•Why do we need biomimicry? Which challenges does it aim to overcome?•Systemic delivery of free drugs has limitations. These limitations include rapid systemic clearance, inadequate levels of drug in ...the target tissue, poor solubility of some drugs, and increased off target toxicity.•Much effort has been invested into the development of different synthetic drug carriers. However, biomimetic carrier systems, inspired by the way different cells in our body behave, hold great therapeutic potential in addressing these challenges.•Several types of cells that interact with the vascular system, including erythrocytes, leukocytes, and thrombocytes, have inspired the design of new biomimetic carriers.•Inspired by native cells' biological functions, biomimetic nano-carrier platforms possess favorable properties such as: longer circulation times, mononuclear phagocyte system (MPS) evasion, and favorable interactions with target cells.
Native cells and their inherent functional moieties, which allow the native cells to evade the biological barriers and reach the target. All the proteins in this figure are membrane proteins and were placed inside the cells only for visualization. Display omitted
The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system
. Recent work indicates that newly formed adrenergic nerve fibres promote tumour growth, but the ...origin of these nerves and the mechanism of their inception are unknown
. Here, by comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We show that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR-34a. Tumour growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents mechanism by which tumour-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumour progression, and is a potential target for anticancer therapy.
Pancreatic cancers, both adenocarcinomas and endocrine tumors are characterized by varying levels of aberrant angiogenesis and fibrotic microenvironment. The difficulty to deliver drugs and treat the ...disease has been attributed in part to the vascular architecture and tissue/ECM density. Here we present longitudinal three‐dimensional intravital imaging of vascular and tumor microenvironment remodeling in spontaneous transgenic tumors (RIP1‐Tag2 insulinomas) and orthotopically injected tumors (KPC adenocarcinomas). Analysis of the data acquired in insulinomas revealed major differences in tumor blood vessel branching, fraction volume, number of branch points segments, vessel straightness and length compared to the normal tissue. The aggressive adenocarcinoma presented widespread peritumoral vascular remodeling and heterogeneous vascular distribution. Longitudinal imaging was used to acquire sequential vascular remodeling data during tumor progression. This work demonstrates the potential for using a pancreatic intravital imaging window for direct visualization of the tumor heterogenic microenvironments during tumor progression.
What's new?
In pancreatic cancer, the difficulty to deliver therapeutic drugs has been attributed partly to the tumor vascular architecture and tissue/extracellular matrix density. Here, the authors present a novel method for longitudinal intravital imaging of preclinical models of pancreatic cancer that enables direct visualization of blood vessels remodeling and quantification of vascular parameters. The results provide information on blood vessel diameter, volume, length, branching, and straightness in spontaneous transgenic tumors and on vessel volume and heterogeneity in syngeneic fluorescent orthotopically‐injected adenocarcinomas. The work provides new monitoring tools together with quantifiable architectural features and potential biomarkers of vascular abnormalities in pancreatic cancer.
