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Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs. 1. In vitro evaluations.

A representative poly(beta-amino ester) (PbAE) with biodegradable and pH-sensitive properties was used to formulate a nanoparticle-based dosage form for tumor-targeted paclitaxel delivery. The polymer undergoes rapid dissolution when the pH of the medium is less than 6.5 and hence is expected to release its contents at once within the acidic tumor microenvironment and endo/lysosome compartments of cells. PbAE nanoparticles were prepared by solvent displacement method and characterized for particle size, charge, and surface morphology. Pluronic F-108, a triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), was blended with PbAE to induce surface modification of the nanoparticles. In vitro cellular uptake of tritiated [(3)H]-paclitaxel in solution form and as a nanoparticulate formulation was studied in MDA-MB-231 human breast adenocarcinoma cells grown in 12-well plates. We also examined the intracellular degradation pattern of the formulations within the cells by estimating the drug release profile. Cytotoxicity assay was performed on the formulations at different doses and time intervals. Nanoparticles prepared from poly(epsilon-caprolactone) (PCL) that do not display pH-sensitive release behavior were used as control. Spherical nanoparticles having positive zeta potential ( approximately 40 mV) were obtained in the size range of 150-200 nm with PbAE. The PEO chains of the Pluronic were well-anchored within the nanomatrix as determined by electron spectroscopy for chemical analysis (ESCA). The intracellular accumulation of paclitaxel within tumor cells was significantly higher when administered in the nanoparticle formulations as compared to aqueous solution. Qualitative fluorescent microscopy confirmed the rapid release of the payload into the cytosol in the case of PbAE nanoparticles, while the integrity of the PCL nanoparticles remained intact. The cytotoxicity assay results showed significantly higher tumoricidal activity of paclitaxel when administered in the nanoparticle formulations. The cell-kill effect was maximal for paclitaxel-loaded PbAE nanoparticles when normalized with respect to intracellular drug concentrations. Thus, PEO-modified PbAE nanoparticles show tremendous potential as novel carriers of cytotoxic agents for achieving improved drug disposition and enhanced efficacy.

Cell Line, Tumor↗

PubMed1993

Molecular mechanisms mediating lymphocyte recirculation, inflammation, and metastasis formation.

A multitude of glycoproteins expressed in cellular membranes have been identified by monoclonal antibodies. Besides mediating transient cell/cell contacts, these molecules unequivocally function as receptor structures capable of transmitting signals for cell growth and differentiation. They are the central determinators of local immune responses, and they allow an adjustment of the recirculating immunocompetent cells to their respective local microenvironments. Given that receptor/ligand interactions are characteristic of particular in vivo sites, knowledge of structural and functional features of adhesion receptors can provide new prospects for a more targeted clinical immune intervention.

Animals↗

PubMed2006

The role of electrospinning in the emerging field of nanomedicine.

The fact that in vivo the extracellular matrix (ECM) or substratum with which cells interact often includes topography at the nanoscale underscores the importance of investigating cell-substrate interactions and performing cell culture at the submicron scale. An important and exciting direction of research in nanomedicine would be to gain an understanding and exploit the cellular response to nanostructures. Electrospinning is a simple and versatile technique that can produce a macroporous scaffold comprising randomly oriented or aligned nanofibers. It can also accommodate the incorporation of drug delivery function into the fibrous scaffold. Endowed with both topographical and biochemical signals such electrospun nanofibrous scaffolds may provide an optimal microenvironment for the seeded cells. This review covers the analysis and control of the electrospinning process, and describes the types of electrospun fibers fabricated for biomedical applications such as drug delivery and tissue engineering.

Animals↗

PubMed1991

The effects on hematopoiesis of recombinant stem cell factor (ligand for c-kit) administered in vivo to mice either alone or in combination with granulocyte colony-stimulating factor.

Stem cell factor (SCF) is the ligand for the receptor encoded by the c-kit proto-oncogene. Mutations of either c-kit or the SCF gene are responsible for the defects of W and SI mutant mice, which both suffer a macrocytic anemia, the former associated with defective stem cells and the latter with a defective hematopoietic microenvironment. PEGylated recombinant rat SCF was administered to normal or splenectomized mice for up to 21 days. SCF was found to be a modest stimulator of peripheral blood neutrophil numbers in both groups of animals. The peak in neutrophil numbers was higher and occurred earlier in splenectomized mice. Bone marrow and spleen cellularity changed little during treatment but the content of interleukin-3-responsive progenitor cells and spleen colony-forming cells (CFU-S) reached very high levels, particularly in the spleen. Using recombinant human granulocyte colony-stimulating factor (rhG-CSF), we have shown that SCF induces a greater than additive increase in both blood neutrophils and blood-borne CFU-S. This synergy was seen throughout the dose range and may indicate a clinical role for SCF either alone or in augmenting the activity of G-CSF upon blood neutrophils and transplantable stem cells.

