Leaky Vasculature Research Articles

Liposomal Nanoformulation-encapsulated Paclitaxel for Reducing Chemotherapy Side Effects in Lung Cancer Treatments: Recent Advances and Future Outlooks.

Paclitaxel is one notable chemotherapy drug that is used to treat a number of cancers, including lung cancer. Nevertheless, it has drawbacks such as toxicity, low solubility in water, and the emergence of multidrug resistance (MDR). This article reviews the use of liposomal formulations to improve paclitaxel administration and efficacy for lung cancer therapy. Paclitaxel's pharmacological characteristics can be improved by liposomes through increased solubility, extended circulation, passive tumor targeting through leaky vasculature, and decreased side effects. Recent developments in paclitaxel liposomal formulations, including as cationic liposomes, conventional liposomes, targeted liposomes with particular ligands, and liposome-loaded microorganisms, are outlined in this article. In comparison to free paclitaxel, these nanoformulations exhibit enhanced cytotoxicity, cellular uptake, apoptosis, tumor growth suppression, and anticancer effects in lung cancer cell lines and animal models. One efficient way to get around the drawbacks of paclitaxel is to alter its size, makeup, and surface characteristics. This will let the medication accumulate and penetrate tumors more easily, avoid multidrug resistance, and cause less systemic toxicity. The article explores clinical studies showcasing the safety and therapeutic efficacy of liposomal paclitaxel for individuals afflicted with lung cancer. In its entirety, the document provides an in-depth examination of the potential enhancement in paclitaxel's dispersion and anti-tumor impacts through the utilization of liposomal technology when addressing diverse manifestations of lung cancer.

109Pd/109mAg in-vivo generator in the form of nanoparticles for combined β- - Auger electron therapy of hepatocellular carcinoma

BackgroundConvenient therapeutic protocols for hepatocellular carcinoma (HCC) are often ineffective due to late diagnosis and high tumor heterogeneity, leading to poor long-term outcomes. However, recently performed studies suggest that using nanostructures in liver cancer treatment may improve therapeutic effects. Inorganic nanoparticles represent a unique material that tend to accumulate in the liver when introduced in-vivo. Typically, this is a major drawback that prevents the therapeutic use of nanoparticles in medicine. However, in HCC tumours, this may be advantageous because nanoparticles may accumulate in the target organ, where the leaky vasculature of HCC causes their accumulation in tumour cells via the EPR effect. On the other hand, recent studies have shown that combining low- and high-LET radiation emitted from the same radionuclide, such as 161Tb, can increase the effectiveness of radionuclide therapy. Therefore, to improve the efficacy of radionuclide therapy for hepatocellular carcinoma, we suggest utilizing radioactive palladium nanoparticles in the form of 109Pd/109mAg in-vivo generator that simultaneously emits β− particles and Auger electrons.ResultsPalladium nanoparticles with a size of 5 nm were synthesized using 109Pd produced through neutron irradiation of natural palladium or enriched 108Pd. Unlike the 109Pd-cyclam complex, where the daughter radionuclide diffuses away from the molecules, 109mAg remains within the nanoparticles after the decay of 109Pd. In vitro cell studies using radioactive 109Pd nanoparticles revealed that the nanoparticles accumulated inside cells, reaching around 50% total uptake. The 109Pd-PEG nanoparticles exhibited high cytotoxicity, even at low levels of radioactivity (6.25 MBq/mL), resulting in almost complete cell death at 25 MBq/mL. This cytotoxic effect was significantly greater than that of PdNPs labeled with β− (131I) and Auger electron emitters (125I). The metabolic viability of HCC cells was found to be correlated with cell DNA DSBs. Also, successful radioconjugate anticancer activity was observed in three-dimensional tumor spheroids, resulting in a significant treatment response.ConclusionThe results indicate that nanoparticles labeled with 109Pd can be effectively used for combined β− - Auger electron-targeted radionuclide therapy of HCC. Due to the decay of both components (β− and Auger electrons), the 109Pd/109mAg in-vivo generator presents a unique potential in this field.

