9 research outputs found
Chemical Tumor-Targeting of Nanoparticles Based on Metabolic Glycoengineering and Click Chemistry
Tumor-targeting strategies for nanoparticles have been predominantly based on optimization of physical properties or conjugation with biological ligands. However, their tumor-targeting abilities remain limited and insufficient. Furthermore, traditional biological binding molecules have intrinsic limitations originating from the limited amount of cellular receptors and the heterogeneity of tumor cells. Our two-step <i>in vivo</i> tumor-targeting strategy for nanoparticles is based on metabolic glycoengineering and click chemistry. First, an intravenous injection of precursor-loaded glycol chitosan nanoparticles generates azide groups on tumor tissue specifically by the enhanced permeation and retention (EPR) effect followed by metabolic glycoengineering. These ‘receptor-like’ chemical groups then enhance the tumor-targeting ability of drug-containing nanoparticles by copper-free click chemistry <i>in vivo</i> during a second intravenous injection. The advantage of this protocol over traditional binding molecules is that there are significantly more binding molecules on the surface of most tumor cells regardless of cell type. The subsequent enhanced tumor-targeting ability can significantly enhance the cancer therapeutic efficacy in animal studies
Precise Targeting of Liver Tumor Using Glycol Chitosan Nanoparticles: Mechanisms, Key Factors, and Their Implications
Herein,
we elucidated the mechanisms and key factors for the tumor-targeting
ability of nanoparticles that presented high targeting efficiency
for liver tumor. We used several different nanoparticles with sizes
of 200–300 nm, including liposome nanoparticles (LNPs), polystyrene
nanoparticles (PNPs) and glycol chitosan-5β-cholanic acid nanoparticles
(CNPs). Their sizes are suitable for the enhanced permeation and retention
(EPR) effect in literature. Different <i>in vitro</i> characteristics,
such as the particle structure, stability, and bioinertness, were
carefully analyzed with and without serum proteins. Also, pH-dependent
tumor cell uptakes of nanoparticles were studied using fluorescence
microscopy. Importantly, CNPs had sufficient stability and bioinertness
to maintain their nanoparticle structure in the bloodstream, and they
also presented prolonged circulation time in the body (blood circulation
half-life <i>T</i><sub>1/2</sub> = about 12.2 h), compared
to the control nanoparticles. Finally, employing liver tumor bearing
mice, we also observed that CNPs had excellent liver tumor targeting
ability <i>in vivo</i>, while LNPs and PNPs demonstrated
lower tumor-targeting efficiency due to the nonspecific accumulation
in normal liver tissue. Liver tumor models were produced by laparotomy
and direct injection of HT29 tumor cells into the left lobe of the
liver of athymic nude mice. This study provides valuable information
concerning the key factors for the tumor-targeting ability of nanoparticles
such as stability, bioinertness, and rapid cellular uptake at targeted
tumor tissues
Kaplan–Meier survival curves in post-liver transplantation sarcopenic and non-sarcopenic patients with survival >6 months.
<p>Log rank test p-value = 0.069.</p
Forest plot of hazard ratios for the associations between post- liver transplantation sarcopenia and survival.
<p>BMI, body mass index; MELD, model for end-stage liver disease; ESRD, end-stage renal disease; HD, hemodialysis; DM, diabetes mellitus; HCC, hepatocellular carcinoma; LT, liver transplantation; CDLT, cadaveric donor liver transplantation; LDLT, living donor liver transplantation; GRWR, graft-to-recipient body weight ratio; CSA, cyclosporine; CI, confidence interval</p
Baseline characteristics of the liver transplantation (LT) recipients.
<p>Continuous variables are presented as means ± standard deviations and were analyzed using Student’s t-tests. Categorical variables are presented as numbers and percentages and were compared using the χ<sup>2</sup> test with Yates' continuity correction.</p><p>BMI, body mass index;</p><p>MELD, model for end-stage liver disease;</p><p>DM, diabetes mellitus;</p><p>HBV, hepatitis B virus,</p><p>HCC, hepatocellular carcinoma;</p><p>LT, liver transplantation;</p><p>GRWR, graft-to-recipient body weight ratio;</p><p>CSA, cyclosporine;</p><p>MMF, mycopenolate mofetil</p><p><sup>a</sup>Based on a comparison of post-LT non-sarcopenia patients and post-LT sarcopenia patients</p><p><sup>b</sup>Postoperative immunosuppressive treatment</p><p><sup>c</sup>Change in calcineurin inhibitors during the postoperative period</p><p>Baseline characteristics of the liver transplantation (LT) recipients.</p
Kaplan–Meier survival curves of patients who remained non-sarcopenic vs. those with newly developed sarcopenia.
<p>Log rank test p-value = 0.027.</p
Changes in sarcopenic status during the peri-transplant period.
<p>LT, liver transplantation</p
Facile Method To Radiolabel Glycol Chitosan Nanoparticles with <sup>64</sup>Cu via Copper-Free Click Chemistry for MicroPET Imaging
An efficient and straightforward
method for radiolabeling nanoparticles
is urgently needed to understand the <i>in vivo</i> biodistribution
of nanoparticles. Herein, we investigated a facile and highly efficient
strategy to prepare radiolabeled glycol chitosan nanoparticles with <sup>64</sup>Cu via a strain-promoted azide–alkyne cycloaddition
strategy, which is often referred to as click chemistry. First, the
azide (N<sub>3</sub>) group, which allows for the preparation of radiolabeled
nanoparticles by copper-free click chemistry, was incorporated to
glycol chitosan nanoparticles (CNPs). Second, the strained cyclooctyne
derivative, dibenzyl cyclooctyne (DBCO) conjugated with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid (DOTA) chelator, was synthesized for preparing the preradiolabeled
alkyne complex with <sup>64</sup>Cu radionuclide. Following incubation
with the <sup>64</sup>Cu-radiolabeled DBCO complex (DBCO-PEG<sub>4</sub>-Lys-DOTA-<sup>64</sup>Cu with high specific activity, 18.5 GBq/μmol),
the azide-functionalized CNPs were radiolabeled successfully with <sup>64</sup>Cu, with a high radiolabeling efficiency and a high radiolabeling
yield (>98%). Importantly, the radiolabeling of CNPs by copper-free
click chemistry was accomplished within 30 min, with great efficiency
in aqueous conditions. In addition, we found that the <sup>64</sup>Cu-radiolabeled CNPs (<sup>64</sup>Cu-CNPs) did not show any significant
effect on the physicochemical properties, such as size, zeta potential,
or spherical morphology. After <sup>64</sup>Cu-CNPs were intravenously
administered to tumor-bearing mice, the real-time, <i>in vivo</i> biodistribution and tumor-targeting ability of <sup>64</sup>Cu-CNPs
were quantitatively evaluated by microPET images of tumor-bearing
mice. These results demonstrate the benefit of copper-free click chemistry
as a facile, preradiolabeling approach to conveniently radiolabel
nanoparticles for evaluating the real-time <i>in vivo</i> biodistribution of nanoparticles