Dense extracellular matrix (ECM) severely impedes the spread of
drugs in solid tumors and induces hypoxia, reducing chemotherapy efficiency.
Different proteolytic enzymes, such as collagenase (Col) or bromelain,
can directly attach to the surface of nanoparticles and improve their
diffusion, but the method of ligation may also impair the enzymatic
activity due to conformational changes or blockage of the active site.
Herein, a “nanoenzyme capsule” was constructed by combining
collagenase nanocapsules (Col-nc) with heavy-chain ferritin (HFn)
nanocages encapsulating the chemotherapy drug doxorubicin (DOX) to
enhance tumor penetration of the nanoparticles by hydrolyzing collagen
from the ECM. Col-nc could protect the activity of the enzyme before
reaching the site of action while being degraded under mildly acidic
conditions in tumors, and the released proteolytic enzyme could digest
collagen. In addition, HFn as a carrier could effectively load DOX
and had a self-targeting ability, enabling the nanoparticles to internalize
into cancer cells more effectively. From in vivo and in vitro studies,
we found that collagen was effectively degraded by Col-nc/HFn(DOX)
to increase the accumulation and penetration of nanoparticles in the
solid tumor site and could alleviate hypoxia inside the tumor to enhance
the antitumor effects of DOX. Therefore, the strategy of increasing
nanoparticle penetration in this system is expected to provide a potential
approach for the clinical treatment of solid tumors.
In the tumor microenvironment (TME), the extracellular matrix (ECM) produced by cancer-associated fibroblasts (CAFs) forms a dense barrier that prevents nanodrugs from penetrating into deep tumor sites, leading to unsatisfactory therapeutic effects. Recently, it has been found that ECM depletion and using small-sized nanoparticles are effective strategies. Herein, we reported a detachable dual-targeting nanoparticle (HA-DOX@GNPs-Met@HFn) based on reducing ECM for enhancing penetration. When these nanoparticles reached the tumor site, the nanoparticles were divided into two parts in response to matrix metalloproteinase-2 overexpressed in TME, causing a decrease in the nanoparticle size from about 124 to 36 nm. One part was Met@HFn, which was detached from the surface of gelatin nanoparticles (GNPs), which effectively targeted tumor cells and released metformin (Met) under acidic conditions. Then, Met downregulated the expression of the transforming growth factor β by the adenosine monophosphate-activated protein kinase pathway to inhibit the activity of CAFs, thereby suppressing the production of ECM including α-smooth muscle actin and collagen I. The other was the small-sized hyaluronic acid-modified doxorubicin prodrug with autonomous targeting ability, which was gradually released from GNPs and internalized into deeper tumor cells. Intracellular hyaluronidases triggered the release of doxorubicin (DOX), which killed tumor cells by inhibiting DNA synthesis. The combination of size transformation and ECM depletion enhanced the penetration and accumulation of DOX in solid tumors. Therefore, the tumor chemotherapy effect was greatly improved.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.