Efficacy from the phase 1 study of FID-007, a novel nanoparticle paclitaxel formulation, in patients with head and neck squamous cell carcinoma.

6042 Background: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) have limited treatment options after progression on first-line immunotherapy with or without platinum-based chemotherapy. Taxanes in this setting have historically demonstrated response rates around 14-27%. FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. This allows the drug to remain in solution until it can enter a cancer cell and preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. Preclinically, FID was more effective at lower or comparable taxane doses, including nab-paclitaxel. In the phase I study of FID, we determined 125 mg/m2 as the recommended phase 2 dose. Here we present updated safety and efficacy data with emphasis on pts with HNSCC. Methods: The study evaluated the safety, PK, and preliminary efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 160mg/m2 using a 3+3 dose escalation. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and < 3 prior lines of cytotoxic therapy. Results: 46 patients were enrolled, of which 9 had HNSCC (2 nasopharynx, 2 sinonasal, 3 oropharynx, 1 oral cavity, and 1 occult primary). Median age (range) was 60 (53-75). ECOG PS was 1 in all HNSCC pts. Median number of prior therapies was 3 (1-5) and all had received prior immune checkpoint inhibitor. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts included rash (72%), alopecia (52%), leukopenia (46%), pruritus (43%), neutropenia (41%), anemia (37%), fatigue (37%), nausea (28%), and anorexia (28%). Grade 3/4 TRAEs occurring in >1 pt were maculopapular rash (35%), neutropenia (20%), leukopenia (20%), anemia (17%), lymphopenia (7%), and febrile neutropenia (4%). No pts experienced > grade 2 peripheral sensory neuropathy; 20% experienced grade 1-2. Across all solid tumors, the overall response rate (ORR) was 17%. In patients with HNSCC, 5 (56%) had a partial response, 2 (22%) had stable disease, and 2 (22%) had PD. Three out of 5 HNSCC patients previously treated with a taxane achieved a partial response. Median duration of treatment was 4 months (1-15). Conclusions: FID demonstrates preliminary evidence of anti-tumor activity in heavily pre-treated HNSCC pts across different primary tumor sites, with an ORR 56%, including those with prior taxane exposure. A phase 2 study of FID with cetuximab in pts with HNSCC is planned to begin enrollment in 2024. Clinical trial information: NCT03537690 .

Esterase responsive release of anti-cancer agents from conjugated lipid nanocarrier and the regulatory considerations.

The release of active agents in tumors rather than normal tissues, limits systemic exposure and toxicities. Targeting over-expressed esterase enzymein the tumor microenvironment can selectively release immune-active agents like Programmed Death-1 (PD-1) and PD-1 ligand inhibitors fromester-sensitivelipidnanocarriers, offering a novel approach compared with conventional therapies. PD-1 and PD-L1 association cause T-cell inactivation, whereas blocking their association improves their cytotoxic mechanism. The patent application US2022/0080051-A1 discloses a novel immune-active agent conjugated with lipid to form a nanocarrier for esterase-sensitive release. These nanocarriers selectively enter leaky vasculature of tumors through enhanced permeability and retention effect, undergo ester cleavage to release agents, and are reported to increase bioavailabilityby 24 times. Further, with other agents or alone it achieves targeted synergistic cancer therapy. Also, the current patent spotlight delves into the crucial formulation considerations necessary for obtaining successful approval of lipidic nano products from relevant regulatory authorities.

Carrier-free poly(glycyrrhetinic acid)-facilitated celastrol-loaded nanoparticle for high-efficiency low-toxicity treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a complex autoimmune disease associated with synovial inflammation and articular cartilage destruction. Currently, high-efficiency low-toxicity management of this intractable disease is highly urgent. Here, a drug-backboned polymer, polyglycyrrhetinic acid (PGA), was synthesized through the condensation of GA, a principal anti-inflammatory component of Glycyrrhiza glabra. PGA was then used as a therapeutic polyprodrug carrier to fabricate carrier-free PGA@Cel nanoparticles (NPs) for treating rheumatoid arthritis. The as-prepared NPs exhibited a uniformly spherical morphology with an average particle size of approximately 180 nm and a celastrol (Cel) loading capacity of around 4.5 %. Upon intravenous injection, the NPs demonstrated prolonged blood circulation, efficient accumulation at inflammatory joints through extravasation via leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS) effect. The present study demonstrated enhanced anti-inflammatory and rheumatic decay efficiency in rat models of antigen-induced arthritis, while simultaneously minimizing off-target toxicity. Overall, our results elucidate that this carrier-free drug-backboned nanopolydrug platform provides a promising strategy for RA therapy.

