Exosomes participate in cancer progression and metastasis by transferring bioactive molecules between cancer and various cells in the local and distant microenvironments. Such intercellular ...cross‐talk results in changes in multiple cellular and biological functions in recipient cells. Several hallmarks of cancer have reportedly been impacted by this exosome‐mediated cell‐to‐cell communication, including modulating immune responses, reprogramming stromal cells, remodeling the architecture of the extracellular matrix, or even endowing cancer cells with characteristics of drug resistance. Selectively, loading specific oncogenic molecules into exosomes highlights exosomes as potential diagnostic biomarkers as well as therapeutic targets. In addition, exosome‐based drug delivery strategies in preclinical and clinical trials have been shown to dramatically decrease cancer development. In the present review, we summarize the significant aspects of exosomes in cancer development that can provide novel strategies for potential clinical applications.
Exosomes in cancer development.
Noninvasive monitoring of kidney elimination of engineered nanoparticles at high temporal and spatial resolution will not only significantly advance our fundamental understandings of nephrology on ...the nanoscale, but also aid in the early detection of kidney disease, which affects more than 10 % of the worldwide population. Taking advantage of strong NIR absorption of the well‐defined Au25(SG)18 nanocluster, photoacoustic (PA) imaging was used to visualize its transport in situ through the aorta to the renal parenchyma and its subsequent filtration into the renal pelvis at a temporal resolution down to 1 s. High temporal and spatial resolution imaging of Au25(SG)18 kidney elimination allowed the accurate quantification of the glomerular filtration rate (GFR) of individual kidneys in normal and pathological conditions, broadening the biomedical applications of engineered nanoparticles in preclinical kidney research.
Photoacoustic imaging was used to visualize the transport of Au25(SG)18 nanoclusters through the aorta to the renal parenchyma and its subsequent filtration into the renal pelvis at a temporal resolution of 1 s, allowing the accurate quantification of the glomerular filtration rate of individual kidneys in normal and pathological conditions. This broadens the biomedical applications of engineered nanoparticles in preclinical kidney research.
Precise control of in vivo transport of anticancer drugs in normal and cancerous tissues with engineered nanoparticles is key to the future success of cancer nanomedicines in clinics. This requires a ...fundamental understanding of how engineered nanoparticles impact the targeting‐clearance and permeation‐retention paradoxes in the anticancer‐drug delivery. Herein, we systematically investigated how renal‐clearable gold nanoparticles (AuNPs) affect the permeation, distribution, and retention of the anticancer drug doxorubicin in both cancerous and normal tissues. Renal‐clearable AuNPs retain the advantages of the free drug, including rapid tumor targeting and high tumor vascular permeability. The renal‐clearable AuNPs also accelerated body clearance of off‐target drug via renal elimination. These results clearly indicate that diverse in vivo transport behaviors of engineered nanoparticles can be used to reconcile long‐standing paradoxes in the anticancer drug delivery.
The best of both worlds: Long‐standing paradoxes in anticancer drug delivery, including high tumor targeting vs. rapid clearance, and high permeability vs. low systemic toxicity, can be addressed by using renal‐clearable gold nanoparticles (AuNPs). Doxorubicin‐loaded AuNPs (DOX@AuNPs) retain the rapid tumor targeting and high tumor permeability of the free drug, and off‐target DOX@AuNPs are more quickly cleared from the body than the free drug.
Enhancing tumor targeting of nanocarriers has been a major strategy for advancing clinical translation of cancer nanomedicines. Herein, we report a head‐to‐head comparison between 5 nm renal ...clearable and 30 nm non‐renal clearable gold nanoparticle (AuNP)‐based drug delivery systems (DDSs) in the delivery of doxorubicin (DOX). While the two DDSs themselves had comparable tumor targeting, we found their different vascular permeability played an even more important role than blood retention in the delivery and intratumoral transport of DOX, of which tumor accumulation, efficacy, and therapeutic index were enhanced 2, 7, and 10‐fold, respectively, for the 5 nm DDS over 30 nm one. These findings indicate that ultrahigh vascular permeability of renal clearable nanocarriers can be utilized to further improve anticancer drug delivery without the need for prolonged blood retention.
Cleared for takeoff: The ultrahigh vascular permeability of renal clearable gold nanoparticles can be utilized to enhance drug delivery, intratumoral transport, and therapeutic efficacy without the need for long blood retention.
With more and more engineered nanoparticles (NPs) being designed renal clearable for clinical translation, fundamental understanding of their transport in the different compartments of kidneys ...becomes increasingly important. Here, we report noninvasive X‐ray imaging of renal clearable gold NPs (AuNPs) in normal and nephropathic kidneys. By quantifying the transport kinetics of the AuNPs in cortex, medulla and pelvis of the normal and injured kidneys, we found that ureteral obstruction not just blocked the NP elimination through the ureter but also slowed down their transport from the medulla to pelvis and enhanced the cellular uptake. Moreover, the transport kinetics of the NPs and renal anatomic details can be precisely correlated with local pathological lesion. These findings not only advance our understandings of the nano‐bio interactions in kidneys but also offer a new pathway to noninvasively image kidney dysfunction and local injuries at the anatomical level.
Imaging of nanoparticle transport: High‐contrast noninvasive X‐ray imaging of the transport process of renal clearable gold nanoparticles makes it possible to quantitatively understand the interactions between the nanoparticles and both a normal and an injured kidney at the anatomical level. The transport kinetics of the nanoparticles and renal anatomic details can be precisely correlated with local pathological lesion.
