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.

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.

Lipid‐coated microbubbles, clinically approved as contrast enhancing agents for ultrasound imaging, are investigated for the first time for their possible applications in bone tissue engineering. Effects of microbubbles (average diameter 1.1 µm) coated by a mixture of lipids (1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine, 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphoethanolamine‐N‐[methoxy(polyethylene glycol)‐2000], and 1,2‐dipalmitoyl‐3‐trimethylmmonium‐propane) in the presence of low intensity pulsed ultrasound (LIPUS) on human mesenchymal stem cells seeded on 3D printed poly(lactic acid) porous scaffolds are investigated. LIPUS stimulation (30 mW cm−2, 1.5 MHz, 20% duty cycle) for 3 min a day with 0.5% v/v microbubbles results in a significant increase in proliferation (up to 19.3%) when compared to control after 1, 3, and 5 d. A 3‐week osteogenic differentiation study shows a significant increase in total protein content (up to 27.5%), calcium deposition (up to 4.3%), and alkaline phosphatase activity (up to 43.1%) initiated by LIPUS with and without the presence of microbubbles. The microbubbles are found to remain stable during exposure, and their sustained oscillations demonstrably help focus the LIPUS energy toward enhanced cellular response. Integrating LIPUS and microbubbles promises to be a novel and effective strategy for bone tissue engineering and regeneration therapies.

» Three-dimensional (3D) printing is an emerging tool in provider and patient education, surgical planning, and the design and implementation of medical devices and implants.» Recent decreases in the cost of 3D printers along with advances in and cost reduction of printable materials have elevated 3D printing within the medical device industry.» The advantages of 3D printing over traditional means of implant manufacturing lie in its ability to use a wide array of materials, its fine control of the macro- and microarchitecture, and its unprecedented customizability.» Barriers to the widespread adoption of 3D-printed implants include questions of implant durability, U.S. Food and Drug Administration (FDA) approval for patient-specific implants, and insurance coverage of those implants.

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.

Objectives-Cancer is characterized by uncontrolled cell proliferation, which makes novel therapies highly desired. In this study, the effects of near-field lowintensity pulsed ultrasound (LIPUS) stimulation on T47D human breast cancer cell and healthy immortalized MCF-12A breast epithelial cell proliferation were investigated in monolayer cultures. Methods-A customized ultrasound (US) exposure setup was used for the variation of key US parameters: intensity, excitation duration, and duty cycle. Cell proliferation was quantified by 5-bromo-2 0-deoxyuridine and alamarBlue assays after LIPUS excitation. Results-At a 20% duty cycle and 10-minute excitation period, we varied LIPUS intensity from to 100 mW/cm 2 (spatial-average temporal-average) to find a gradual decrease in T47D cell proliferation, the decrease being strongest at 100 mW/cm 2. In contrast, healthy MCF-12A breast cells showed an increase in proliferation when exposed to the same conditions. Above a 60% duty cycle, T47D cell proliferation decreased drastically. Effects of continuous wave US stimulation were further explored by varying the intensity and excitation period. Conclusions-These experiments concluded that, irrespective of the waveform (pulsed or continuous), LIPUS stimulation could inhibit the proliferation of T47D breast cancer cells, whereas the same behavior was not observed in healthy cells. The study demonstrates the beneficial bioeffects of LIPUS on breast cancer cells and offers the possibility of developing novel US-mediated cancer therapy.

In article number https://doi.org/10.1002/adbi.201800257, Kausik Sarkar and co‐workers explore a novel application of microbubbles along with low intensity pulsed ultrasound (LIPUS) in bone tissue engineering. The lipid coated microbubbles enhance proliferation and osteogenic differentiation of human mesenchymal stem cells on 3D printed poly(lactic) acid scaffolds. The effect is found to be greater than that with LIPUS alone. It promises great therapeutic potential for the treatment of bone injuries that afflict millions worldwide with debilitating pain and crippling disabilities.

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