2 research outputs found
Enhanced anti-hepatocarcinoma efficacy by GLUT1 targeting and cellular microenvironment-responsive PAMAM–camptothecin conjugate
<p>The efficient targeting of drugs to tumor cell and subsequent rapid drug release remain primary challenges in the development of nanomedicines for cancer therapy. Here, we constructed a glucose transporter 1 (GLUT1)-targeting and tumor cell microenvironment-sensitive drug release Glucose–PEG–PAMAM-s-s–Camptothecin-Cy7 (GPCC) conjugate to tackle the dilemma. The conjugate was characterized by a small particle size, spherical shape, and glutathione (GSH)-sensitive drug release. <i>In vitro</i> tumor targeting was explored in monolayer (2D) and multilayer tumor spheroid (3D) HepG2 cancer cell models (GLUT1<sup>+</sup>). The cellular uptake of GPCC was higher than that in the control groups and that in normal L02 cells (GLUT1<sup>−</sup>), likely due to the conjugated glucose moiety. Moreover, the GPCC conjugate exhibited stronger cytotoxicity, higher S arrest and enhanced apoptosis and necrosis rate in HepG2 cells than control groups but not L02 cells. However, the cytotoxicity of GPCC was lower than that of free CPT, which could be explained by the slower release of CPT from the GPCC compared with free CPT. Additional <i>in vivo</i> tumor targeting experiments demonstrated the superior tumor-targeting ability of the GPCC conjugate, which significantly accumulated in tumor meanwhile minimize in normal tissues compared with control groups. The GPCC conjugate showed better pharmacokinetic properties, enabling a prolonged circulation time and increased camptothecin area under the curve (AUC). These features contributed to better therapeutic efficacy and lower toxicity in H22 hepatocarcinoma tumor-bearing mice. The GLUT1-targeting, GSH-sensitive GPCC conjugate provides an efficient, safe and economic approach for tumor cell targeted drug delivery.</p
Overcoming Multidrug Resistance through the GLUT1-Mediated and Enzyme-Triggered Mitochondrial Targeting Conjugate with Redox-Sensitive Paclitaxel Release
Multidrug resistance (MDR) is thought
to be the major obstacle leading to the failure of paclitaxel (PTX)
chemotherapy. To solve this problem, a glucose transporter-mediated
and matrix metalloproteinase 2 (MMP2)-triggered mitochondrion-targeting
conjugate [glucose-polyethylene glycol (PEG)–peptide–triphenylphosponium–polyamidoamine
(PAMAM)–PTX] composed of a PAMAM dendrimer and enzymatic detachable
glucose-PEG was constructed for mitochondrial delivery of PTX. The
conjugate was characterized by a 30 nm sphere particle, MMP2-sensitive
PEG outer layer detachment from PAMAM, and glutathione (GSH)-sensitive
PTX release. It showed higher cellular uptake both in glucose transporter
1 (GLUT1) overexpressing MCF-7/MDR monolayer cell (2D) and multicellular
tumor spheroids (3D). The subcellular location study showed that it
could specifically accumulate in the mitochondria. Moreover, it exhibited
higher cytotoxicity against MCF-7/MDR cells, which significantly reverse
the MDR of MCF-7/MDR cells. The MDR reverse might be caused by reducing
the ATP content through destroying the mitochondrial membrane as well
as by down-regulating P-gp expression. In vivo imaging and tissue
distribution indicated more conjugate accumulated in the tumor of
the tumor-bearing mice model. Consequently, the conjugate showed better
tumor inhibition rate and lower body weight loss, which demonstrated
that it possessed high efficiency and low toxicity. This study provides
glucose-mediated GLUT targeting, MMP2-responsive PEG detachment, triphenylphosponium-mediated
mitochondria targeting, and a GSH-sensitive intracellular drug release
conjugate that has the potential to be exploited for overcoming MDR
of PTX