Low systemic toxicity nanocarriers fabricated from heparin-mPEG and PAMAM dendrimers for controlled drug release

Vu, Minh Thành; Nguyen, Thi Hiep; Tran, Tuong Vi; Ngoc, Uyen-Thi Phan; Ho, Minh Nhat; Nguyen, Thi Phuong; Chau, Yen Nguyen Tram; Le, Van Thu; Trân, Ngoc Quyên; Nguyen, Cuu Khoa; Nguyen, Dai Hai

doi:10.1016/j.msec.2017.07.051

Cited by 60 publications

(38 citation statements)

References 49 publications

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“…Polyamidoamine (PAMAM) dendrimers were synthesized from the repeating steps of Michael addition reaction and amidation one as previously reported . In this study, PAMAM generation 4.0 (G4) was used.…”

Section: Methodsmentioning

confidence: 99%

PEGylated PAMAM dendrimers loading oxaliplatin with prolonged release and high payload without burst effect

Bạch

Nguyen

et al. 2019

Biopolymers

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Oxaliplatin (OXA) was coupled to PEGylated polyamidoamine dendrimers of fourth generation (G4-PEG@OXA) in the comparison to PEGylated ones of odd generation (G3.5-PEG@OXA).Proton nuclear magnetic resonance and Fourier-transform infrared spectroscopy were used to confirm the successful incorporation of OXA as well as the synthesis of carrier systems. Both two types of carrier systems exhibited in sphere nanoparticle shape with size of less than 100 nm that was in the range being able to cause toxicity on cancer cells. The average drug loading efficiency (DLE) of G4-PEG@OXA was obtained at 84.63% that was higher than DLE of G3.5-PEG of 75.69%. The release kinetic of G4-PEG@OXA and G3.5-PEG@OXA did not show any burst release phenomenon while free OXA was released over 40% at the first hour. The sustainable release of OXA was achieved when it was encapsulated in these carriers, but the G4 generation liberated OXA (3.4%-6.4%) slower than G3.5 one (11.9%-22.8%). The in vitro cytotoxicities of G4-PEG@OXA were evaluated in HeLa cell lines using resazurin assay and live/dead staining test. Although the free OXA showed a rather moderate killing ability, the G4-PEG@OXA still displayed the low viability of HeLa that was better to the result of G3.5-PEG@OXA due to released OXA amount. The benefit of this system was to overcome the burst release phenomenon to minimize OXA toxicity without compromising its efficiency. K E Y W O R D Scancer, drug delivery, nanoparticles, oxaliplatin, PAMAM dendrimers

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Section: Methodsmentioning

confidence: 99%

PEGylated PAMAM dendrimers loading oxaliplatin with prolonged release and high payload without burst effect

Bạch

Nguyen

et al. 2019

Biopolymers

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“…32 PAMAM has distinctive advantages, such as monodispersity, tunable size, cavity structure inside, and numerous functional groups for chemical modifications. [33][34][35] Therefore, PAMAM can increase biodistribution of drugs, and possibly enhance the EPR effect in targeting tumors. However, the unmodified PAMAM has a positive charge under physiological conditions due to a large number of amino groups on the surface.…”

Section: Introductionmentioning

confidence: 99%

A novel RGDyC/PEG co-modified PAMAM dendrimer-loaded arsenic trioxide of glioma targeting delivery system

