An Engineered Probiotic Platform for Cancer Epitope-Independent Targeted Radionuclide Therapy of Solid Tumors.

Targeted radionuclide therapy (TRT) is an emerging therapeutic modality for the treatment of various solid cancers. Current approaches rely on the presence of cancer-specific epitopes and receptors against which a radiolabeled ligand is systemically administered to specifically deliver cytotoxic doses of α and ß particles to tumors. In this proof-of-concept study, tumor-colonizing Escherichia coli Nissle 1917 (EcN) is utilized to deliver a bacteria-specific radiopharmaceutical to solid tumors in a cancer-epitope independent manner. In this microbe-based pretargeted approach, the siderophore-mediated metal uptake pathway is leveraged to selectively concentrate copper radioisotopes, 64 Cu and 67 Cu, complexed to yersiniabactin (YbT) in the genetically modified bacteria. 64 Cu-YbT facilitates positron emission tomography (PET) imaging of the intratumoral bacteria, whereas 67 Cu-YbT delivers a cytotoxic dose to the surrounding cancer cells. PET imaging with 64 Cu-YbT reveals persistence and sustained growth of the bioengineered microbes in the tumor microenvironment. Survival studies with 67 Cu-YbT reveals significant attenuation of tumor growth and extends survival of both MC38 and 4T1  tumor-bearing mice harboring the microbes. Tumor response to this pretargeted approach correlates with promising anti-tumor immunity, with noticeable CD8+ T:Treg cell ratio. Their strategy offers a pathway to target and ablate multiple solid tumors independent of their epitope and receptor phenotype.

Engineered Bacteria Enhance Immunotherapy and Targeted Therapy through Stromal Remodeling of Tumors.

Desmoplastic solid tumors are characterized by the rapid build-up of extracellular matrix (ECM) macromolecules, such as hyaluronic acid (HA). The resulting physiological barrier prevents the infiltration of immune cells and also impedes the delivery of anticancer agents. The development of a hypervesiculating Escherichia coli Nissle (ΔECHy) based tumor targeting bacterial system capable of distributing a fusion peptide, cytolysin A (ClyA)-hyaluronidase (Hy) via outer membrane vesicles (OMVs) is reported. The capability of targeting hypoxic tumors, manufacturing recombinant proteins in situ and the added advantage of an on-site OMV based distribution system makes the engineered bacterial vector a unique candidate for peptide delivery. The HA degrading potential of Hy for stromal modulation is combined with the cytolytic activity of ClyA followed by testing it within syngeneic cancer models. ΔECHy is combined with immune checkpoint antibodies and tyrosine kinase inhibitors (TKIs) to demonstrate that remodeling the tumor stroma results in the improvement of immunotherapy outcomes and enhancing the efficacy of biological signaling inhibitors. The biocompatibility of ΔECHy is also investigated to show that the engineered bacteria are effectively cleared, elicit minimal inflammatory and immune responses, and therefore could be a reliable candidate as a live biotherapeutic.

Exosomes: Biological Pharmaceutical Nanovectors for Theranostics.

Exosomes are natural cell-derived nanovesicles of endocytic origin that enable cellular crosstalk by transferring encapsulated molecular cargos across biological barriers, thereby holding significantly complex implications in the etiology and progression of diverse disease states. Consequently, the development of exosomes-based nano-theranostic strategies has received immense consideration for advancing therapeutic interventions and disease prognosis. Their favorable biopharmaceutical properties make exosomes a unique nanoparticulate carrier for pharmaceutical drug delivery. This review provides an update on the contemporary strategies utilizing exosomes for theranostic applications in nanomedicine. In addition, we provide a synopsis of exosomal features and insights into strategic modifications that control in vivo biodistribution. We further discuss their opportunities, merits and pitfalls for cell/tissue targeted drug delivery in personalized nanotherapy.

WITHDRAWN: Appraisal of Bone Targeting Potential of Nanohydroxyapatite Based Drug Carriers Conjugated with Pamidronate in Osteoporosis Treatment

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Box-Behnken Design of Experiment Assisted Development and Optimization of Bendamustine HCl loaded Hydroxyapatite Nanoparticles.

