MMP-2-Sensitive HA End-Conjugated Poly(amidoamine) Dendrimers via Click Reaction To Enhance Drug Penetration into Solid Tumor

Abstract

Currently, the limited penetration of nanoparticles remains a major challenge for antitumor nanomedicine to penetrate into the tumor tissues. Herein, we propose a size-shrinkable drug delivery system based on a polysaccharide-modified dendrimer with tumor microenvironment responsiveness for the first time to our knowledge, which was formed by conjugating the terminal glucose of hyaluronic acid (HA) to the superficial amidogen of poly(amidoamine) (PAMAM), using a matrix metalloproteinase-2 (MMP-2)-cleavable peptide (PLGLAG) via click reaction. These nanoparticles had an initial size of ∼200 nm, but once deposited in the presence of MMP-2, they experienced a dramatic and fast size change and dissociated into their dendrimer building blocks (∼10 nm in diameter) because of cleavage of PLGLAG. This rapid size-shrinking characteristic not only promoted nanoparticle extravasation and accumulation in tumors benefited from the enhanced permeability and retention effect but also achieved faster nanoparticle diffusion and penetration. We have further conducted comparative studies of MMP-2-sensitive macromolecules (HA-pep-PAMAM) and MMP-2-insensitive macromolecules (HA-PAMAM) synthesized with a similar particle size, surface charge, and chemical composition and evaluated in both monolayer cells and multicellular spheroids. The results confirmed that the enzyme-responsive size shrink is an implementable strategy to enhance drug penetration and to improve therapeutic efficacy. Meanwhile, macromolecule-based nanoparticles with size-variable characteristics not only promote drug penetration, but they can also be used as gene delivery systems, suggesting great potential as nano-delivery systems.

Rational Design of Nanoparticles with Deep Tumor Penetration for Effective Treatment of Tumor Metastasis

“…The size and surface charge alterations significantly promoted diffusion into the center region of tumor and facilitate their uptake by CSCs and non‐CSC cancer cells, thereby achieving superior tumor inhibition activity and effective CSC‐killing capacity in vivo. Additionally, an intelligent switch can be achieved by exploring highly expressed MMPs in tumor tissues . Based on a multistage size/charge alteration strategy, nanoparticles can be rationally designed with prominent advantages for enhanced tumor penetration and efficient drug delivery.…”

Supramolecular Complex of Methyl-β-cyclodextrin with Adamantane-Grafted Hyaluronic Acid as a Novel Antitumor Agent

“…Recently, a number of HA-based drug carriers for antitumor drugs have been developed, [43][44][45][46] and they improved antitumor activity of the drugs in vivo. However, antitumor drugs often cause adverse effects, but M-β-CyD is expected to provide slight side effects because it has been widely used as pharmaceutical excipients, compared to common antitumor drugs.…”

Stimulus-Responsive Nanomedicines for Disease Diagnosis and Treatment

“…To improve permeability, antitumor efficacy and biodegradability, a size-shrinkable drug delivery system has been designed based on polysaccharide-modified dendrimers, which contained poly (amidoamine), hyaluronic acid and MMP2-sensitive peptide linker (PLGLAG). The system retained good stability in blood circulation, and underwent degradation upon the action of MMP2, leading to enhanced uptake in tumor cells [ 81 ]. In addition, polypeptide GPLGVRG [ 82 , 83 ], polypeptide GPLGVRGDG [ 84 ] and triglyceride monostearate (TGMS) [ 85 ] have also been synthesized for MMP2 sensitive drug delivery systems.…”