Han

Zheng

et al. 2018

IJN

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BackgroundThe Traditional Chinese Medicine, arsenic trioxide (ATO, As2O3) could inhibit growth and induce apoptosis in a variety of solid tumor cells, but it is severely limited in the treatment of glioma due to its poor BBB penetration and nonspecifcity distribution in vivo.PurposeThe objective of this study was encapsulating ATO in the modified PAMAM den-drimers to solve the problem that the poor antitumor effect of ATO to glioma, which provide a novel angle for the study of glioma treatment.MethodsThe targeting drug carrier (RGDyC-mPEG-PAMAM) was synthesized based on Arg-Gly-Asp (RGDyC) and αvβ3 integrin targeting ligand, and conjugated to PEGylated fifth generation polyamidoamine dendrimer (mPEG-PAMAM). It was characterized by nuclear magnetic resonance, fourier transform infrared spectra, Nano-particle size-zeta potential analyzer,etc. The in vitro release characteristics were studied by dialysis bag method. MTT assay was used to investigate the cytotoxicity of carriers and the antitumor effect of ATO formulation. In vitro blood-brain barrier (BBB) and C6 cell co-culture models were established to investigate the inhibitory effect of different ATO formulation after transporting across BBB. Pharmacokinetic and antitumor efficacy studies were investigated in an orthotopic murine model of C6 glioma.ResultsThe prepared RGDyC-mPEG-PAMAM was characterized for spherical dendrites, comparable size (21.60±6.81 nm), and zeta potential (5.36±0.22 mV). In vitro release showed that more ATO was released from RGDyC-mPEG-PAMAM/ATO (79.5%) at pH 5.5 than that of pH 7.4, during 48 hours. The cytotoxicity of PEG-modified carriers was lower than that of the naked PAMAM on both human brain microvascular endothelial cells and C6 cells. In in vitro BBB model, modification of RGDyC heightened the cytotoxicity of ATO loaded on PAMAM, due to an increased uptake by C6 cells. The results of cell cycle and apoptosis analysis revealed that RGDyC-mPEG-PAMAM/ATO arrested the cell cycle in G2-M and exhibited threefold increase in percentage of apoptosis to that in the PEG-PAMAM/ATO group. Compared with ATO-sol group, both RGDyC-mPEG-PAMAM/ATO and mPEG-PAMAM/ATO groups prolonged the half-life time, increased area under the curve, and improved antitumor effect, significantly. While the tumor volume inhibitory of RGDyC-mPEG-PAMAM/ATO was 61.46±12.26%, it was approximately fourfold higher than the ATO-sol group, and twofold to the mPEG-PAMAM/ATO group.ConclusionIn this report, RGDyC-mPEG-PAMAM could enhance the antitumor of ATO to glioma, it provides a desirable strategy for targeted therapy of glioma.

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“…This difference was attributed to the presence of outer layer SS-ADA@CD-mPEG on the surface of PNS nanoparticles. Previous studies have indicated that nanoparticles less than 20–30 nm are rapidly eliminated by renal excretion, whereas nanoparticles in the range of 30–150 nm can stay in the circulatory system for a longer period of time [ 23 ]. One of the most critical insights of PNS is that the bioactive molecules can be significantly loaded into the porous pores of silica nanoparticles.…”

Section: Resultsmentioning

confidence: 99%

Efficient Self-Assembly of mPEG End-Capped Porous Silica as a Redox-Sensitive Nanocarrier for Controlled Doxorubicin Delivery

Nguyen

Bao

et al. 2018

International Journal of Biomaterials

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Porous nanosilica (PNS) has been regarded as a promising candidate for controlled delivery of anticancer drugs. Unmodified PNS-based nanocarriers, however, showed a burst release of encapsulated drugs, which may limit their clinical uses. In this report, PNS was surface conjugated with adamantylamine (ADA) via disulfide bridges (-SS-), PNS-SS-ADA, which was further modified with cyclodextrin-poly(ethylene glycol) methyl ether conjugate (CD-mPEG) to form a core@shell structure PNS-SS-ADA@CD-mPEG for redox triggered delivery of doxorubicin (DOX), DOX/PNS-SS-ADA@CD-mPEG. The prepared PNS-SS-ADA@CD-mPEG nanoparticles were spherical in shape with an average diameter of 55.5 ± 3.05 nm, a little larger than their parentally PNS nanocarriers, at 49.6 ± 2.56 nm. In addition, these nanoparticles possessed high drug loading capacity, at 79.2 ± 3.2%, for controlled release. The release of DOX from DOX/PNS-SS-ADA@CD-mPEG nanoparticles was controlled and prolonged up to 120 h in PBS medium (pH 7.4), compared to less than 40 h under reducing condition of 5 mM DTT. Notably, the PNS-SS-ADA@CD-mPEG was a biocompatible nanocarrier, and the toxicity of DOX was dramatically reduced after loading drugs into the porous core. This redox-sensitive PNS-SS-ADA@CD-mPEG nanoparticle could be considered a potential candidate with high drug loading capacity and a lower risk of systemic toxicity.

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Low systemic toxicity nanocarriers fabricated from heparin-mPEG and PAMAM dendrimers for controlled drug release

Cited by 60 publications

References 49 publications

PEGylated PAMAM dendrimers loading oxaliplatin with prolonged release and high payload without burst effect

PEGylated PAMAM dendrimers loading oxaliplatin with prolonged release and high payload without burst effect

A novel RGDyC/PEG co-modified PAMAM dendrimer-loaded arsenic trioxide of glioma targeting delivery system

Efficient Self-Assembly of mPEG End-Capped Porous Silica as a Redox-Sensitive Nanocarrier for Controlled Doxorubicin Delivery

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