BACKGROUND: Bendamustine HCl, an antineoplastic drug, has a very short life of about 40 minutes which necessitates administration of large doses which leads to increased side effects as well as costs. OBJECTIVE: The present work describes the fabrication, optimization, and evaluation of bioactive hydroxyapatite nanoparticles to achieve sustained delivery of bendamustine HCl. METHODS: Hydroxyapatite nanoparticles (NPs) were prepared by the wet chemical precipitation method by reacting a calcium and phosphate precursor and the reaction was optimized via Box-Behnken DOE. The drug was loaded on particles by physical adsorption. Various analytical studies were performed on the fabricated nanoparticles in addition to biodistribution studies to establish the physicochemical and biological characteristics of the designed formulation. RESULTS: pH of the reactant solution was found to have a more profound effect on the particle size and size distribution in comparison to reactant concentration. The particles were found to have a spherical morphology by SEM. Size of the blank and drug-loaded nanoparticles was found to be 130±20 nm by TEM. Energy Dispersive X-ray Spectroscopy (EDS) studies confirmed the presence of hydroxyapatite as the dominant phase while DSC studies indicated the presence of the drug in its amorphous form after its adsorption on NPs. Tissue distribution studies further suggested that the majority of drug concentration was released in blood rather than the other organs implying low organ toxicity. CONCLUSION: Bendamustine loaded hydroxyapatite nanoparticles were successfully optimized and fabricated. Favorable results were obtained in in vitro, in vivo, and analytical studies.

Synergistic anticancer efficacy of Bendamustine Hydrochloride loaded bioactive Hydroxyapatite nanoparticles: In-vitro, ex-vivo and in-vivo evaluation.

The present work evaluates the synergistic anticancer efficacy of bioactive Hydroxyapatite (HA) nanoparticles (HA NPs) loaded with Bendamustine HCl. Hydroxyapatite is a material with an excellent biological compatibility, a well-known fact which was also supported by the results of the Hemolytic studies and a high IC50 value observed in the MTT assay. HA NPs were prepared by the chemical precipitation method and loaded with the drug via physical adsorption. In-vitro release study was performed, which confirmed the sustained release of the drug from the drug loaded HA NPs. MTT assay, Cell Uptake and FACS studies on JURKAT E6.1 cell line and in-vivo pharmacokinetic studies in Wistar rats revealed that the drug loaded HA NPs could be easily internalized by the cells and release drug in a sustained manner. The drug loaded HA NPs showed cytotoxicity similar to the drug solution at 1/10th of the drug content, which indicates a possible synergism between the activity of the anticancer drug and calcium ions derived from the carrier. An increase in intracellular Ca(2+) ions is reported to induce apoptosis in cells. Tumor regression study in Balb/c mice Ehrlich's ascites model presented a similar synergistic efficacy. The drug solution was able to decrease the tumor volume by half, while the drug loaded HA NPs reduced the tumor size by 6 times.

Revisiting bone targeting potential of novel hydroxyapatite based surface modified PLGA nanoparticles of risedronate: Pharmacokinetic and biochemical assessment.

Hydroxyapatite based biodegradable mPEG-PLGA nanoparticles of risedronate (mPEG-PLGA-RIS-HA) were prepared by water miscible dialysis method for synergistic treatment of osteoporosis. The bone targeting potential of prepared nanoparticles was evaluated by performing the cell viability study and protein estimation in pre-osteoblast cell line (MC3T3E1). Biochemical and in-vivo pharmacokinetic studies on osteoporotic rat model treated with different formulations were performed. Under the biochemical study ALP, TRAP, HxP and Calcium levels were determined. Osteoporotic model treated with prepared nanoparticles indicated significant effect on bone. Pharmacokinetic studies revealed 6-fold and 4-fold increase in the relative bioavailability after intravenous and oral administration of nanoparticles respectively as compared to marketed formulation confirming better effective drug transport. Biochemical investigations also showed a significant change in biomarker level which ultimately lead to bone formation/resorption. A stability analysis has also been carried out according to ICH guidelines (Q1AR2) and shelf life was found to be 1year and 4 months for the prepared formulation. Thus the results of present studies indicated that mPEG-PLGA-RIS-HA NPs has a great potential for sustained delivery of RIS for the treatment and prevention of osteoporosis and to minimize the adverse effects of RIS typically induced by its oral administration.

Ceramic Nanoparticles: Fabrication Methods and Applications in Drug Delivery.

Ceramic nanoparticles are primarily made up of oxides, carbides, phosphates and carbonates of metals and metalloids such as calcium, titanium, silicon, etc. They have a wide range of applications due to a number of favourable properties, such as high heat resistance and chemical inertness. Out of all the areas of ceramic nanoparticles applications, biomedical field is the most explored one. In the biomedical field, ceramic nanoparticles are considered to be excellent carriers for drugs, genes, proteins, imaging agents etc. To be able to act as a good and successful drug delivery agent, various characteristics of nanoparticles need to be controlled, such as size range, surface properties, porosity, surface area to volume ratio, etc. In achieving these properties on the favourable side, the method of preparation and a good control over process variables play a key role. Choosing a suitable method to prepare nanoparticles, along with loading of significant amount of drug(s) leads to development of effective drug delivery systems which are being explored to a great extent. Ceramic nanoparticles have been successfully used as drug delivery systems against a number of diseases, such as bacterial infections, glaucoma, etc., and most widely, against cancer. This review gives a detailed account of commonly used methods for synthesising nanoparticles of various ceramic materials, along with an overview of their recent research status in the field of drug delivery.