Ternary Nanoparticles with a Sheddable Shell Efficiently Deliver MicroRNA-34a against CD44-Positive Melanoma

PEGylation can stabilize drug delivery systems for cancer therapy by creating repulsive interactions with biological components <i>in vivo</i>. While these interactions reduce nonspecific adsorption of drug-loaded particles onto nontarget surfaces, they also inhibit internalization of particles into target cells. To circumvent this so-called “PEG-dilemma”, we have developed nanoparticles with a PEG coating that is shed after arrival in target tissue. Positively charged polycation nanoparticles were assembled with microRNA-34a via electrostatic interactions and then coated again via electrostatic interactions with an anionic PEG derivative that separates from the nanoparticle in the acidic tumor microenvironment. The resulting ternary nanoparticles with a sheddable shell have nearly neutral surface charge, which markedly reduces nonspecific adsorption. Shedding the PEG coat enhanced nanoparticle uptake into CD44-positive melanoma cells and promoted microRNA-34a release, which down-regulated CD44 expression and thereby inhibited tumor growth. We conclude that nanocarriers with a sheddable shell show promise for cancer therapy

Myristic Acid-Modified ^DA7R Peptide for Whole-Process Glioma-Targeted Drug Delivery

The clinical treatment of aggressive glioma has been a great challenge, mainly because of the complexity of the glioma microenvironment and the existence of the blood–brain tumor barrier (BBTB)/blood–brain barrier (BBB), which severely hampers the effective accumulation of most therapeutic agents in the glioma region. Additionally, vasculogenic mimicry (VM), angiogenesis, and glioma stem cells (GSC) in malignant glioma also lead to the failure of clinical therapy. To address the aforementioned issues, a whole-process glioma-targeted drug delivery strategy was proposed. The ^DA7R peptide has effective BBTB-penetrating and notable glioma-, angiogenesis-, and VM-targeting abilities. Herein, we designed a myristic acid modified ^DA7R ligand (MC-^DA7R), which combines tumor-homing ^DA7R with BBB-penetrable MC. MC-^DA7R was then immobilized to PEGylated liposomes (MC-^DA7R-LS) to form a whole-process glioma-targeting system. MC-^DA7R-LS exhibited exceptional internalization in glioma, tumor neovascular, and brain capillary endothelial cells. Enhanced BBTB- and BBB-traversing efficiencies were also observed on MC-^DA7R-LS. Ex vivo imaging on brain tumors also demonstrated the feasibility of MC-^DA7R-LS in intracranial glioma-homing, whereas the immunofluorescence studies demonstrated its GSC and angiogenesis homing. Furthermore, doxorubicin-loaded MC-^DA7R-LS accomplished a remarkable therapeutic outcome, as a result of a synergistic improvement on the glioma microenvironment. Our study highlights the potential of the MC-modified ^DA7R peptide as a great candidate for the whole-process glioma-targeted drug delivery

Stapled RGD Peptide Enables Glioma-Targeted Drug Delivery by Overcoming Multiple Barriers

Malignant glioma, the most frequent and aggressive central nervous system (CNS) tumor, severely threatens human health. One reason for its poor prognosis and short survival is the presence of the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB), which restrict the penetration of therapeutics into the brain at different stages of glioma. Herein, inspired by the peptide stapling technique, we designed a cyclic RGD ligand via an all-hydrocarbon staple (stapled RGD, sRGD) to facilitate BBB penetration while retaining the capacity of BBTB penetration and targeting ability to glioma cells. As expected, sRGD-modified micelles were able to penetrate the in vitro BBB model while retaining the glioma targeted capability. The results of the in vivo imaging studies further revealed that this nanocarrier could not only efficiently transverse the intact BBB of normal mice, but also could specifically target glioma cells of intracranial glioma-bearing nude mice. Furthermore, Paclitaxel-loaded sRGD-modified micelles exhibited improved antiglioma efficacy in vitro and significantly prolonged survival time of glioma-bearing nude mice. Overall, this sRGD peptide showed potency for glioma-targeted drug delivery by overcoming multiple barriers