Lipid nanoparticles are used widely as anticancer drug and gene delivery systems. Internalizing into the target cell is a prerequisite for the proper activity of many nanoparticulate drugs. We show ...here, that the lipid composition of a nanoparticle affects its ability to internalize into triple-negative breast cancer cells. The lipid headgroup had the greatest effect on enhancing cellular uptake compared to other segments of the molecule. Having a receptor-targeted headgroup induced the greatest increase in cellular uptake, followed by cationic amine headgroups, both being superior to neutral (zwitterion) phosphatidylcholine or to negatively-charged headgroups. The lipid tails also affected the magnitude of cellular uptake. Longer acyl chains facilitated greater liposomal cellular uptake compared to shorter tails, 18:0 > 16:0 > 14:0. When having the same lipid tail length, unsaturated lipids were superior to saturated ones, 18:1 > 18:0. Interestingly, liposomes composed of phospholipids having 14:0 or 12:0-carbon-long-tails, such as DMPC and DLPC, decreased cell viability in a concertation dependent manner, due to a destabilizing effect these lipids had on the cancer cell membrane. Contrarily, liposomes composed of phospholipids having longer carbon tails (16:0 and 18:0), such as DPPC and HSPC, enhanced cancer cell proliferation. This effect is attributed to the integration of the exogenous liposomal lipids into the cancer-cell membrane, supporting the proliferation process. Cholesterol is a common lipid additive in nanoscale formulations, rigidifying the membrane and stabilizing its structure. Liposomes composed of DMPC (14:0) showed increased cellular uptake when enriched with cholesterol, both by endocytosis and by fusion. Contrarily, the effect of cholesterol on HSPC (18:0) liposomal uptake was minimal. Furthermore, the concentration of nanoparticles in solution affected their cellular uptake. The higher the concentration of nanoparticles the greater the absolute number of nanoparticles taken up per cell. However, the efficiency of nanoparticle uptake, i.e. the percent of nanoparticles taken up by cells, decreased as the concentration of nanoparticles increased. This study demonstrates that tuning the lipid composition and concentration of nanoscale drug delivery systems can be leveraged to modulate their cellular uptake.
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Melanoma originates in the epidermis and becomes metastatic after invasion into the dermis. Prior interactions between melanoma cells and dermis are poorly studied. Here, we show that melanoma cells ...directly affect the formation of the dermal tumour niche by microRNA trafficking before invasion. Melanocytes, cells of melanoma origin, are specialized in releasing pigment vesicles, termed melanosomes. In melanoma in situ, we found melanosome markers in distal fibroblasts before melanoma invasion. The melanosomes carry microRNAs into primary fibroblasts triggering changes, including increased proliferation, migration and pro-inflammatory gene expression, all known features of cancer-associated fibroblasts (CAFs). Specifically, melanosomal microRNA-211 directly targets IGF2R and leads to MAPK signalling activation, which reciprocally encourages melanoma growth. Melanosome release inhibitor prevented CAF formation. Since the first interaction of melanoma cells with blood vessels occurs in the dermis, our data suggest an opportunity to block melanoma invasion by preventing the formation of the dermal tumour niche.
Acidic pH in the tumor microenvironment is associated with cancer metabolism and creates a physiological barrier that prevents from drugs to penetrate cells. Specifically, ionizable weak-base drugs, ...such as doxorubicin, freely permeate membranes in their uncharged form, however, in the acidic tumor microenvironment these drugs become charged and their cellular permeability is retarded. In this study, 100-nm liposomes loaded with sodium bicarbonate were used as adjuvants to elevate the tumor pH. Combined treatment of triple-negative breast cancer cells (4T1) with doxorubicin and sodium-bicarbonate enhanced drug uptake and increased its anti-cancer activity. In vivo, mice bearing orthotropic 4T1 breast cancer tumors were administered either liposomal or free bicarbonate intravenously. 3.7 ± 0.3% of the injected liposomal dose was detected in the tumor after twenty-four hours, compared to 0.17% ± 0.04% in the group injected free non-liposomal bicarbonate, a 21-fold increase. Analyzing nanoparticle biodistribution within the tumor tissue revealed that 93% of the PEGylated liposomes accumulated in the extracellular matrix, while 7% were detected intracellularly. Mice administered bicarbonate-loaded liposomes reached an intra-tumor pH value of 7.38 ± 0.04. Treating tumors with liposomal bicarbonate combined with a sub-therapeutic dose of doxorubicin achieved an improved therapeutic outcome, compared to mice treated with doxorubicin or bicarbonate alone. Interestingly, analysis of the tumor microenvironment demonstrated an increase in immune cell’ population (T-cell, B-cell and macrophages) in tumors treated with liposomal bicarbonate. This study demonstrates that targeting metabolic adjuvants with nanoparticles to the tumor microenvironment can enhance anticancer drug activity and improve treatment.
