Abstract
Rapid blood clearance and premature burst release are inherent drawbacks of conventional nanoparticles, resulting in poor tumor selectivity. iRGD peptide is widely recognized as an efficient cell membrane penetration peptide homing to αVβ3 integrins. Herein, core-shell nanocapsules (NCs) and iRGD-modified NCs (iRGD-NCs) with high drug payload for paclitaxel (PTX) were prepared to enhance the antitumor activities of chemotherapy agents with poor water solubility. Improved in vitro and in vivo tumor targeting and penetration were observed with NCs and iRGD-NCs; the latter exhibited better antitumor activity because iRGD enhanced the accumulation and penetration of NCs in tumors. The NCs were cytocompatible, histocompatible, and non-toxic to other healthy tissues. The endocytosis of NCs was mediated by lipid rafts in an energy-dependent manner, leading to better cytotoxicity of PTX against cancer cells. In contrast with commercial product, PTX-loaded NCs (PTX-NCs) increased area under concentration-time curve (AUC) by about 4-fold, prolonged mean resident time (MRT) by more than 8-fold and reduced the elimination rate constant by greater than 68-fold. In conclusion, the present nanocarriers with high drug-loading capacity represent an efficient tumor-targeting drug delivery system with promising potential for cancer therapy.
Highlights
Rapid blood clearance and premature burst release are inherent drawbacks of conventional nanoparticles, resulting in poor tumor selectivity. iRGD peptide is widely recognized as an efficient cell membrane penetration peptide homing to αVβ3 integrins
Αvβ[3] integrin is a cell-adhesive receptor that is overexpressed on tumor vessels but not on normal tissue vessels[25,26,27], whereas Neuropilin-1 (Nrp-1) is a transmembrane receptor that is highly expressed in a variety of human carcinoma cells and is correlated with angiogenesis and vascular permeability28. iRGD (CRGDRCPDC), a cell-penetrating peptide, first binds to the αvβ[3] integrin, exposing a binding motif for Nrp-1 through proteolytic cleavage and mediating receptor-related endocytosis[28,29]
Transmission electron microscope (TEM) observation indicated that the iRGD-NCs were uniform spheroids with diameters ranging from 150 to 220 nm (Fig. 1B), in general in line with the results from the dynamic light scattering (DLS) measurement
Summary
Rapid blood clearance and premature burst release are inherent drawbacks of conventional nanoparticles, resulting in poor tumor selectivity. iRGD peptide is widely recognized as an efficient cell membrane penetration peptide homing to αVβ3 integrins. IRGD peptide is widely recognized as an efficient cell membrane penetration peptide homing to αVβ3 integrins. Core-shell nanocapsules (NCs) and iRGD-modified NCs (iRGD-NCs) with high drug payload for paclitaxel (PTX) were prepared to enhance the antitumor activities of chemotherapy agents with poor water solubility. The present nanocarriers with high drug-loading capacity represent an efficient tumor-targeting drug delivery system with promising potential for cancer therapy. Its clinical implementation is limited due to poor solubility in aqueous solutions; non-specific distribution throughout the body that causes insufficient penetration into tumors; toxicity to healthy tissues, which limits the dose and frequency of the treatment; and cancer cell resistance[4,5,6,7]. The iRGD-modified nanocarriers would have enhanced tumor-targeting activity due to the iRGD-integrin interaction
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