Truly Tiny Acoustic Biomolecules for Ultrasound Imaging and Therapy.

Nanotechnology offers significant advantages for medical imaging and therapy, including enhanced contrast and precision targeting. However, integrating these benefits into ultrasonography is challenging due to the size and stability constraints of conventional bubble-based agents. Here bicones, truly tiny acoustic contrast agents based on gas vesicles (GVs), a unique class of air-filled protein nanostructures naturally produced in buoyant microbes, are described. It is shown that these sub-80nm particles can be effectively detected both in vitro and in vivo, infiltrate tumors via leaky vasculature, deliver potent mechanical effects through ultrasound-induced inertial cavitation, and are easily engineered for molecular targeting, prolonged circulation time, and payload conjugation.

Possible physical mechanisms of the high echogenicity of lipid coated nanobubbles

Lipid coated nanobubbles (NBs) have attracted a great level of interest as ultrasound (US) contrast agents due to their ability to extravagate through leaky tumor vasculature. Their linear resonance frequency is in the range of ∼50 M Hz–200 MHz, leading to confusion over their observed strong contrast in diagnostic US frequencies. By solving the Marmottant model, the dynamics of uncoated and lipid coated NBs and microbubbles (MBs) are studied over the frequency and pressure ranges (6–12 MHz, 0.1–1.2 MPa) generally used in diagnostic US. A novel bifurcation analysis in tandem with the analysis of the frequency component of the scattered pressure are conducted. Results show that despite the increased linear resonance frequency and viscous damping due to the lipid shell, buckling and rupture of the shell enhances the generation of the 2nd and 3rd harmonic resonances at pressures as low as 0.2 MPa, not observed with uncoated NBs. The generation of the harmonic resonances are concomitant with an abrupt increase in the 2nd and 3rd harmonic frequency component of the scattered pressure with their pressure threshold (PT) increasing with decreasing NBs size. For the same gas volume, and above the PT, the maximum non-destructive 2nd and 3rd harmonic powers of NBs can become higher than the 2–4 μm MBs. Similar to the lower subharmonic pressure threshold of MBs, the dynamic variation of the NBs effective surface tension due to buckling and rupture may be the potential reason behind the observed harmonic echogenicity.

Structured wound angiogenesis instructs mesenchymal barrier compartments in the regenerating nerve

Organ injury stimulates the formation of new capillaries to restore blood supply raising questions about the potential contribution of neoangiogenic vessel architecture to the healing process. Using single-cell mapping, we resolved the properties of endothelial cells that organize a polarized scaffold at the repair site of lesioned peripheral nerves. Transient reactivation of an embryonic guidance program is required to orient neovessels across the wound. Manipulation of this structured angiogenic response through genetic and pharmacological targeting of Plexin-D1/VEGF pathways within an early window of repair has long-term impact on configuration of the nerve stroma. Neovessels direct nerve-resident mesenchymal cells to mold a provisionary fibrotic scar by assembling an orderly system of stable barrier compartments that channel regenerating nerve fibers and shield them from the persistently leaky vasculature. Thus, guided and balanced repair angiogenesis enables the construction of a "bridge" microenvironment conducive for axon regrowth and homeostasis of the regenerated tissue.