Animals↗

PubMed1990

Congenital amegakaryocytic thrombocytopenia: an intrinsic hematopoietic stem cell defect.

Serial studies of bone marrow (BM) hematopoiesis using clonogenic assays were performed in an infant with congenital amegakaryocytic thrombocytopenia. Initially, when the only hematological abnormality was isolated thrombocytopenia, the number of clonogenic BM hematopoietic progenitors was comparable to controls, including the number of megakaryocyte precursors. As the disease evolved into aplastic anemia over an 11-month period, the peripheral blood counts declined, and colony numbers from four classes of BM progenitors--termed BFU-E, CFU-GM, CFU-Mix, and CFU-Meg--also declined in parallel. When added to the marrow cultures, patient's plasma was not inhibitory to either control or to patient's BM colony growth. Similarly, no cellular inhibition of hematopoiesis was observed when patient's BM was cultured after depleting the sample of T lymphocytes and after adding the T lymphocytes back. Furthermore, stromal cells established from short-term and long-term cultures of patient's BM showed normal proliferative activity and yielded a "fertile" marrow microenvironment for patient's and control BM colony growth. Our data suggest that the central problem in congenital amegakaryocytic thrombocytopenia is an intrinsic hematopoietic stem cell defect, rather than an abnormality of the marrow milieu. The findings are consistent with either a progressive, quantitative attrition of progenitors or their inability to proliferate into colonies in vitro and into differentiated, functional cells in vivo.

Blood Cell Count↗

PubMed1997

Effects of the aged microenvironment on CD4+ T cell maturation.

Contributing to the functional alterations of the aged immune system is the accumulation of memory CD4+ T lymphocytes and decline in the proportion of naive cells occurring with advancing age. During attempts to alter the naive to memory ratio of CD4+ cells in aged mice, it was observed that regeneration of the peripheral T cell compartment resulted in a population which possessed the same memory cell-enriched characteristics as the unmanipulated age-matched controls. Thymopoiesis in aged mice does not appear to be altered in such a way as to give rise to emigrants with 'memory-like' characteristics. The aged peripheral microenvironment does, however, cause the accelerated maturation of mature, naive CD4+ T cells to the memory state.

Animals↗

PubMed1980

Cell-mediated immunity in genetically obese C57BL/6J ob/ob) mice.

The thymus and spleen of genetically obese (C57BL/6J ob/ob) mice weighed less and contained fewer mononuclear cells and Thy 1.2-positive lymphocytes compared with findings in lean controls. The number of splenic antibody forming cells, particularly IgG-producing lymphocytes, was reduced. There was a marked increase in natural killer cell activity and a slight increase in antibody-dependent cell-mediated cytotoxicity in the obese animals. Cytotoxic response of spleen cells of obese mice immunized in vivo was markedly lower than that of lean controls, whereas the generation of T killer cells against alloantigens after in vitro immunization was unimpaired, which points to a deleterious "microenvironment" in obesity. It is suggested that metabolic, nutritional, and endocrine changes in obesity may contribute to altered immunocompetence.

Animals↗

PubMed1991

Studies on the induction of anterior chamber-associated immune deviation (ACAID). II. Eye-derived cells participate in generating blood-borne signals that induce ACAID.

Despite an ever increasing body of information concerning general in vivo immune reactivity to exogenous Ag, relatively little is known concerning regional tissue influences on these responses. One expression of regionally distinct immune regulation is the deviant form of systemic immunity induced after the introduction of Ag, such as BSA, into the anterior chamber of the eye--anterior chamber-associated immune deviation (ACAID). ACAID is characterized by a selective, systemic immune deficiency in which both Ag-specific delayed hypersensitivity (DH) and complement-fixing antibody production are impaired by populations of Ts lymphocytes, although other immune effector modalities are preserved. Recent evidence demonstrates that the blood of mice that receive an anterior chamber injection of BSA 48 h earlier contains leukocytes capable of inducing cell-mediated Ag-specific efferent suppression of DH similar to that seen in mice with ACAID. Additional analysis of these bloodborne suppression-inducing leukocytes revealed them to express the mature macrophage/monocyte marker F4/80. On the basis of these findings, we wished to determine the source of the ACAID-inducing cells present in the peripheral blood of mice after anterior chamber inoculation of BSA. The data reveal that cells harvested from the normal eye are capable of selective induction of DH suppressive activity similar to that seen in ACAID. Interestingly, this property is unique to F4/80 expressing cells of the iris and ciliary body (I/CB). F4/80- I/CB cells do not possess this property. Although the F4/80 expressing cells that are present in extraocular sites do not constitutively possess ACAID-inducing properties, exposure of these cells to the anterior chamber microenvironment endows them with this ability. Finally, I/CB cells exposed to Ag in situ, via direct anterior chamber Ag inoculation, induce suppressed Ag-specific DH reactivity when infused into naive syngeneic recipients--a form of systemic immune deviation similar to that seen in mice with ACAID. The results presented here represent the first in vivo description of APC, altered by factors in a local microenvironment, that can initiate a systemic immune response characterized by Ag-specific immune suppression.

