CRGD-functionalized mPEG-PLGA-PLL nanoparticles for imaging and therapy of breast cancer
Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.25, Lane 2200, Xietu Road, Shanghai 200032, PR China. Biomaterials
(Impact Factor: 8.56).
07/2012; 33(28):6739-47. DOI: 10.1016/j.biomaterials.2012.06.008
Cyclic peptide (arginine-glycine-aspartic-glutamic-valine acid, cRGD)-modified monomethoxy (polyethylene glycol)-poly (D,L-lactide-co-glycolide)-poly (L-lysine) nanoparticles (mPEG-PLGA-PLL-cRGD NPs) with antitumor drug Mitoxantrone (DHAQ) or fluorescence agent Rhodamine B (Rb) encapsulated in their interior were prepared. The remarkable features of the mPEG-PLGA-PLL-cRGD NPs are the effective improvement for the cytotoxicity and uptake of the cell in vitro, and the significant enhancement of delivery ability for DHAQ or Rb in vivo. As a consequence, an excellent therapeutic efficiency for cancer is obtained, demonstrating the mPEG-PLGA-PLL-cRGD NPs play a key role in enhancing cancer therapeutic efficiency.
Available from: Seyedsina Moeinzadeh
- "Although chemotherapeutic agents are stabilized in the PLA matrix against dissolution by hydrophobic interaction, and drug release kinetics is controlled by matrix degradation , surface active agents are used to prevent NPs aggregation , reduce the initial burst release, or improve the cell uptake of NPs    . These active agents include amphiphilic PEG-based copolymers  , biomolecules such as vitamin E , peptides  , and proteins . These modifiers not only stabilize NPs against aggregation and improve cell uptake, but also they affect the drug safety profile including immunogenicity and systemic toxicity . "
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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 were 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.
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ABSTRACT: Construction on the nanoparticles with lower toxicity and specific tumor targeting properties is challenging and requires careful design of composition, size, physicochemical properties tailored for the nanoparticles. Here the epidermal growth factor (EGF) modified methoxy polyethylene glycol-polylactic-co-glycolic acid-polylysine (mPEG-PLGA-PLL) encapsulated cisplatin (CDDP) nanoparticles (CDDP-NPs-EGF) was prepared to for solving the toxicity of CDDP and improving therapeutic efficiency. The remarkable features of CDDP-NPs-EGF are increasing cytotoxicity that attribute to effective cell cycle arrest and high cell apoptosis in vitro. In vivo, the CDDP-NPs-EGF change drug distribution, decrease the nephrotoxicity of CDDP and improve significantly therapeutic efficiency without inducing obvious system toxicity, verifying its key role of the CDDP-NPs-EGF in lowering drug toxicity and enhancing the antitumor efficiency for SKOV3 cancer in mice.
Available from: Stephanie Schubert
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