Enhanced Drug Delivery by Nanoscale Integration of a Nitric Oxide Donor To Induce Tumor Collagen Depletion

Abstract

Delivery of therapeutics into the solid tumor microenvironment is a major challenge for cancer nanomedicine. Administration of certain exogenous enzymes which deplete tumor stromal components has been proposed as a method to improve drug delivery. Here we present a protein-free collagen depletion strategy for drug delivery into solid tumors, based on activating endogenous matrix metalloproteinases (MMP-1 and -2) using nitric oxide (NO). Mesoporous silica nanoparticles (MSN) were loaded with a chemotherapeutic agent, doxorubicin (DOX) as well as a NO donor (S-nitrosothiol) to create DN@MSN. The loaded NO results in activation of MMPs which degrade collagen in the tumor extracellular matrix. Administration of DN@MSN resulted in enhanced tumor penetration of both the nanovehicle and cargo (DOX), leading to significantly improved antitumor efficacy with no overt toxicity observed.

The role of collagen in cancer: from bench to bedside

“…Collagenase combined with trastuzumab via thermosensitive hydrogels exerted an anticancer effect on animals [212]. Nitric oxide activated endogenous MMP-1 and MMP-2 to deplete collagen, and it significantly improved anticancer efficacy while exerting no overt toxicity in animal models [213]. Under hypoxic cancer conditions, hyperbaric oxygen therapy decreased collagen deposition to enhance chemotherapy efficacy and photodynamic upconversion nanophotosensitizer cancer therapy [214].…”

Biomimetic, Hypoxia‐Responsive Nanoparticles Overcome Residual Chemoresistant Leukemic Cells with Co‐Targeting of Therapy‐Induced Bone Marrow Niches

“…The MSN nanovehicle was prepared according to the procedures previously described . For DNR loading, 20 mg empty MSN were dispersed in 20 mL PBS (0.01 m ) containing DNR (1 mg mL −1 ).…”

“…The membrane coating was also identified using a FRET assay. Briefly, MSN core was labeled with iFluor 647 (iFluor 647‐MSN) as previously described, and the CM vesicles were labeled with DiI (DiI‐CM). The dual‐fluorophore‐labeled nanosystem, CMSN (iFluor 647, DiI), was then generated.…”

“…Cell uptake of the nanoparticles was also quantified using flow cytometry. PEGylated MSN (MSN‐PEG) prepared as described and CMSN (empty) were included as control.…”

Tumor Targeting Strategies of Smart Fluorescent Nanoparticles and Their Applications in Cancer Diagnosis and Treatment

“…According to their results, DN@MSN enhanced the EPR effect of NPs and improved the tumor penetration of both the nanovehicle and cargo (DOX), leading to significantly improved antitumor efficacy. [185] Therefore, it is necessary to study the TME from both biological and philosophical perspectives.…”