α_Vβ₃ Integrin-Targeted PLGA-PEG Nanoparticles for Enhanced Anti-tumor Efficacy of a Pt(IV) Prodrug

Abstract

Targeted delivery of therapeutics to tumor neovasculature is potentially a powerful approach for selective cancer treatment. Integrins are heterodimeric transmembrane proteins involved in cell adhesion and cell signaling, and their expression is commonly upregulated in cancers and inflammatory diseases. The αvβ3 integrin is differentially upregulated on angiogenic endothelial cells as well as on many cancer cells. Here we demonstrate the differential targeting of cisplatin prodrug-encapsulated poly(D,L-lactic-co-glycolic acid)-block-polyethylene glycol (PLGA-PEG) nanoparticles (NPs) to the αvβ3 integrin on cancer cells using the cyclic pentapeptide c(RGDfK). Cisplatin is one of the most widely used anticancer drugs and approaches that can improve its therapeutic index are of broad importance. The RGD-targeted Pt(IV)-encapsulated NPs displayed enhanced cytotoxicity as compared to cisplatin administered in its conventional dosage form in model prostate and breast cancer epithelial cells in vitro. Cytotoxicities were also elevated in comparison to those of previously reported systems, a small molecule Pt(IV)-RGD conjugate and a Pt(IV) nanoscale coordination polymer carrying RGD moieties. This result encouraged us also to evaluate the anticancer effect of the new construct in an animal model. The RGD-targeted PLGA-PEG NPs were more efficacious and better tolerated by comparison to cisplatin in an orthotopic human breast cancer xenograft model in vivo.

Polyethylene glycol–polylactic acid nanoparticles modified with cysteine–arginine–glutamic acid–lysine–alanine fibrin-homing peptide for glioblastoma therapy by enhanced retention effect

“…However, these changes were so minimal that they could be ignored, as they would not have changed the in vitro and in vivo behavior of NPs. 31 Conjugation efficiency of CREKA with nanoparticles and creKa density on the nanoparticle surface Under our experiment conditions (mass ratio of Mal-PEG-PLA to CREKA 3 mg:18 μg, reaction time 4 hours), only about 0.6 μg of free CREKA was detected in the supernatant, and the CREKA conjugation efficiency was approximately 96.7%. The density of CREKA on the surface of NPs was 220±36, which is reasonable for an actively targeting drugdelivery system.…”

“…31,32 The in vitro release curves showed that the conjugation of CREKA did not significantly change the release profiles of DiR or coumarin 6 from NPs (Figure 2A, B). After 72 hours, the cumulative release of DiR was lower than 1% in PBS (pH 7.4) and approximately 3% in 10% FBS.…”

Controlling and Monitoring Intracellular Delivery of Anticancer Polymer Nanomedicines

“…[9][10][11] The α v β 3 integrin is another receptor that is frequently targeted and exploited to enhance cellular internalization by decorating delivery systems with the arginine-glycine-aspartic acid tripeptide ligand. [12][13][14] A third example of a receptor that is exploited for tumor targeting is the epidermal growth factor receptor (EGFR), which is generally overexpressed and therefore used in the treatment of neck cancer, glioblastoma, and lung adenocarcinoma. [15] To this purpose, antibodies, aptamers, and peptides were designed as targeting ligands.…”

Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma

“…PLGA, a controlled release polymer, has been used in the preparation of a wide variety of drug delivery systems, because its safety in the clinic is well established. 23,24 PLGA can protect loaded drug from degradation. Sustained release of drug from NPs based on PLGA is …”