ANGI-03. NOVEL ROLE OF ENDOTHELIAL CELL AQUAPORIN-1 IN GLIOBLASTOMA VASCULAR PERMEABILITY AND TUMOR-ASSOCIATED EDEMA

Abstract Glioblastomas are the most common malignant brain tumors in adults, with a median survival of only 12-15 months. Glioblastomas are marked by an aberrant, leaky vasculature that promotes a hypoxic, immunosuppressive microenvironment. This aberrant vascularity not only affects treatment sensitivity but the integrity of the blood brain barrier (BBB). Disruption of the BBB can lead to increased flow of water into intercellular spaces, causing vasogenic edema. Increased intracranial pressure due to vasogenic edema in glioblastoma patients is a significant cause of morbidity and mortality. Severity of edema not only correlates with patient survival, but causes numerous harmful side effects, such as aphasia, cognitive decline, and acute herniation syndrome. Currently, the mainstay of treatment for brain tumor edema is glucocorticosteroids, such as dexamethasone. However, this treatment causes immune suppression and severe long-term adverse effects. To determine the potential role of vascular endothelial cells (ECs) in edema formation, we performed single cell RNAseq on a genetically engineered glioblastoma mouse model, which recapitulates the edema seen in human patients. We found that ECs from glioblastomas and normal brain tissue had distinct expression patterns, with selective expression of a water channel protein called Aquaporin-1 (AQP1) in glioblastoma ECs. In addition, siRNA-mediated AQP1 knockdown decreased GBM EC monolayer permeability. Inhibiting the water channel function of AQP1 alone through Bacopaside II treatment, however, did not alter EC monolayer permeability. Several tight junctions are downregulated in GBM ECs compared to normal brain ECs, and knocking down AQP1 via siRNA restored expression of the tight junction protein Claudin-5. These data suggest that AQP1 induces brain tumor edema by inhibiting tight junction protein expression via its non-water-channel function and that targeting AQP1 in glioblastoma ECs would be a novel therapeutic strategy to improve the BBB and decrease edema levels in vivo.

Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrate.

Liver cancers exhibit abnormal (leaky) vasculature, hypoxia and an immunosuppressive microenvironment. Normalization of tumor vasculature is an emerging approach to treat many cancers. Blockmir CD5-2 is a novel oligonucleotide-based inhibitor of the miR-27a interaction with VE-Cadherin, the endothelial-specific cadherin. The combination of a vasoactive medication with inhibition of immune checkpoints such as programmed cell death protein 1 (PD1) has been shown to be effective in treating liver cancer in humans. We aimed to study the effect of CD5-2 combined with checkpoint inhibition (using an antibody against PD1) on liver tumor growth, vasculature and immune infiltrate in the diethylnitrosamine (DEN)-induced liver tumor mouse model. We first analyzed human miR-27a and VE-Cadherin expression data from The Cancer Genome Atlas for hepatocellular carcinoma. CD5-2 and/or anti-PD1 antibody were given to the DEN-treated mice from age 7-months until harvest at age 9-months. Tumor and non-tumor liver tissues were analyzed using histology, immunohistochemistry, immunofluorescence and scanning electron microscopy. Human data showed high miR-27a and low VE-Cadherin were both significantly associated with poorer prognosis. Mice treated with CD5-2 plus anti-PD1 antibody had significantly smaller liver tumors (50% reduction) compared to mice treated with either agent alone, controls, or untreated mice. There was no difference in tumor number. Histologically, tumors in CD5-2-treated mice had less leaky vessels with higher VE-Cadherin expression and less tumor hypoxia compared to non-CD5-2-treated mice. Only tumors in the combination CD5-2 plus anti-PD1 antibody group exhibited a more favorable immune infiltrate (significantly higher CD3+ and CD8+ T cells and lower Ly6G+ neutrophils) compared to tumors from other groups. CD5-2 normalized tumor vasculature and reduced hypoxia in DEN-induced liver tumors. CD5-2 plus anti-PD1 antibody reduced liver tumor size possibly by altering the immune infiltrate to a more immunosupportive one.

Antibody-conjugated nanoparticles for target-specific drug delivery of chemotherapeutics.