Fluorescence imaging has emerged as a promising technique for monitoring and assessing various biologically relevant species in cells and organisms, driving the demand for effective fluorescent ...agents with good biocompatibility and high fluorescence performance. However, traditional fluorescent agents, such as quantum dots (QDs) and organic dyes, either suffer from toxicity concerns or poor fluorescence performance (e.g., low photobleaching-resistance). In this regard, citrate-based fluorescent biomaterials, which are synthesized from the natural and biocompatible precursor of citric acid (CA), have become competitive alternatives for fluorescence imaging owing to their biocompatibility, cost effectiveness, straightforward synthetic routes, flexible designability, as well as strong fluorescence with adjustable excitation/emission wavelengths. Accordingly, numerous citrate-based biomaterials, including carbon dots (CDs), biodegradable photoluminescent polymers (BPLPs), and small molecular fluorophores, have been developed and researched in the past few decades. This review discusses recent progress in the research and development of citrate-based fluorescent materials with emphasis on their design and synthesis considerations, material properties, fluorescence properties and mechanisms, as well as biomedical applications. It is expected that this review will provide an insightful discussion on the citrate-based fluorescent biomaterials, and lead to innovations for the next generation of fluorescent biomaterials and fluorescence-based biomedical technology.
As a “silent killer”, kidney disease is often hardly detected at an early stage but can cause lethal kidney failure later on. Thus, a preclinical imaging technique that can readily differentiate ...between the stages of kidney dysfunction is highly desired for improving our fundamental understanding of kidney disease progression. Herein, we report that in vivo fluorescence imaging, enabled by renal‐clearable near‐infrared‐emitting gold nanoparticles, can noninvasively detect kidney dysfunction, report on the dysfunctional stages, and even reveal adaptive function in a mouse model of unilateral obstructive nephropathy, which cannot be diagnosed with routine kidney function markers. These results demonstrate that low‐cost fluorescence kidney functional imaging is highly sensitive and useful for the longitudinal, noninvasive monitoring of kidney dysfunction progression in preclinical research.
A noninvasive, inexpensive method for the noninvasive staging of kidney dysfunction is based on the use of renal‐clearable near‐infrared‐emitting gold nanoparticles as imaging agents for in vivo fluorescence imaging. The various stages of kidney dysfunction could thus be readily differentiated in a unilateral‐ ureteral‐obstruction mouse model.
Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of ...cell‐mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer‐specific drug delivery. Theranostic NPs are fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP‐PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti‐BRAF V600E mutant melanoma specific drug (PLX4032) is loaded into BPLP‐PLA nanoparticles. Muramyl tripeptide is also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles are internalized within macrophages, which are tracked via the intrinsic fluorescence of BPLP‐PLA. Macrophages carrying nanoparticles deliver drugs to melanoma cells via cell–cell binding. Pharmacological studies also indicate that the PLX4032 loaded nanoparticles effectively kill melanoma cells. The “self‐powered” immune cell‐mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies.
By taking advantage of the innate immune cell's ability to target tumor cells, a novel drug delivery system is developed by using THP‐1 cells as both nanoparticle‐carriers and navigators to achieve cancer‐specific drug delivery. The “self‐powered” immune cell‐mediated theranostic biodegradable photoluminescent poly (lactic acid) nanoparticle‐based drug delivery system represents a potentially significant advancement in targeted theranostic cancer nanotechnologies.
Targeting immunosuppressive metastatic cancer cells is a key challenge in therapy. We recently have shown that a rigid‐rod aromatic, pBP−NBD, that responds to enzymes and kill immunosuppressive ...metastatic osteosarcoma (mOS) and castration resistant prostate cancer (CRPC) cells in mimetic bone microenvironment. However, pBP−NBD demonstrated moderate efficacy against CRPC cells. To enhance activity, we incorporated the unnatural amino acid L‐ or D‐4,4′‐biphenylalanine (L‐ or D−BiP) into pBP−NBD, drastically increasing cellular uptake and CRPC inhibition. Specifically, we inserted BiP into pBP−NBD to target mOS (Saos2 and SJSA1) and CRPC (VCaP and PC3) cells with overexpressed phosphatases. Our results show that the D‐peptide backbone with an aspartate methyl diester at the C‐terminal offers the highest activity against these immunosuppressive mOS and CRPC cells. Importantly, imaging shows that the peptide assemblies almost instantly enter the cells and accumulate primarily within the endoplasmic reticulum of Saos2, SJSA1, and PC3 cells and at the lysosomes of VCaP cells. By using BiP to boost cellular uptake and self‐assembly within cancer cells, this work illustrates an unnatural hydrophobic amino acid as a versatile and effective residue to boost endocytosis of synthetic peptides for intracellular self‐assembly.
This research demonstrates that the integration of unnatural amino acids (L‐ or D‐4,4′‐biphenylalanine) into peptide assemblies significantly accelerates their accumulation within prostate cancer cells, boosting their capacity to hinder cancer proliferation. This work paves a way for engineering supramolecular medicine, potentially heightening the efficacy of peptide‐based treatments for prostate cancer. It may lead to more effective therapeutic strategies for treating other cancers.
Small noncoding RNAs identified thus far are all encoded by the nuclear genome. Here, we report that the murine and human mitochondrial genomes encode thousands of small noncoding RNAs, which are ...predominantly derived from the sense transcripts of the mitochondrial genes （host genes）, and we termed these small RNAs mitochondrial genome-encoded small RNAs （mitosRNAs）. DICER inactivation affected, but did not completely abolish mitosRNA production. MitosRNAs appear to be products of currently unidentified mitochondrial ribonucleases. Overexpression of mitosRNAs enhanced expression levels of their host genes in vitro, and dysregulated mitosRNA expression was generally associated with aberrant mitochondrial gene expression in vivo. Our data demonstrate that in addition to 37 known mitochondrial genes, the mammalian mitochondrial genome also encodes abundant mitosRNAs, which may play an important regulatory role in the control of mitochondrial gene expression in the cell.
PDF