Animals↗

PubMed2006

Evaluation of chondrogenesis within PEGT: PBT scaffolds with high PEG content.

Porous poly(ethylene glycol) terephthalate:poly (butylene terephthalate) (PEGT:PBT) scaffolds with high PEG molecular weight (1000 g/mole) and PEGT content (60%) were fabricated using two different processes-paraffin templating and compression molding-for cartilage engineering applications. This polymer composition has previously been shown to enable chondrocyte adhesion and maintain differentiated phenotype in 2D monolayer culture. The influence of 3D polymer scaffold processing on the formation of cartilaginous tissue was studied by seeding primary immature bovine chondrocytes within cylindrical scaffolds in mixed flask reactors for 3 days, followed by cultivation in culture plates for a total of 10 or 24 days. Tissue-polymer constructs were evaluated morphologically by SEM and histology, and quantitatively for cellularity, total collagen, and glycosaminoglycan content, all of which remained statistically equivalent for each time point tested, irrespective of fabrication method. These data demonstrate that the polymers engineered for this study were able to support chondrogenesis independent of scaffold fabrication process, with the influence of pore architecture lessened by the highly hydrated scaffold microenvironments induced by high PEG content.

Animals↗

PubMed1994

Modulations of 92kDa gelatinase B and its inhibitors are associated with HIV-1 infection in human macrophage cultures.

The macrophage-secreted 92-kDa type IV collagenase and metalloproteinases play a critical role in cell microenvironment regulation and cell movement. HIV infection of macrophages might be capable of deregulating the expression of these gelatinases. Hence, human monocyte-derived-macrophages were infected by lymphotropic HIV-1/Lai and monocytropic HIV-1/DAS isolates. Gelatinase activity and gelatinase and inhibitor (TIMP, alpha 2M) biosyntheses were evaluated in supernatants and cellular extracts. Our data suggest that HIV infection facilitates gelatinase secretion and intracellular inhibitor retention. These argue for the increase of free proteinase that could degrade barriers, which would permit cell movement and viral dissemination into tissues.

Cells, Cultured↗

PubMed2007

Life and death in the granuloma: immunopathology of tuberculosis.

During tuberculosis (TB) infection, the granuloma provides the microenvironment in which antigen-specific T cells colocate with and activate infected macrophages to inhibit the growth of Mycobacterium tuberculosis. Although the granuloma is the site for mycobacterial killing, virulent mycobacteria have developed a variety of mechanisms to resist this macrophage-mediated killing. These surviving mycobacteria become dormant, however, if host cellular immunity or the signals maintaining granuloma structure wane, or if mycobacteria resume replication, leading to reactivation of TB. This balance of life and death applies not only to the mycobacterium but also to the host macrophages that may undergo apoptosis or necrosis, leading to the characteristic caseous necrosis within the granuloma, and the potential spread of TB infection. The immunological factors controlling the development and maintenance of the granuloma will be reviewed.

Adaptation, Biological↗

PubMed2003

The origin and development of the immune system with a view to stem cell therapy.

Careful study of the phylogeny and ontogeny of the three components of the immune system reveals that the macrophage, lymphatic, and hematopoietic systems originate independently of each other. Chronologically, the most ancient is the macrophage system, which arises in the coelomic cavity as mesenchymal ameboid cells having the properties to recognize self from non-self and to ingest foreign particles. The lymphatic system later develops from the endoderm of pharyngeal pouches, where the thymic anlage differentiates. The lymphocytes that originate here seed all lymphatic organs and retain the ability to divide and thereby form multiple colonies (lymphatic nodules) in the respiratory and digestive tract; further diversification of lymphocytes follows after confrontation with antigens. The last component of the immune system to appear is the hematopoietic system, which originates from the splanchnic mesoderm of the yolk sac as hematogenic tissue, containing hemangioblasts. The hematogenic tissue remains attached to the outer wall of the vitelline vessels, which provides an efficient mechanism for introducing the hematogenic tissue into the embryo. In an appropriate microenvironment, the hemangioblasts give rise to sinusoidal endothelium and to hemocytoblasts - the bone marrow stem cells for erythrocytes, myeloid cells, and megakaryocytes. The facts and opinions presented in this article are not in agreement with the currently accepted dogma that a common "hematolymphatic stem cell" localized in the marrow generates all of the cellular components of blood and the immune system.

