title: Efficient delivery of antitumor drug to the nuclei of tumor cells by amphiphilic biodegradable poly(L-aspartic acid-co-lactic acid)/DPPE co-polymer nanoparticles.
abstract: The use of biodegradable polymeric nanoparticles (NPs) for controlled drug delivery has shown significant therapeutic potential. Polyaspartic acid and polylactic acid are the most intensively studied biodegradable polymers. In the present study, novel amphiphilic biodegradable co-polymer NPs, poly(L-aspartic acid-co-lactic acid) with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) (poly(AA-co-LA)/DPPE) is synthesized and subsequently used to encapsulate an antitumor drug doxorubicin (DOX). The formulation parameters of the NPs are optimized to improve encapsulation efficiency. The resulting drug-loaded NPs possess better size homogeneity (polydispersity) and exhibit pH-responsive drug release profiles. Cellular viability assays indicate that the poly(AA-co-LA)/DPPE NPs did not induce cell death, whereas doxorubicin encapsulated NPs were cytotoxic to various types of tumor cells. In addition, the free NPs could not enter the cell nuclei after internalized in tumor cells. The DOX-loaded NPs exhibit efficient intracellular delivery in tumor cells with co-localization in lysosome and delay entering into the nucleus, which suggests a time- and pH-dependent drug release profile within cells. When applied to deliver chemotherapeutics to a mouse xenograft model of human lung adenocarcinoma, DOX-loaded NPs have a comparable antitumor activity with free DOX, and greatly reduce systemic toxicity and mortality. The delivery of cytotoxic drugs directly to the nucleus specifically within tumor cells is of great interest. These results demonstrate the feasibility of the application of the amphiphilic polyaspartic acid derivative, poly(AA-co-LA)/DPPE, as a nanocarrier for cell nuclear delivery of potent antitumor drugs.
authors.affiliation: CAS Key Lab for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, China.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Han
authors.forename: Yuexian
authors.initials: Y
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Nie
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Fang
authors.initials: F
authors.lastname: Jiao
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Chunying
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001672:Biocompatible Materials / Q000737:chemistry; D001673:Biodegradation, Environmental / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D019344:Lactic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D008027:Light; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D011091:Polyesters / Q000138:chemical synthesis / Q000737:chemistry*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D012542:Scattering, Radiation; D013501:Surface-Active Agents / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D010455:Peptides; D010714:Phosphatidylethanolamines; D011091:Polyesters; D011108:Polymers; D013501:Surface-Active Agents; C576175:poly(aspartic acid-co-lactic acid); C007510:1,2-dipalmitoyl-3-phosphatidylethanolamine; D019344:Lactic Acid; C033616:poly(lactide); D004317:Doxorubicin