Tumor Microenvironment and Angiogenic Blood Vessels Dual-Targeting for Enhanced Anti-Glioma Therapy

Abstract

Advances in active targeting drug delivery system (DDS) have revolutionized glioma diagnosis and therapy. However, the lack of the sufficient targets on glioma cells and limited penetration capability of DDS have significantly compromised the treatment efficacy. In this study, by taking advantages of the abundant extracellular matrix-derived heparan sulfate proteoglycan (HSPG) and enhanced tumor penetration ability mediated by neuropilin-1 (NRP-1) protein, we reported the ATWLPPR and CGKRK peptide dual-decorated nanoparticulate DDS (designated AC-NP) to achieve angiogenic blood vessels and tumor microenvironment dual-targeting effect. The resulted AC-NP displayed the particle size of 123 ± 19.47 nm. Enhanced cellular association of AC-NP was achieved on HUVEC cells and U87MG cells. AC-NP was internalized via caveolin- and lipid raft-mediated mechanism with the involvement of energy and lysosome in HUVEC cells and via caveolin- and lipid raft-mediated pathway with the participation of energy, microtubulin, and lysosome in U87MG cells. After loading with anticancer drug, paclitaxel (PTX), the enhanced apoptosis induction and antiproliferative activity were achieved by AC-NP. Furthermore, in vitro U87MG tumor spheroids assays showed a deeper penetration and an enhanced inhibitory effect against the U87MG tumor spheroids achieved by AC-NP. In vivo animal experiment showed that decoration of AC peptide on the nanoparticulate DDS resulted in extensive accumulation at glioma site and improved anti-glioma efficacy. Collectively, the results suggested that AC-NP holds great promise to serve as an effective tumor blood vessel and tumor microenvironment dual-targeting DDS with enhanced penetration capability, holding great potential in improving anti-glioma efficacy.

Sequential Targeting TGF‐β Signaling and KRAS Mutation Increases Therapeutic Efficacy in Pancreatic Cancer

“…The free drug can also slightly regulate TME in vivo, but compare with targeted nanoformulation, the effect is far less significant. The NP‐CGKRK we used can not only improve drug circulation but also increase the distribution and accumulation in tumor sites (Figure ) dependent on the enhanced permeability and retention (EPR) effect and the affinity of CGKRK peptide with its receptor heparan sulfate proteoglycan that overexpressed in tumor microenvironment …”

“…The NP-CGKRK we used can not only improve drug circulation but also increase the distribution and accumulation in tumor sites ( Figure 1) dependent on the enhanced permeability and retention (EPR) effect and the affinity of CGKRK peptide with its receptor heparan sulfate proteoglycan that overexpressed in tumor microenvironment. [30,31,[43][44][45] To study the distribution of LCP-ApoE3 vehicle in orthotropic pancreatic tumor models, we administrated DiR-labeled LCP and LCP-ApoE3 intravenously and measured the fluorescence intensity via an IVIS spectrum optical imaging device. Obviously, most of both nanoparticles accumulated in livers at 4 h and decreased gradually in the following 20 h (Figure 4A).…”

“…Here, we developed the fraxinellone‐loaded poly(ethylene glycol) (PEG)‐poly(lactic acid) (PLA) nanoparticles to regulate the stromal TME of pancreatic cancer and explored its underlying mechanism. The nanoparticle was surface modified with CGKRK peptide to enhance the targeting distribution in tumor sites through binding to the heparan sulfate proteoglycan overexpressing in the TME . Simultaneously, we applied siRNA drugs with favorable safety and gene silencing efficiency to interfere with KRAS mutation.…”

“…The nano particle was surface modi-fied with CGKRK peptide to enhance the targeting distribution in tumor sites through binding to the heparan sulfate proteoglycan overexpressing in the TME. [30,31] Simultaneously, we applied siRNA drugs with favorable safety and gene silencing efficiency to interfere with KRAS mutation. Biomimetic high-density lipoprotein (HDL) nanoparticles with a calcium phosphate (CaP) core and self-assembled apolipoprotein E3 (ApoE3) were harnessed to realize efficient siRNA delivery.…”

Endobronchial Ultrasound (EBUS) for Local Drug Application: Future Methodology

“…[22] The major issue that has to be discussed before any kind of application is the dosage of the formulation which should be based on the tissue volume, drug and matrix of the designated tissue. [22,25] The major issue is to create a molecule that can efficiently penetrate the tumor tissue indifferent of its microenvironment, and with a smaller drug concentration to have a higher apoptosis rate. If these parameters are carefully combined then the drug formulation will be distributed homogenously within the tumor and the treatment will be effective.…”