroma,presenting many potential targets for PDAC therapy.Activated pancreatic stellate cells within PDAC tissue express specific proteins and secrete various cytokines and metabolites,which directly contribute to the proliferation,invasion,and metastasis of PDAC cells.These elements are critical in extracellular matrix production,connective tissue hyperplasia,immune tolerance,and drug resistance.Immune cells,such as macrophages and neutrophils,exert immunosuppressive and tumor-promoting roles in PDAC progression.The extracellular matrix,which serve as a natural physical barrier,induces interstitial hypertension and reduces blood supply,thereby hindering the delivery of drugs to the tumor.Additionally,it helps the metastasis and differentiation of PDAC cells,reducing the efficacy of clinical chemotherapy and immunotherapy.Although chemotherapeutic agents like gemcitabine have been used in the clinical treatment of PDAC for more than 20 years,the curative effect is obstructed by their poor stability in the bloodstream,low cellular uptake,and poor targeting.While small-molecule inhibitors targeting mutations such as KRASG12C,BRCA,and NTRK fusion have shown great potential for molecular targeted treatments and gene therapies of PDAC,their broader application is limited by side effects and restricted scope of patients.The advancement of nanotechnology brings new strategies for PDAC treatment.By virtue of unique size characteristics and actual versatility,different drug-delivery nanosystems contribute to overcome the dense stromal barrier,prolong the circulation time of therapeutics and realize precise PDAC treatment by targeted drug delivery.Clinical nanodrugs such as albumin-bound paclitaxel(nab-paclitaxel)and irinotecan liposome greatly improve the pharmacokinetics of conventional chemotherapeutics and promote drug accumulation inside the tumor,thereby are applying to the first-line treatment of PDAC.It is noteworthy that none nanodrugs with active targeting design have been approved for clinical treatment yet,though many are in clinical trials.In this review,we discuss promising targeting strategies based on different nanodrug delivery systems for treatment of PDAC.One major nanostrategy focuses on the tumor cell targeting and its applications in chemotherapy,molecular targeting therapy,gene therapy,and immunotherapy of PDAC.Another nanostrategy targets the tumor microenvironment,which highlights the nanosystems specifically regulating pancreatic stellate cells,immune cells and the extracellular matrix.Recent progress of developing new nanotheraputics for breakthrough in the fight of PDAC are elaborated in this review.We also provide our perspectives on the challenges and opportunities in the field.
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