title: Drug release kinetics, cell uptake, and tumor toxicity of hybrid VVVVVVKK peptide-assembled polylactide nanoparticles.
abstract: An exciting approach to tumor delivery is encapsulation of the drug in self-assembled polymer-peptide nanoparticles. The objective of this work was to synthesize a conjugate of low molecular weight polylactide (LMW PLA) and V6K2 peptide and investigate self-assembly, drug release kinetics, cell uptake and toxicity, drug pharmacokinetics, and tumor cell invasion with Doxorubicin (DOX) or paclitaxel (PTX). The results for PLA-V6K2 self-assembled NPs were compared with those of polyethylene glycol stabilized PLA (PLA-EG) NPs. The size of PLA-V6K2 and PLA-EG NPs was 100 ± 20 and 130 ± 50 nm, respectively, with polydispersity index of 1.04 and 1.14. The encapsulation efficiency of DOX in PLA-V6K2 and PLA-EG NPs was 44 ± 9% and 55 ± 5%, respectively, and that of PTX was >90 for both NP types. The release of DOX and PTX from PLA-V6K2 was slower than that of PLA-EG, and the release rate was relatively constant with time. Based on molecular dynamic simulation, the less hydrophobic DOX was distributed in the lactide core as well as the peptide shell, while the hydrophobic PTX was localized mainly to the lactide core. PLA-V6K2 NPs had significantly higher cell uptake by 4T1 mouse breast carcinoma cells compared to PLA-EG NPs, which was attributed to the electrostatic interactions between the peptide and negatively charged moieties on the cell membrane. PLA-V6K2 NPs showed no toxicity to marrow stromal cells. DOX-loaded PLA-V6K2 NPs showed higher toxicity to 4T1 cells and the DNA damage response, and apoptosis was delayed compared to the free DOX. DOX or PTX encapsulated in PLA-V6K2 NPs significantly reduced invasion of 4T1 cells compared to those cells treated with the drug in PLA-EG NPs. Invasion of 4T1 cells treated with DOX in PLA-V6K2 and PLA-EG NPs was 5 ± 1% and 30 ± 5%, respectively, and that of PTX was 11 ± 2% and 40 ± 7%. The AUC of DOX in PLA-V6K2 NPs was 67% and 21% higher than those of free DOX and PLA-EG NPs, respectively. DOX-loaded PLA-V6K2 NPs injected in C3HeB/FeJ mice inoculated with MTCL syngeneic breast cancer cells displayed higher tumor toxicity than PLA-EG NPs and lower host toxicity than the free DOX. Cationic PLA-V6K2 NPs with higher tumor toxicity than the PLA-EG NPs are potentially useful in chemotherapy.
authors.affiliation: Department of Chemical Engineering, University of South Carolina, SC 29208, United States. jabbari@engr.sc.edu
authors.forename: Esmaiel
authors.initials: E
authors.lastname: Jabbari
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yang
authors.forename: Seyedsina
authors.initials: S
authors.lastname: Moeinzadeh
authors.forename: Xuezhong
authors.initials: X
authors.lastname: He
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D053758:Nanoparticles / Q000633:toxicity; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000633:toxicity; D011091:Polyesters / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
chemical_list: D009842:Oligopeptides; D011091:Polyesters; C033616:poly(lactide)