Enzymatically Transformable Polymersome‐Based Nanotherapeutics to Eliminate Minimal Relapsable Cancer

Abstract

Prevention of metastatic and local‐regional recurrence of cancer after surgery remains difficult. Targeting postsurgical premetastatic niche and microresiduals presents an excellent prospective opportunity but is often challenged by poor therapeutic delivery into minimal residual tumors. Here, an enzymatically transformable polymer‐based nanotherapeutic approach is presented that exploits matrix metalloproteinase (MMP) overactivation in tumor‐associated tissues to guide the codelivery of colchicine (microtubule‐disrupting and anti‐inflammatory agent) and marimastat (MMP inhibitor). The dePEGylation of polymersomes catalyzed by MMPs not only exposes the guanidine moiety to improve tissue/cell‐targeting/retention to increase bioavailability, but also differentially releases marimastat and colchicine to engage their extracellular (MMPs) and intracellular (microtubules) targets of action, respectively. In primary tumors/overt metastases, the vasculature‐specific targeting of nanotherapeutics can function synchronously with the enhanced permeability and retention effect to deter malignant progression of metastatic breast cancer. After the surgical removal of large primary tumors, nanotherapeutic agents are localized in the premetastatic niche and at the site of the postsurgical wound, disrupting the premetastatic microenvironment and eliminating microresiduals, which radically reduces metastatic and local‐regional recurrence. The findings suggest that nanotherapeutics can safely widen the therapeutic window to resuscitate colchicine and MMP inhibitors for other inflammatory disorders.

Emerging Nano-Based Strategies Against Drug Resistance in Tumor Chemotherapy

“…An ideal drug delivery system should adequately protect drug cargo, minimize nonspecific interactions with biological species, and allow efficient aggregation to target sites. In addition, the drug delivery system, once accumulated in tumor tissue, should provide sufficient penetration to deliver the drug throughout the tumor tissue, resulting in mass apoptosis of tumor cells ( Li et al, 2014 ; Li et al, 2015 ; Li et al, 2021 ). For a long time, we have been tried to design more complex nanomaterials in many circumstances.…”

“…Li et al reported an enzymatically polymer to simultaneously deliver colchicine chemotherapeutics and marimastat, which is a potent MMPs inhibitor ( Figure 9 ). Based on the efficient drug delivery, this nanosystem could disrupt the microtubules of tumor cells by colchicine, and simultaneously prevent tumor metastasis microenvironment, which could reduce the primary post-surgical recurrence and distant metastasis significantly ( Li et al, 2021 ). To be noted that, MMPs are commonly activated in some tumor tissues, some nanosystem were developed to release chemotherapeutics in MMP-responsive manner ( Yao et al, 2018 ; Vaghasiya et al, 2020 ), displaying an enhanced chemotherapeutical response.…”

“… Schematic illustration of MMPs inhibition to eliminate tumor metastasis. Reproduced with permission ( Li et al, 2021 ). Copyright 2021, Wiley.…”

Current Perspectives on Synthetic Compartments for Biomedical Applications

“…Successful in vitro evaluation of nanocompartments leads to in vivo studies for various biomedical applications and treatments, such as enzyme replacement [ 78 , 89 , 120 , 138 ] and gene therapy [ 80 ], cancer [ 76 , 77 ], hyperammonemia [ 95 ], diabetes [ 87 ], and osteoporosis [ 69 ]. When L-asparaginase was loaded in poly(ethylene glycol)- block -2-hydroxypropyl methacrylate (PEG- b -PHPMA) polymersomes, the enzyme was more protected from proteolytic attack in vitro and in vivo than native or PEGylated enzymes.…”

“…These catalytic nanocompartments exhibited high efficacy in suppressing the tumor size in lung tumor-bearing mice, increasing the survival rate from 0% for untreated and camptothecin-treated animals to 80% in 90 days while their systemic toxicity remained low. Meanwhile, taking advantage of the overexpression of matrix metalloproteinases (MMPs) in tumor sites, polymersomes composed of triblock copolymers of MMP-cleavable peptide-linked poly(ethylene glycol), poly(ε-carprolactone) (PEG-GPLGVRG-PCL), and CPP-mimicking polymer poly(3-guanidinopropyl methacrylamide) (PGPMA) were loaded with the MMP inhibitor marimastat and colchicine, an inhibitor of microtubule formation [ 77 ]. The nanocompartments not only reduced the tumor size by almost 1.5 times in orthotopic and metastatic breast cancer-bearing mice but were successful in inhibiting its relapse after surgical abscission in almost 70% of the animals.…”