Exosomes,
biological extracellular vesicles, have recently begun
to find use in targeted drug delivery in solid tumor research. Ranging
from 30–120 nm in size, exosomes are secreted from cells and
isolated from bodily fluids. Exosomes provide a unique material platform
due to their characteristics, including physical properties such as
stability, biocompatibility, permeability, low toxicity, and low immunogenicityall
critical to the success of any nanoparticle drug delivery system.
In addition to traditional chemotherapeutics, natural products and
RNA have been encapsulated for the treatment of breast, pancreatic,
lung, prostate cancers, and glioblastoma. This review discusses current
research on exosomes for drug delivery to solid tumors.
Nanoparticles are becoming an increasingly popular tool for biomedical imaging and drug delivery. While the prevalence of nanoparticle drug-delivery systems reported in the literature increases yearly, relatively little translation from the bench to the bedside has occurred. It is crucial for the scientific community to recognize this shortcoming and re-evaluate standard practices in the field, to increase clinical translatability. Currently, nanoparticle drug-delivery systems are designed to increase circulation, target disease states, enhance retention in diseased tissues, and provide targeted payload release. To manage these demands, the surface of the particle is often modified with a variety of chemical and biological moieties, including PEG, tumor targeting peptides, and environmentally responsive linkers. Regardless of the surface modifications, the nano–bio interface, which is mediated by opsonization and the protein corona, often remains problematic. While fabrication and assessment techniques for nanoparticles have seen continued advances, a thorough evaluation of the particle’s interaction with the immune system has lagged behind, seemingly taking a backseat to particle characterization. This review explores current limitations in the evaluation of surface-modified nanoparticle biocompatibility and in vivo model selection, suggesting a promising standardized pathway to clinical translation.
Biological
nanoparticles, such as exosomes, offer an approach to
drug delivery because of their innate ability to transport biomolecules.
Exosomes are derived from cells and an integral component of cellular
communication. However, the cellular cargo of human exosomes could
negatively impact their use as a safe drug carrier. Additionally,
exosomes have the intrinsic yet enigmatic, targeting characteristics
of complex cellular communication. Hence, harnessing the natural transport
abilities of exosomes for drug delivery requires predictably targeting
these biological nanoparticles. This manuscript describes the use
of two chemical modifications, incorporating a neuropilin receptor
agonist peptide (iRGD) and a hypoxia-responsive lipid for targeting
and release of an encapsulated drug from bovine milk exosomes to triple-negative
breast cancer cells. Triple-negative breast cancer is a very aggressive
and deadly form of malignancy with limited treatment options. Incorporation
of both the iRGD peptide and hypoxia-responsive lipid into the lipid
bilayer of bovine milk exosomes and encapsulation of the anticancer
drug, doxorubicin, created the peptide targeted, hypoxia-responsive
bovine milk exosomes, iDHRX. Initial studies confirmed the presence
of iRGD peptide and the exosomes’ ability to target the αvβ3 integrin, overexpressed on triple-negative
breast cancer cells’ surface. These modified exosomes were
stable under normoxic conditions but fragmented in the reducing microenvironment
created by 10 mM glutathione. In vitro cellular internalization studies
in monolayer and three-dimensional (3D) spheroids of triple-negative
breast cancer cells confirmed the cell-killing ability of iDHRX. Cell
viability of 50% was reached at 10 μM iDHRX in the 3D spheroid
models using four different triple-negative breast cancer cell lines.
Overall, the tumor penetrating, hypoxia-responsive exosomes encapsulating
doxorubicin would be effective in reducing triple-negative breast
cancer cells’ survival.
Exosomes, naturally secreted extracellular bilayer vesicles (diameter 40–130 nm), have been rendered echogenic (responsive to ultrasound) allowing their potential use as a dual agent for drug delivery and ultrasound imaging.
While many classes of chemotherapeutic agents exist to treat solid tumors, few can generate a lasting response without substantial off-target toxicity despite significant scientific advancements and investments. In this review, the paths of development for nanoparticles, oncolytic viruses, and oncolytic bacteria over the last 20 years of research towards clinical translation and acceptance as novel cancer therapeutics are compared. Novel nanoparticle, oncolytic virus, and oncolytic bacteria therapies all start with a common goal of accomplishing therapeutic drug activity or delivery to a specific site while avoiding off-target effects, with overlapping methodology between all three modalities. Indeed, the degree of overlap is substantial enough that breakthroughs in one therapeutic could have considerable implications on the progression of the other two. Each oncotherapeutic modality has accomplished clinical translation, successfully overcoming the potential pitfalls promising therapeutics face. However, once studies enter clinical trials, the data all but disappears, leaving pre-clinical researchers largely in the dark. Overall, the creativity, flexibility, and innovation of these modalities for solid tumor treatments are greatly encouraging, and usher in a new age of pharmaceutical development.
Sequestra, present in many cancers and orthopedic infections, provide a safe harbor for the development of drug resistance. In the face of burgeoning drug resistance, the importance of nanoscale, microenvironment-triggered drug delivery cannot be overestimated. Such strategies may preserve pharmaceutical efficacy and significantly alter the etiology of many orthopedic diseases. Although temperature-, pH- and redox-responsive nanoparticle-based systems have been extensively studied, local drug delivery from polymeric nanoparticles can be triggered by a variety of energy forms. This review offers an overview of the state of the field as well as a perspective on the safety and efficacy of ultrasound, hyperthermia and radio frequency-triggered internal delivery systems in a variety of applications.
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