Original ArticleSpatial controlled multistage nanocarriers through hybridization of dendrimers and gelatin nanoparticles for deep penetration and therapy into tumor tissue
Graphical Abstract
A spatially controlled multistage nanocarrier with small polyamidoamine (PAMAM) dendrimers (~5 nm) encapsulating into large gelatin NPs (~200 nm). With an outer gelatin layer to act as a shield, these multistage nanocarriers were more stable during systematic circulation for their relatively large particle size and electrically neutral surface, than positively charged PAMAM dendrimers alone. However, gelatin NPs were degraded via matrix metalloproteinase-2 (MMP-2) enzymes in tumor tissue, triggering an internal release of PAMAM dendrimers that possessed small particle sizes and a positive charge, which guaranteed improved subsequent deep penetration and high intracellular uptake into tumor cells through electrostatic adsorptive endocytosis.
Section snippets
Preparation of multistage nanocarriers
Blank gelatin nanoparticles were prepared by the nanoprecipitation method as reported earlier with some modifications.38 Briefly, 40 mg of gelatin was dissolved in 2 mL deionized water at 50 °C. This solution was added dropwise to 30 mL of methanol-containing Lutrol F127 (2%), and subsequently crosslinked with 0.5 mL of a glutaraldehyde solution (5%). The system was stirred overnight to allow particles to form crosslinks. After crosslink, the suspension was centrifuged by centrifuge (TG16-WS,
Preparation of FITC labeled PAMAM dendrimers
The H1-NMR results are shown in Figure 1, A. From the H1-NMR spectrum of FITC-PAMAM, both the characteristic peaks of PAMAM dendrimers (δ = 2.484 ppm, δ = 2.627 ppm, δ = 2.751–2.849 ppm, and δ = 3.110–3.489 ppm) and of FITC (δ = 6.548–6.641 ppm, δ =7.208 ppm, and δ = 7.939 ppm) were found. The UV spectrum also proved that the FITC and PAMAM has been conjugated successfully as the absorbance peak of FITC has moved from 492 nm to 501 nm, which is similar to our previous research. The integral value of these
Discussions
In this study, we designed a tumor-microenvironment-responsive multistage nanocarrier that remains stable at a relatively large scale during blood circulation. After entering tumor tissues, the large-scale nanocarriers were digested by MMP-2 enzymes and subsequently released smaller-scale dendrimers. Released dendrimers were able to deeply penetrate into tumor tissues and enter tumor cells with high efficiency; therefore, these nanocarriers may have applications as ideal drug carriers to
Acknowledgements
This work was supported by the National Natural Science Foundation of China [grant numbers 81402859].
References (41)
- et al.
Factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles
J Control Release
(2013) - et al.
Role of liposome size and RES blockade in controlling biodistribution and tumor uptake of GM1-containing liposomes
Biochim Biophys Acta
(1992) - et al.
Non-specific binding and steric hindrance thresholds for penetration of particulate drug carriers within tumor tissue
J Control Release
(2016) - et al.
Hepatoma-targeting and pH-sensitive nanocarriers based on a novel d-galactopyranose copolymer for efficient drug delivery
Int J Pharm
(2014) - et al.
Doxorubicin-loaded pH-sensitive dextran-retinal nanoparticles suppress tumor growth by inducing both apoptosis and cell senescence
J Control Release
(2015) - et al.
Quantum dots based molecular beacons for in vitro and in vivo detection of MMP-2 on tumor
Biosens Bioelectron
(2014) - et al.
Hyaluronic acid nanogels with enzyme-sensitive cross-linking group for drug delivery
J Control Release
(2015) - et al.
Fabrication of Plasmonic Nanorod-embedded dipeptide microspheres via the freeze-quenching method for near-infrared laser-triggered drug-delivery applications
Biomacromolecules
(2016) - et al.
Multifunctional liposomes having target specificity, temperature-triggered release, and near-infrared fluorescence imaging for tumor-specific chemotherapy
J Control Release
(2015) - et al.
Monoclonal antibody-targeted, temperature-sensitive liposomes: in vivo tumor chemotherapeutics in combination with mild hyperthermia
J Control Release
(2014)