Embryonic and Fetal Development↗

PubMed1999

Secretion of glutathione S-transferase isoforms in the seminiferous tubular fluid, tissue distribution and sex steroid binding by rat GSTM1.

The seminiferous tubular fluid (STF) provides the microenvironment necessary for spermatogenesis in the adluminal compartment of the seminiferous tubule (ST), primarily through secretions of the Sertoli cell. Earlier studies from this laboratory demonstrated the presence of glutathione S-transferase (GST) in STF collected from adult rat testis and in the spent media of ST cultures. This study describes the cellular source, isoform composition and possible function of GSTs in the STF. The major GST isoforms present in STF in vivo share extensive N-terminal similarity with rat GSTM1 (rGSTM1), rGSTM2, rGSTM3 and rGST-Alpha. Molecular masses of rGSTM2, rGSTM3 and rGST-Alpha from liver and testis sources were similar, unlike STF-GSTM1, which was larger by 325 Da than its liver counterpart. Peptide digest analysis profiles on reverse-phase HPLC between liver and STF isoforms were identical, and N-terminal sequences of selected peptides obtained by digestion of the various isoforms were closely similar. The above results confirmed close structural similarity between liver and STF-GST isoforms. Active synthesis and secretion of GSTs by the STs were evident from recovery of radiolabelled GST from the spent media of ST cultures. Analysis of secreted GST isoforms showed that GST-Alpha was not secreted by the STs in vitro, whereas there was an induction of GST-Pi secretion. Detection of immunostainable GST-Mu in Sertoli cells in vitro and during different stages of the seminiferous epithelium in vivo, coupled with the recovery of radiolabelled GST from Sertoli cell-culture media, provided evidence for Sertoli cells as secretors of GST. In addition, STF of 'Sertoli cell only' animals showed no change in the profile of GST isoform secretion, thereby confirming Sertoli cells as prime GST secretors. Non-recovery of [35S]methionine-labelled GSTs from germ cell culture supernatants, but their presence in germ cell lysates, confirm the ability of the germ cells to synthesize, but not to release, GSTs. Functionally, STF-GSTM1 appeared to serve as a steroid-binding protein by its ability to bind to testosterone and oestradiol, two important hormones in the ST that are essential for spermatogenesis, with binding constants of <9.8x10(-7) M for testosterone and 9x10(-6) M for oestradiol respectively.

Animals↗

PubMed2002

Role of the paraventricular nucleus microenvironment in stress integration.

The hypothalamic paraventricular nucleus is the primary controller of hypothalamo-pituitary-adrenocortical glucocorticoid release. In performing this function, the paraventricular nucleus summates a variety of information from both external and internal sources into a net secretory signal to the adrenal cortex. In this review, we will provide an overview of neuronal circuit mechanisms governing activation and inhibition of hypophysiotrophic neurons, highlight recent developments in our understanding of nonsynaptic mechanisms regulating paraventricular cellular activity, including dendritic neuropeptide release, direct steroid feedback, cytokine cascades and gaseous neurotransmission, and illustrate the capacity for hypophysiotrophic, neurohypophysial and preautonomic paraventricular effector pathways to work together in control of glucocorticoid release. The current state of knowledge reveals the paraventricular nucleus to be a dynamic entity, capable of integrating diverse classes of signals into control of adrenocortical activation.

Animals↗

PubMed2026

Unveiling tumor heterogeneity by single cell RNA-sequencing: From basic considerations to clinical applications.