Nanotechnology provides effective methods for precisely delivering chemotherapeutics to cancer cells, thereby improving efficacy and reducing off-target side effects. The targeted delivery of nanoscale chemotherapeutics is accomplished by two different approaches, namely the exploitation of leaky tumor vasculature (EPR effect) and the surface modification of nanoparticles (NPs) with various tumor-homing peptides, aptamers, oligonucleotides, and monoclonal antibodies (mAbs). Because of higher binding affinity and specificity, mAbs have received a lot of attention for the detection of selective cancer biomarkers and also for the treatment of various types of cancer. Antibody-conjugated nanoparticles (ACNPs) are an effective targeted therapy for the efficient delivery of chemotherapeutics specifically to the targeted cancer cells. ACNPs combine the benefits of NPs and mAbs to provide high drug loads at the tumor site with better selectivity and delivery efficiency. The mAbs on the NP surfaces recognize their specific receptors expressed on the target cells and release the chemotherapeutic agent in a controlled manner. Appropriately designed and synthesized ACNPs are essential to fully realize their therapeutic benefits. In blood stream, ACNPs instantly interact with biological molecules, and a protein corona is formed. Protein corona formation triggers an immune response and affects the targeting ability of the nanoformulation. In this review, we provide recent findings to highlight several antibody conjugation methods such as adsorption, covalent conjugation, and biotin-avidin interaction. This review also provides an overview of the many effects of the protein corona and the theranostic applications of ACNPs for the treatment of cancer.

Carrier-Free Gambogic Acid Dimer Self-Assembly Nanomedicines for Rheumatoid Arthritis Treatment.

The insufficient targeting delivery of therapeutic agents greatly impeded the treatment outcomes of rheumatoid arthritis (RA). Despite the recognized therapeutic advantages of gambogic acid (GBA) in inflammatory diseases, its high delivery efficiency to inflammatory site still limits its clinical application. Self-assembly of drug dimers into carrier-free nanoparticles (NPs) has become a straightforward and attractive approach to develop nanomedicines for RA treatment. Herein, homodimers of GBA were designed to form the carrier-free NPs by self-assembly for RA treatment. The synthetic gambogic acid dimers (GBA2) were self-assembled into NPs using a one-step solvent evaporation method. The size distribution, morphology, drug-loading efficiency (DLE) and storage stability were evaluated. A molecular dynamic simulation was conducted to gain further insight into the self-assembly mechanisms of GBA2/NPs. Besides, we investigated the cytotoxicity, apoptosis and cellular uptake profiles of GBA2/NPs in macrophages and osteoclasts. Finally, the specific biodistribution on the ankles of adjuvant-induced arthritis (AIA) mice, and the anti-RA efficacy of the AIA rat model were assessed. GBA2/NPs exhibited the uniform spherical structure, possessing excellent colloidal stability, high self-assembly stability, high drug loading and low hemolytic activity. Comparing with GBA, GBA2/NPs showed higher cytotoxicity, cellular uptake and apoptosis rate against osteoclasts. In addition, GBA2/NPs exhibited much higher accumulation in ankle joints in vivo. As expected, the systematic administration of GBA2/NPs resulted in the greater alleviation of arthritic symptoms, cartilage protection, and inflammation, notably the reduced systemic toxicity compared to free GBA. GBA2/NPs formed GBA dimers exhibited the superior accumulation in the inflamed joint and anti-RA activity, potentially attributing to the similar extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration ("ELVIS") effects in inflamed joint and the enhanced cellular uptake in macrophages and osteoclasts. Our findings provide substantial evidence that self-assembly of GBA2/NPs would be a promising therapeutic alternative for RA treatment.

Nanomedicine Strategies for Targeting Tumor Stroma.

The tumor stroma, or the microenvironment surrounding solid tumors, can significantly impact the effectiveness of cancer therapies. The tumor microenvironment is characterized by high interstitial pressure, a consequence of leaky vasculature, and dense stroma created by excessive deposition of various macromolecules such as collagen, fibronectin, and hyaluronic acid (HA). In addition, non-cancerous cells such as cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM) itself can promote tumor growth. In recent years, there has been increased interest in combining standard cancer treatments with stromal-targeting strategies or stromal modulators to improve therapeutic outcomes. Furthermore, the use of nanomedicine, which can improve the delivery and retention of drugs in the tumor, has been proposed to target the stroma. This review focuses on how different stromal components contribute to tumor progression and impede chemotherapeutic delivery. Additionally, this review highlights recent advancements in nanomedicine-based stromal modulation and discusses potential future directions for developing more effective stroma-targeted cancer therapies.