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•100-nm sodium bicarbonate liposomes were characterized and used as adjuvants.•Combined treatment of doxorubicin and sodium bicarbonate enhanced drug uptake.•Combination of doxorubicin and liposomal bicarbonate resulted in improved therapeutic outcomes.•Liposomal bicarbonate showed an increase in CD45+ immune cells in the tumor tissue.
Despite numerous advances in medical treatment, sepsis remains one of the leading causes of death worldwide. Sepsis is characterized by the involvement of all organs and tissues as a consequence of ...blood poisoning, resulting in organ failure and eventually death. Effective treatment remains an unmet need and novel approaches are urgently needed. The growing evidence of clinical and biological heterogeneity of sepsis suggests precision medicine as a possible key for achieving therapeutic breakthroughs. In this scenario, biomimetic nanomedicine represents a promising avenue for the treatment of inflammatory diseases, including sepsis. We investigated the role of macrophage-derived biomimetic nanoparticles, namely leukosomes, in a lipopolysaccharide-induced murine model of sepsis. We observed that treatment with leukosomes was associated with significantly prolonged survival. In vitro studies elucidated the potential mechanism of action of these biomimetic vesicles. The direct treatment of endothelial cells (ECs) with leukosomes did not alter the gene expression profile of EC-associated cell adhesion molecules. In contrast, the interaction of leukosomes with macrophages induced a decrease of pro-inflammatory genes (IL-6, IL-1b, and TNF-α), an increase of anti-inflammatory ones (IL-10 and TGF-β), and indirectly an anti-inflammatory response on ECs. Taken together, these results showed the ability of leukosomes to regulate the inflammatory response in target cells, acting as a bioactive nanotherapeutic.
Cancer is usually not symptomatic in its early stages. However, early detection can vastly improve prognosis. Liquid biopsy holds great promise for early detection, although it still suffers from ...many disadvantages, mainly searching for specific cancer biomarkers. Here, a new approach for liquid biopsies is proposed, based on volatile organic compound (VOC) patterns in the blood headspace. An artificial intelligence nanoarray based on a varied set of chemi‐sensitive nano‐based structured films is developed and used to detect and stage cancer. As a proof‐of‐concept, three cancer models are tested showing high incidence and mortality rates in the population: breast cancer, ovarian cancer, and pancreatic cancer. The nanoarray has >84% accuracy, >81% sensitivity, and >80% specificity for early detection and >97% accuracy, 100% sensitivity, and >88% specificity for metastasis detection. Complementary mass spectrometry analysis validates these results. The ability to analyze such a complex biological fluid as blood, while considering data of many VOCs at a time using the artificially intelligent nanoarray, increases the sensitivity of predictive models and leads to a potential efficient early diagnosis and disease‐monitoring tool for cancer.
Early cancer detection can immensely improve prognosis. Here, a potential early diagnosis and disease‐monitoring tool is proposed based on volatile organic compound (VOC) patterns in the blood headspace. An artificial intelligence nanoarray in combination with machine learning models gives high performances for early cancer (>84% accuracy) and metastasis (>97% accuracy) detection.
Throughout the female menstrual cycle, physiological changes occur that affect the biodistribution of nanoparticles within the reproductive system. We demonstrate a 2-fold increase in nanoparticle ...accumulation in murine ovaries and uterus during ovulation, compared to the nonovulatory stage, following intravenous administration. This biodistribution pattern had positive or negative effects when drug-loaded nanoparticles, sized 100 nm or smaller, were used to treat different cancers. For example, treating ovarian cancer with nanomedicines during mouse ovulation resulted in higher drug accumulation in the ovaries, improving therapeutic efficacy. Conversely, treating breast cancer during ovulation, led to reduced therapeutic efficacy, due to enhanced nanoparticle accumulation in the reproductive system rather than at the tumor site. Moreover, chemotherapeutic nanoparticles administered during ovulation increased ovarian toxicity and decreased fertility compared to the free drug. The menstrual cycle should be accounted for when designing and implementing nanomedicines for females.
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