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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.

Natural products, such as curcumin and artemisinin, have shown clinical improvement in breast cancer patients. However, the beneficial effects can be enhanced by delivering the compounds to tumors through nanocarriers. For example, encapsulation in nanoparticles overcomes the low water solubility of these natural products, alters biodistribution, targets the cancer cells, and leads to higher accumulation in the malignant tissues. Exosomes, liposomes, polymersomes, magnetic nanoparticles, and protein-based nanoparticles have been tested for carrying the natural products for the treatment of breast cancer. This chapter discusses the major advantages, disadvantages, and future translational potential of these nanoparticles for delivering curcumin, epigallocatechin gallate, resveratrol, and artemisinin.

Exosomes are naturally secreted extracellular bilayer vesicles (diameter 40–130 nm), which have recently been found to play a critical role in cell-to-cell communication and biomolecule delivery. Their unique characteristics—stability, permeability, biocompatibility and low immunogenicity—have made them a prime candidate for use in delivering cancer therapeutics and other natural products. Here we present the first ever report of echogenic exosomes, which combine the benefits of the acoustic responsiveness of traditional microbubbles with the non-immunogenic and small-size morphology of exosomes. Microbubbles, although effective as ultrasound contrast agents, are restricted to intravascular usage due to their large size. In the current study, we have rendered bovine milk-derived exosomes echogenic by freeze drying them in the presence of mannitol. Ultrasound imaging and direct measurement of linear and nonlinear scattered responses were used to investigate the echogenicity and stability of the prepared exosomes. A commercial scanner registered enhancement (28.9% at 40 MHz) in the brightness of ultrasound images in presence of echogenic exosomes at 5 mg mL−1. The exosomes also showed significant linear and nonlinear scattered responses—11 dB enhancement in fundamental, 8.5 dB in subharmonic and 3.5 dB in second harmonic all at 40 μg mL−1 concentration. Echogenic exosomes injected into the tail vein of mice and the synovial fluid of rats resulted in significantly higher brightness—as much as 300%—of the ultrasound images, showing their promise in a variety of in vivo applications. The echogenic exosomes, with their large-scale extractability from bovine milk, lack of toxicity and minimal immunogenic response, successfully served as ultrasound contrast agents in this study and offer an exciting possibility to act as an effective ultrasound responsive drug delivery system.

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.

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 immunogenicity-all 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.

Biomaterials, of either natural or synthetic origin, have become essential to current medical practice. Unfortunately, all materials that come in contact with the biological milieu are subjected to almost immediate and ubiquitous protein biofouling. This interfacial protein layer typifies the beginning of the inherent biological response to an invading foreign body, the foreign body response (FBR). Manipulating the pathology of the FBR response to a material has become of critical importance for clinical care. Despite numerous commercial biomaterials with coatings to mask the material and provide “seamless” integration with biology, many challenges, facets of biocompatibility, remain for novel biodegradable polymers, including hemocompatibility. As with the majority of issues surrounding the biocompatibility of a material, hemocompatibility is mediated by the interaction at the blood-material interface. In addition to the ubiquitous host protein coating, biocompatibility is also influenced by material degradation, as degradation products often provoke coagulation. Hence, the advent of hybrid biodegradable biomaterials, which provide material flexibility to improve the overall hemocompatibility of the implant, may prove promising alternatives. In this chapter, different types of biodegradable and hybrid biodegradable materials along with their underlying polymer compositions and modifications are discussed in the context of hemocompatibility.

Exosomes are naturally secreted bilayer vesicles ranging in size from 40 to 200 nm that play a critical role in cell-to-cell communications and protein and RNA delivery. Researchers have explored exosomes as potential drug delivery vehicles due to their natural morphology and small size. Here, for the first time, bovine milk derived exosomes have been modified to be acoustically responsive as potential ultrasound contrast agents or a drug carrier. The echogenic exosomes were formed through a freeze-drying process in the presence of mannitol. The size and morphology of the particles were assessed with a qNano™ and atomic force microscopy (AFM). The ultrasound response of these particles was characterized through linear and non-linear scattering behaviors. The presence of the echogenic exosomes enhances the scattered signal by 11.4 ± 6.3 dB. The stability of these particles under constant ultrasound exposure were assessed to be similar to that of echogenic polymersomes. The variation of mannitol concentration was assessed. To assess the imaging improvement of ultrasound imaging, the exosomes were injected through a tail vein in mice. The modification of the echogenic exosomes shows to have great promise as potential ultrasound contrast agents or ultrasound responsive drug delivery system.

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.