A phase 1 dose escalation/expansion study of FID-007, a novel nanoparticle paclitaxel formulation, in patients with solid tumors.

3026 Background: FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. In addition to allowing the drug to remain in solution until it can enter a cancer cell, the PEOX nanoparticle preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. In xenograft studies, FID reduced or limited tumor growth in multiple tumor types including lung, gastric, breast, pancreatic, and ovarian cancer. Preclinically, FID was more effective at lower or comparable taxane doses, including nab-paclitaxel, with fewer side effects. We present the first-in-human trial of FID. Methods: The study is evaluating the safety, PK, and efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 160mg/m2 using a standard 3+3 dose escalation design. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and ≤ 3 prior lines of cytotoxic therapy for advanced disease. Results: Thirty-six patients were treated across 7 dose levels. Median age was 61 (39-65). ECOG PS was 2 in 1 patient, 1 in 69% of patients. Median number of prior therapies was 2 (1-5). Median number of cycles was 2.5 (1-30). There were 2 DLTs of grade 3 rash at 100 mg/m2. Given the transient nature of the rash and response to topical therapy, DLT definition was modified to exclude grade 3 rash that lasts ≤ 7 days and 3 additional patients were treated at 100 mg/m2 which was deemed tolerable. There was 1 DLT of grade 4 WBC decrease at 125 mg/m2, and 1 DLT of G3 febrile neutropenia at 160 mg/m2. There was no MTD. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts were rash (64%), alopecia (56%), leukopenia (47%), pruritus (44%), neutropenia (42%), anemia (42%), fatigue (39%), nausea (33%), anorexia (31%), dysgeusia (25%) and peripheral sensory neuropathy (25%). Grade 3/4 TRAEs occurring in >1 pt were maculopapular rash (25%), anemia, neutropenia, and leukopenia (17% each). Of 36 evaluable patients, 7 (19%) had a partial response by RECIST 1.1 (pancreatic, biliary tract, and HNSCC) and 13 (36%) had stable disease. Three out of 4 HNSCC patients with PR had previously been treated with docetaxel. PK is linear and dose proportional. There is no paclitaxel accumulation after weekly dosing, and t1/2 is between 18-26 hours. Based on overall tolerability and PK, the dose of 125mg/m2 (dose level 6) has been chosen as RP2D. Conclusions: FID has a manageable safety profile and demonstrates preliminary evidence of anti-tumor activity in heavily pre-treated pts across different tumor types. No high-grade neuropathy has been noted to date. RP2D of FID is set at 125mg/m2. PK is linear, dose proportional and comparable to that of nab-paclitaxel. Clinical trial information: NCT03537690 .

Macromolecular Dexamethasone Prodrug Ameliorates Neuroinflammation and Prevents Bone Loss Associated with Traumatic Brain Injury (S28.001)

