Nanoparticle (NP) delivery of therapeutics aided in mitigating some of the toxicities associated with systemic drug delivery, yet, low NP accumulation and retention compromise the therapeutic efficacy. Herein, we developed a dual-sensitive nanoparticle (Dual-NP) composed of oxidized dextran NPs (~180 nm) surrounded by dendrimer NPs (~20 nm) that are initially bound by a cleavable linker —designed to enhance tumor accumulation owing to their initial large NP size (~200 nm)— engineered to rapidly disassemble under high matrix metalloproteinases (MMP) concentration and at low pH found in the tumor microenvironment (TME) —to enhance tumor penetration— followed by the in situ formation of nanohydrogels. Formation of the Dual-NP was confirmed by agarose gel retardation assay. Results showed that the highest conjugation was achieved at the 2.5:10 w/w ratio of dendrimer:dextran. Rapid cleavage of the dual sensitive linker was achieved in vitro after incubation with MMP-9 enzyme within the first 8 h. Similarly, a significant increase in the hydrolysis of the pH sensitive imine bond was found at pH 5.8 within the first 24 h. A rapid hydrolysis of the imine bond and cleavage of the MMP linker is important to promote the fast formation of the nanohydrogel in the tumor site. To assess the antitumor activity of the Dual-NP, 4T1 cells were incubated with MMP-9 pre-treated Dual-NPs loaded with Dox. High cytotoxicity was found owing to the release of small dendrimers carrying the drug which facilitates the internalization of Dox by cancer cells. Confocal images further confirmed a higher internalization of dendrimers in 4T1 cells after cleavage of the dual-sensitive linker. Dual-NPs and dendrimer NPs were tested in vivo using 4T1 cells in mice. 24 h following systemic administration, high accumulation of Dual-NP was found in the tumor site, owing to its initial larger size. Prolonged retention of NPs forming Dual-NPs was evident in vivo more than 10 days after local administration due to the formation of nanohydrogels that retain at the tumor tissue. The Dual-NP is a promising delivery platform of therapeutic agents that takes advantage of the specific characteristics of the tumor milieu and that can be leveraged to deliver a range of therapeutics to treat the primary tumor and metastatic lesions of triple-negative breast cancer, as well as other types of solid tumors.

Dual-nanoparticle system for enhanced drug accumulation and prolonged retention in metastatic cancers

ACS Spring Meeting 2021

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