Tumor heterogeneity-encompassing diverse cellular phenotypes, genomic alterations, and microenvironmental contexts-is a principal barrier to effective cancer therapy. Single-cell RNA sequencing (scRNA-seq) has transformed our ability to resolve this complexity by capturing transcriptomes at single-cell resolution. Here, we review the technical foundations required for high-quality scRNA-seq studies. We then trace the evolution of scRNA-seq platforms from manual micromanipulation to high-throughput systems, and describe the computational pipelines that enable reliable data interpretation. The application of scRNA-seq is exemplarily shown in the context of lung cancer, where single-cell profiling has revealed (i) the clonal and sub-clonal architecture of tumors, (ii) extensive remodeling of the immune microenvironment, iii) key mechanisms underlying resistance to targeted agents and immune-checkpoint blockade, and (iv) the dynamics of neo-antigen-specific T-cell responses. Integrating machine-learning techniques-such as deep-learning classifiers and graph-based models-with single-cell transcriptomic data has markedly sped up biomarker discovery, produced more accurate risk-stratification scores, and enabled the generation of patient-specific therapeutic predictions. We surveyed the major trial registry ClinicalTrials.gov and identified ∼380 ongoing or completed studies that explicitly incorporate scRNA-seq as a correlative or pharmacodynamic endpoint. Overall, the analysis shows that scRNA-seq becomes an increasingly important component of modern trials, providing high-resolution cellular and molecular readouts that complement conventional imaging and bulk-omics endpoints. While key challenges remain, ranging from costs, scalability and need for rigorous validation before routine clinical deployment, ongoing technological advances continue to expand the potential of scRNA-seq as a cornerstone of precision medicine.

Humans↗

PubMed2026

Distinct spatial immune microenvironment features of different EGFR mutation subtypes in early-stage lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinoma (LUAD), yet their influence on the spatial tumor immune microenvironment (TIME) in early-stage disease remains unclear. We characterized the spatial TIME in 144 treatment-naïve, early-stage LUADs using integrated genomic sequencing and multiplex immunohistochemistry (mIHC). Although EGFR-mutant tumors overall displayed reduced CD8 + T-cell infiltration compared with EGFR-wild-type tumors, substantial heterogeneity was observed among EGFR subtypes. Specifically, L858R and rare-variant subtypes exhibited higher tumor mutational burden, greater CD8 + T-cell density, and enrichment of T-cell-dominant cellular neighborhoods relative to 19del subtype, consistent with a comparatively immune-infiltrated phenotype. In contrast, 19del tumors showed lower T-cell infiltration. TP53 co-mutation was also associated with enhanced CD8 + T-cell infiltration. These cross-sectional findings identify hypothesis-generating spatial immune phenotypes across EGFR-mutant LUAD subtypes; their potential relevance to perioperative treatment selection requires prospective validation in outcome-annotated treatment cohorts.

Humans↗

PubMed2005

Hepatic progenitor cell resistance to TGF-beta1's proliferative and apoptotic effects.

The success of hepatocellular therapies using stem or progenitor cell populations is dependent upon multiple factors including the donor cell, microenvironment, and etiology of the liver injury. The following experiments investigated the impact of TGF-beta1 on a previously described population of hepatic progenitor cells (HPC). The majority of the hepatic progenitor cells were resistant to endogenously produced TGF-beta1's proapoptotic and anti-proliferative effects unlike more well-differentiated cellular populations (e.g., mature hepatocytes). Surprisingly, in vitro TGF-beta1 supplementation significantly inhibited de novo hepatic progenitor cell colony formation possibly via an indirect mechanism(s). Therefore despite the HPC's direct resistance to supplemental TGF-beta1, this cytokine's inhibitory effect on colony formation could have a potential negative impact on the use of these cells as a therapy for patients with liver disease.

Animals↗

PubMed2006

The clinical and biologic importance of neovascularization and angiogenic signaling pathways in chronic lymphocytic leukemia.

Angiogenesis has been found to be an important regulator in the growth and metastasis of solid tumors. More recent studies have also demonstrated the importance of this biologic process in normal hematopoietic cell development and the pathophysiology of several hematologic malignancies. This review provides an overview of the clinical and biologic importance of angiogenesis in chronic lymphocytic leukemia (CLL). Patients with CLL have detectable levels of both plasma and cellular pro- and anti-angiogenic cytokines, as well as abnormal neovascularization in the marrow and lymph nodes. Recent evidence suggests a vascular endothelial growth factor (VEGF)-based autocrine pathway promotes the survival of CLL B cells in part through upregulation of anti-apoptotic proteins. Additionally, interactions between CLL B cells and their microenvironment generate alterations in the secretion of angiogenic factors that result in enhanced leukemic B-cell resistance to apoptotic cell death. From a clinical standpoint, interpatient variation is observed in markers of angiogenesis and appears to have prognostic implications. Several clinical trials evaluating the efficacy of anti-angiogenic agents for treatment of patients with CLL are underway with promising preliminary results. Additional research is needed to identify the regulation of aberrant and critical angiogenic pathways in CLL B cells, to determine how angiogenic markers can be used to improve prognostication for CLL patients, and to explore how the angiogenic characteristics of CLL B cells can best be manipulated for therapeutic benefit.

Angiogenesis Inducing Agents↗