<h3>Objective:</h3> We hypothesized that systemically administered N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrugs (P-Dex) will target the brain trauma injury sites, substantially enhance the Glucocorticoid therapy efficacy, and improve its systemic safety. <h3>Background:</h3> Traumatic brain injury is (TBI) a leading cause of morbidity and mortality in children and adults. The pathology of TBI is heterogeneous, resulting from both primary and secondary injury mechanisms, the latter being attributed to the inflammatory response. Use of conventional glucocorticoid formulations (free DEX) leads to limited distribution to the brain, pulsatile brain tissue concentration and systemic side effects, with controversial benefit in being neuroprotective. Dex and prodrugs (P-Dex) passively target inflammation through the leaky vasculature associated with the underlying pathologies. Given the compromised blood brain barrier (BBB) and brain inflammation in the secondary injury phase of the TBI patients, we hypothesized that the systemically administrated P-Dex will passively target the brain trauma injury sites and reduce inflammation with least systemic side effects. <h3>Design/Methods:</h3> 30 mice were randomly assigned into 2 groups: TBI (Cortical impact model) and healthy mice. All mice received Saline, P-Dex or free Dex. They underwent optical imaging, Neurological severity score, Static weight bearing, Immunohistochemistry and Mico-CT analysis. <h3>Results:</h3> We found that P-Dex passively targeted the traumatic brain tissue and had sustained accumulation at the inflamed tissue for over 14 days. Histological evidence demonstrates the P-Dex’s therapeutic effect on the amelioration of neuroinflammation and prevention of neurodegeneration. Behaviorally, the P-Dex treated animals showed better recovery of the imbalance and better neurological severity score post-TBI. Higher bone mineral density and better bone microarchitecture was found in the skeletal tissues from P-Dex treated animals, comparing to the free Dex, and Saline treated animals, confirming the P-Dex bone protection effect. <h3>Conclusions:</h3> P-Dex can be a potential therapy targeting neuro-inflammation and preserving the neurons from death, avoiding bone loss post-TBI. <b>Disclosure:</b> Dr. Wei has nothing to disclose. Dr. Zhao has nothing to disclose. Jia Zhenshan has nothing to disclose. Zhao Zhifeng has nothing to disclose. Dr. Chen has nothing to disclose. Miss Sun has nothing to disclose. Dr. Kelso has received personal compensation for serving as an employee of Agilent Technologies. Dr. Kelso has stock in Agilent Technologies. Dr. Rathore has nothing to disclose. Dr. Wang has nothing to disclose.

Hypoxia, a Targetable Culprit to Counter Pancreatic Cancer Resistance to Therapy

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it is a disease of dismal prognosis. While immunotherapy has revolutionized the treatment of various solid tumors, it has achieved little success in PDAC. Hypoxia within the stroma-rich tumor microenvironment is associated with resistance to therapies and promotes angiogenesis, giving rise to a chaotic and leaky vasculature that is inefficient at shuttling oxygen and nutrients. Hypoxia and its downstream effectors have been implicated in immune resistance and could be contributing to the lack of response to immunotherapy experienced by patients with PDAC. Paradoxically, increasing evidence has shown hypoxia to augment genomic instability and mutagenesis in cancer, suggesting that hypoxic tumor cells could have increased production of neoantigens that can potentially enable their clearance by cytotoxic immune cells. Strategies aimed at relieving this condition have been on the rise, and one such approach opts for normalizing the tumor vasculature to reverse hypoxia and its downstream support of tumor pathogenesis. An important consideration for the successful implementation of such strategies in the clinic is that not all PDACs are equally hypoxic, therefore hypoxia-detection approaches should be integrated to enable optimal patient selection for achieving improved patient outcomes.

The promise of targeting heme and mitochondrial respiration in normalizing tumor microenvironment and potentiating immunotherapy.

Cancer immunotherapy shows durable treatment responses and therapeutic benefits compared to other cancer treatment modalities, but many cancer patients display primary and acquired resistance to immunotherapeutics. Immunosuppressive tumor microenvironment (TME) is a major barrier to cancer immunotherapy. Notably, cancer cells depend on high mitochondrial bioenergetics accompanied with the supply of heme for their growth, proliferation, progression, and metastasis. This excessive mitochondrial respiration increases tumor cells oxygen consumption, which triggers hypoxia and irregular blood vessels formation in various regions of TME, resulting in an immunosuppressive TME, evasion of anti-tumor immunity, and resistance to immunotherapeutic agents. In this review, we discuss the role of heme, heme catabolism, and mitochondrial respiration on mediating immunosuppressive TME by promoting hypoxia, angiogenesis, and leaky tumor vasculature. Moreover, we discuss the therapeutic prospects of targeting heme and mitochondrial respiration in alleviating tumor hypoxia, normalizing tumor vasculature, and TME to restore anti-tumor immunity and resensitize cancer cells to immunotherapy.

