Targeting Nanocarriers Activated By Tumor Acidity For Antitumor Drug Delivery

Traditional chemotherapy has non-specific recognition function when the small molecule chemotherapeutic drugs applied to the body.And the amount of small molecule chemotherapeutic drugs that reach the tumor site is usually only a few thousandths to thousands of thousands.Drugs distributed to normal tissues and organs can cause toxic side effects.Improving the efficiency of delivery of chemotherapeutic drugs to tumor tissues and reducing the dosage are the focus of current research on cancer treatment.Nanocarriers are increasingly used to deliver chemotherapy drugs to cancer treatment but the delivery efficiency of existing nanocarriers still needs to be further improved to enhance their efficient uptake by tumor cells.Targeting modification is one of the commonly used strategies to improve the delivery efficiency of nanocarriers at present.It mainly uses the interaction between the targeting molecules on the surface of nanocarriers and the receptor molecules on the surface of tumor cells to enhance the uptake of nanocarriers by tumor cells.But it needs to be pointed out that the expression of tumor cell surface receptors in different patients is extremely different,and the expression of tumor cell surface receptors in the same patient is also dynamically changed.These heterogeneity restrict the application of targeted nanocarriers.Cell-penetrating peptides(CPPs)are a class of short peptides,which can effectively increase the uptake of cells and are independent of cell surface receptors.However,CPPs have the ability of non-specific recognition,which cause to enhance the uptake by normal cells,making it limited in clinical applications.In recent years,cell-penetrating peptides were designed with corresponding stimulating responses according to the tumor microenvironment have been gradually exposed in the public view.In this parper,we constructed a polymeric nanoparticle with tumor acidity-activatable R9 peptide to enhance tumor cell uptake.Polyarginine(R9)was modified on the block copolymer Mal-PEG-b-PHEP,then encapsulated the chemotherapy drug doxorubicin(DOX)to form drug-loaded nanoparticles R9-NPDOX.Next we coated the polyanion PPC-DA,which has response to tumor tumor microacid environment,on the nanoparticle surface through electrostatic interaction to form DA@R9-NPDOX,which can hide the non-specific recognition function of R9 peptide.At p H 6.5,the surface charge of the particles increased from-19.59 m V to +5.51 m V,at the same time,we verified that it can be more efficiently taken up by cells.After tail vein injection,nanoparticles reached the tumor site by blood circulation.Due to the microacid environment of tumor,the amide bond of polyanion PPC-DA would be hydrolyzed,causing DA@R9-NPDOX to remove the outer layer of PPC-DA and re-expose the R9 peptide,then increasing the uptake of drug-loaded nanoparticles by tumor cells,significantly improving the anti-tumor effect of chemotherapy drugs on tumor-bearing mice.This provides an effective strategy to deliver chemotherapy drug in cancer treatment.