Therapeutic Enzyme‐Responsive Nanoparticles for Targeted Delivery and Accumulation in Tumors

Abstract

In this Communication, we describe an enzyme-responsive, paclitaxel-loaded nanoparticle and assess its safety and efficacy in vivo in a human fibrosarcoma murine xenograft. The material was generated via graft-through block copolymerization of norbornene monomers with hydrophilic targeting peptides together with hydrophobic paclitaxel prodrugs. This work represents a proof-of-concept study demonstrating the utility of enzyme-responsive nanoscale drug carriers capable of targeted accumulation and retention in tumor tissue in response to overexpressed endogenous enzymes. Critically, we observed low systemic toxicity in healthy mice following intravenous administration, with the maximum tolerated dose (MTD) exceeding 240 mg/kg with respect to paclitaxel. Furthermore, we observed efficacy against tumorigenesis paralleling that of paclitaxel at equivalent intravenous dosing, and near complete tumor growth suppression when administered intratumorally. This work represents a significant departure from traditional targeted drug delivery systems and presents a new avenue of exploration for nanomedicine.

Enzyme-targeted nanoparticles for delivery to ischemic skeletal muscle

“…Lastly, although we did not explore therapeutic molecule delivery here, it is important to note that the PPA system is amenable to the incorporation of a variety of therapeutics. In our hands, similar types of PPA particles have been prepared that contain small molecule drugs in the core, 18 or other peptides or nucleic acids in the shell. 20 Thus, this system can be easily modified for future therapeutic delivery.…”

“…We have previously shown that this system initially designed for cancer diagnosis and treatment can also be applied to non-invasive NP delivery to ischemic myocardium. 13 Furthermore, the system is easily tunable and has been conjugated to a variety of imaging and therapeutic functionalities, 18–20 providing proof of concept for minimally-invasive drug delivery and subsequent targeted retention. Our goal was to design enzyme-targeted PPA NPs and demonstrate their delivery and optimal biodistribution for targeting to ischemic muscle in a preclinical model of PAD.…”

Biosynthetic Polymers as Functional Materials

“…300,200 A similar shapechanging system demonstrated active cargo release of bound drugs at the site of scaffold assembly in a fibrosarcoma tumor model. 76 These proof-of-concept works demonstrate exceptional utility achieved by the dynamic morphological response of enzyme-responsive micellar assemblies in two ways: first as a discrete vehicle for noninvasive intravenous delivery and second as a stationary scaffold for diagnostics and localized drug release.…”

“…As such, considerable effort has been devoted toward the direct polymerization of complex peptides, 72 nucleobases, 73 bioderived polyesters, 74 imaging agents, 75 and therapeutic drugs. 76 These biosynthetic polymers possess extreme complexity with rigorous control over polymer assembly and in some cases biofunctionality as tumor targeting 77 and protease resistant materials. 78 In particular, protected and/or deprotected peptide-based monomers, which range in size from 5 to 30 amino acids, can be polymerized into dense brushes as homopolymers 79 or amphiphilic block copolymers that self-assemble into micellar nanoparticles.…”

Drug-Loaded Polymeric Spherical Nucleic Acids: Enhancing Colloidal Stability and Cellular Uptake of Polymeric Nanoparticles through DNA Surface-Functionalization

“…4,5 In particular, the ease with which these nanoparticles can be surface-functionalized 2 with a multitude of biologically active entities 2,6 has shown promise in many drug delivery applications. 5,7,8 Previously, we reported that ROMP-based doxorubicin-loaded PNPs can be modified with cationic surface moieties post-assembly to improve their stability in buffered media and in vitro cellular uptake. 7 However, the large diameters of these particles (~100–200 nm) may limit their cellular uptake 9 and tumor penetration when delivered in vivo .…”