Dataset Information

Matrix Metalloproteinase-9-Responsive Nanogels for Proximal Surface Conversion and Activated Cellular Uptake.

ABSTRACT: Here, we have exploited the heightened extracellular concentration of matrix metalloproteinase-9 (MMP-9) to induce surface-conversional properties of nanogels with the aim of tumor-specific enhanced cellular uptake. A modular polymeric nanogel platform was designed and synthesized for facile formulation and validation of MMP-9-mediated dePEGylation and generation of polyamine-type surface characteristics through peptide N-termini. Nanogels containing MMP-9-cleavable motifs and different poly(ethylene glycol) corona lengths (350 and 750 g/mol) were prepared, and enzymatic surface conversional properties were validated by MALDI characterization of cleaved byproducts, fluorescamine assay amine quantification, and zeta potential. The nanogel with a shorter PEG length, mPEG350-NG, exhibited superior surface conversion in response to extracellular concentrations of MMP-9 compared to that of the longer PEG length, mPEG750-NG. Confocal microscopy images of HeLa cells incubated with both fluorescein-labeled nanogels and DiI-encapsulated nanogels demonstrated greater uptake following MMP-9 "activation" for mPEG350-NG compared to its nontreated "passive" mPEG350-NG parent, demonstrating the versatility of such systems to achieve stimuli-responsive uptake in response to cancer-relevant proteases.

SUBMITTER: Gordon MR

PROVIDER: S-EPMC6298948 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Matrix Metalloproteinase-9-Responsive Nanogels for Proximal Surface Conversion and Activated Cellular Uptake.

Gordon Mallory R MR Zhao Bo B Anson Francesca F Fernandez Ann A Singh Khushboo K Homyak Celia C Canakci Mine M Vachet Richard W RW Thayumanavan S S

Biomacromolecules 20180208 3

Here, we have exploited the heightened extracellular concentration of matrix metalloproteinase-9 (MMP-9) to induce surface-conversional properties of nanogels with the aim of tumor-specific enhanced cellular uptake. A modular polymeric nanogel platform was designed and synthesized for facile formulation and validation of MMP-9-mediated dePEGylation and generation of polyamine-type surface characteristics through peptide N-termini. Nanogels containing MMP-9-cleavable motifs and different poly(eth ...[more]

PMID: 29360342

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Project description:Physiological barriers inside of tumor tissue often result in poor interstitial penetration and heterogeneous intratumoral distribution of nanoparticle-based drug delivery systems (DDS). Novel, matrix metalloproteinase (MMP)-sensitive peptide-crosslinked nanogels (pNGs) as multistage DDS are reported with a beneficial size reduction property to promote the process of deep tissue penetration. Methods: The presented pNGs are based on a dendritic polyglycerol (dPG) scaffold crosslinked by a modified MMP-sensitive fluorogenic peptide. The crosslinker integrates degradability in response to proteases present in the tumor microenvironment. Surfactant-free, inverse nanoprecipitation is employed to prepare the nanogels using strain-promoted click chemistry. The size and crosslinking density of the pNGs are controlled by the functionalization degree of dPG with cyclooctyne groups and by the peptide crosslinker fraction. The intrinsic reporter moiety of the crosslinker was used to study the influence of pNG compositions on the degradation profile. The therapeutic drug Doxorubicin was conjugated through a pH-sensitive linkage to dPG to form a multistage DDS. The penetration behavior of the pNGs was studied using agarose matrix and multicellular tumor spheroids (MCTS). Results: Nanogel sizes were controlled in the range of 150-650 nm with narrow size distributions and varying degrees of crosslinking. The pNGs showed stability in PBS and cell media but were readily degraded in the presence of MMP-7. The crosslinking density influenced the degradation kinetic mediated by MMP-7 or cells. Stable conjugation of DOX at physiological pH and controlled drug release at acidic pH were observed. The digestions of nanogels lead to a size reduction to polymer-drug fragments which efficiently penetrated into agarose gels. Moreover, the degradable multistage pNGs demonstrated deeper penetration into MCTS as compared to their non-degradable counterparts. Thus, degradable pNGs were able to deliver their cargo and efficiently reduce the cell viability in MCTS. Conclusion: The triggered size reduction of the pNGs by enzymatic degradation can facilitate the infiltration of the nanocarrier into dense tissue, and thereby promote the delivery of its cargo.

Project description:Elevated levels of intracellular hydrogen peroxide (H2O2) are closely related to the development of cancers. Specific imaging of H2O2 in tumor sites would be significant not only for cancer diagnosis but also for gaining a deep understanding of the role of H2O2 in cancer. However, traditional fluorescent probes based only on responses to overexpression levels of H2O2 in cancer cells are insufficient to distinguish cancer cells from other unhealthy or healthy cells in complex biological systems. Herein, we developed a smart, two-photon fluorescent GC-NABP nanoprobe with pH-dependent surface charge conversion for tumor-targeted imaging of H2O2. The nanoprobe was constructed by the self-assembly of amphiphilic GC-NABP, which was synthesized by grafting the hydrophobic, H2O2-responsive and two-photon fluorophore, NABP, onto hydrophilic biopolymer glycol chitosan (GC). Taking advantage of pH-titratable amino groups on GC, the nanoprobe had the capability of surface charge conversion from negative at physiologic pH to positive in the acidic tumor microenvironment. The positive charge of the nanoprobe promoted electrostatic interactions with cell membranes, leading to enhanced cellular uptake in acidic environment. Upon cellular uptake, the high level of H2O2 in tumor cells triggered boronate deprotections of the nanoprobe, generating a "turn-on" fluorescence emission for H2O2 imaging. The nanoprobe exhibited good sensitivity and selectivity to H2O2 with a detection limit down to 110 nM in vitro. The results from flow cytometry and two-photon fluorescence imaging of H2O2 in living cells and tissues evidenced the enhanced cellular uptake and targeted imaging of intracellular H2O2 in acidic environment. Compared to control nanoparticles that lack pH sensitivity, our nanoprobe showed enhanced accumulation in tumor sites and was applied to targeted imaging of H2O2 in a tumor-bearing mouse model. This work demonstrates that the nanoprobe GC-NABP holds great promise for tumor-specific imaging of cellular H2O2, providing a potential tool to explore the role of H2O2 in tumor sites.

Dataset Information

Matrix Metalloproteinase-9-Responsive Nanogels for Proximal Surface Conversion and Activated Cellular Uptake.

Publications

Matrix Metalloproteinase-9-Responsive Nanogels for Proximal Surface Conversion and Activated Cellular Uptake.

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