Emerging nano-strategies against tumour microenvironment (TME): a review

The non-cancerous cells and substances found in tumours, including the chemicals they create and release, are referred to as the tumour microenvironment. Carcinogenesis relies on the tumour microenvironment because it contains tumour cells that communicate with neighbouring cells via the circulatory and lymphatic systems. During all stages of carcinogenesis, non-malignant cells in the tumour microenvironment promote unchecked cell proliferation. Changes in the genetics and epigenetics of tumour cells and the rearrangement of TME components, which happen when these two things work together, affect the formation and growth of tumours. Tissue-specific exchanges between tumour cells and their surroundings are critical to understanding the underlying mechanism. With the tremendous advancements in nanomedicine, TME modulation has made significant strides lately. Drug distribution using nanotechnology has a number of benefits, including increased circulation time, cargo delivery to the appropriate location, enhanced bioavailability, reduced toxicity, etc. High interstitial pressure and dense stroma prevent the extravasation and uniform distribution of nanocarriers in TME, but leaky vasculature, acidic, and hypoxic circumstances of TME aid in the aggregation of customised nanoparticles. The goal of the review is to look into the idea of the tumour microenvironment by doing a critical analysis of past research. By briefly analysing stromal components, therapeutic opportunities, and limitations provided by TME for nanoparticulate drug delivery, this paper primarily analyses the potential of nanotherapeutics in targeting TME. Additionally, updated details on TME remodelling techniques for better drug delivery and precise targeting of particular stromal components are provided.

Understanding and harnessing triple-negative breast cancer-related microbiota in oncology.

Bacterial inhabitants of the body have the potential to play a role in various stages of cancer initiation, progression, and treatment. These bacteria may be distal to the primary tumour, such as gut microbiota, or local to the tissue, before or after tumour growth. Breast cancer is well studied in this context. Amongst breast cancer types, Triple Negative Breast Cancer (TNBC) is more aggressive, has fewer treatment options than receptor-positive breast cancers, has an overall worse prognosis and higher rates of reoccurrence. Thus, an in-depth understanding of the bacterial influence on TNBC progression and treatment is of high value. In this regard, the Gut Microbiota (GM) can be involved in various stages of tumour progression. It may suppress or promote carcinogenesis through the release of carcinogenic metabolites, sustenance of proinflammatory environments and/or the promotion of epigenetic changes in our genome. It can also mediate metastasis and reoccurrence through interactions with the immune system and has been recently shown to influence chemo-, radio-, and immune-therapies. Furthermore, bacteria have also been found to reside in normal and malignant breast tissue. Several studies have now described the breast and breast tumour microbiome, with the tumour microbiota of TNBC having the least taxonomic diversity among all breast cancer types. Here, specific conditions of the tumour microenvironment (TME) - low O2, leaky vasculature and immune suppression - are supportive of tumour selective bacterial growth. This innate bacterial ability could enable their use as delivery agents for various therapeutics or as diagnostics. This review aims to examine the current knowledge on bacterial relevance to TNBC and potential uses while examining some of the remaining unanswered questions regarding mechanisms underpinning observed effects.

Amphiphilic Micelles as Superior Nanocarriers in Drug Delivery: from Current Preclinical Surveys to Structural Frameworks

AbstractThe designing of suitable carriers for the delivery of hydrophobic drugs is highly challenging for researchers. Solubilization of drugs is of immense importance for drug development since most drugs are water insoluble. Among various techniques employed for drug solubilization, the use of micellar solutions has been most common and prevalent for the solubilization of hydrophobic drugs now a days. The application of miceller systems for drug carriers shows some significance than that of other alternatives. Micelles can reside for longer time to afford gradual accumulation in the affected area in the body and more importantly their sizes allow them to accrue in the regions with leaky vasculature. Moreover, micelles can be obtained in a simple and reproducible way and their use for drug delivery has avoided many potential risks associated with other injectable formulations. These molecular self‐assembled nanostructures solubilize the drugs and protect them from undesirable external environments. Hence it is necessary to have appropriate knowledge on the self‐assembly phenomena associated with surfactant drug mixtures before proceeding for drug delivery. This review highlights details about important phenomenon associated with micellar systems and their role in drug delivery.