Matrix Metalloproteinase-sensitive Multistage Nanogels Promote Drug Transport in 3D Tumor Model

Abstract

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.

Engineering precision nanoparticles for drug delivery

“…have been explored in depth in the tumour microenvironment, as NP penetration and stability are challenging in solid tumours 107,146 . Many characteristics of the tumour microenvironment -including the vasculature, interstitial fluid pressure and extracellular matrix (ECM) density -contribute to the limited permeation and penetration of NPs 3,[147][148][149][150] . Thus, the exact cause of successful NP accumulation in tumours has been highly debated, with only a few established trends correlating NP design to tumour delivery.…”

Mannose-Decorated Dendritic Polyglycerol Nanocarriers Drive Antiparasitic Drugs To Leishmania infantum-Infected Macrophages

“…Dendritic polyglycerols (PG) of hyperbranched character possess a variety of OH groups (linear and dendritic) that are easy to functionalize, with high control on their loading and position [ 38 , 39 ]. In recent communications, we reported the use of chemical linkers sensitive to changes on the pH or enzyme activity to conjugate prodrugs based on doxorubicin, methotrexate and paclitaxel to PG [ 40 , 41 , 42 , 43 , 44 ]. The modular character of the synthetic strategy that we developed enables the preparation of multifunctional nanocarriers, provided with solubilization enhancers (PEG, for instance), imaging agents and targeting moieties, in a simple procedure [ 45 , 46 , 47 , 48 , 49 ].…”

Tuneable peptide cross-linked nanogels for enzyme-triggered protein delivery

“…Release studies were performed in triplicate by incubating OG-BSA loaded nanogels (batches A-C) with various MMP-7 concentrations in a physiologically relevant nanomolar range. 58,59 FCS curves recorded at different time points in the presence or absence of MMP-7 revealed the release kinetics ( Fig. 6d and Fig.…”