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Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of poly(d , l -lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and bisphosphonate (or alendronate, a targeting ligand). The engineered NPs were formulated by blending varying ratios of the synthesized polymers: PLGA- b -PEG and alendronate-conjugated polymer PLGA- b -PEG-Ald, which ensured long circulation and targeting capabilities, respectively. The bone-binding ability of Ald-PEG-PLGA NPs was investigated by hydroxyapatite binding assays and ex vivo imaging of adherence to bone fragments. In vivo biodistribution of fluorescently labeled NPs showed higher retention, accumulation, and bone homing of targeted Ald-PEG-PLGA NPs, compared with nontargeted PEG-PLGA NPs. A library of bortezomib-loaded NPs (bone-targeted Ald-Bort-NPs and nontargeted Bort-NPs) were developed and screened for optimal physiochemical properties, drug loading, and release profiles. Ald-Bort-NPs were tested for efficacy in mouse models of multiple myeloma (MM). Results demonstrated significantly enhanced survival and decreased tumor burden in mice pretreated with Ald-Bort-NPs versus Ald-Empty-NPs (no drug) or the free drug. We also observed that bortezomib, as a pretreatment regimen, modified the bone microenvironment and enhanced bone strength and volume. Our findings suggest that NP-based anticancer therapies with bone-targeting specificity comprise a clinically relevant method of drug delivery that can inhibit tumor progression in MM.

Background We previously showed that cerium oxide (CeO 2 ), barium sulfate (BaSO 4 ) and zinc oxide (ZnO) nanoparticles (NPs) exhibited different lung toxicity and pulmonary clearance in rats. We hypothesize that these NPs acquire coronas with different protein compositions that may influence their clearance from the lungs. Methods CeO 2 , silica-coated CeO 2 , BaSO 4 , and ZnO NPs were incubated in rat lung lining fluid in vitro. Then, gel electrophoresis followed by quantitative mass spectrometry was used to characterize the adsorbed proteins stripped from these NPs. We also measured uptake of instilled NPs by alveolar macrophages (AMs) in rat lungs using electron microscopy. Finally, we tested whether coating of gold NPs with albumin would alter their lung clearance in rats. Results We found that the amounts of nine proteins in the coronas formed on the four NPs varied significantly. The amounts of albumin, transferrin and α-1 antitrypsin were greater in the coronas of BaSO 4 and ZnO than that of the two CeO 2 NPs. The uptake of BaSO 4 in AMs was less than CeO 2 and silica-coated CeO 2 NPs. No identifiable ZnO NPs were observed in AMs. Gold NPs coated with albumin or citrate instilled into the lungs of rats acquired the similar protein coronas and were cleared from the lungs to the same extent. Conclusions We show that different NPs variably adsorb proteins from the lung lining fluid. The amount of albumin in the NP corona varies as does NP uptake by AMs. However, albumin coating does not affect the translocation of gold NPs across the air-blood barrier. A more extensive database of corona composition of a diverse NP library will develop a platform to help predict the effects and biokinetics of inhaled NPs.

Abstract Chronic myeloid leukemia is a myeloproliferative neoplasm which can present in chronic phase, accelerated phase, or blast crisis. Most of the children present in chronic phase. Tyrosine kinase inhibitors are used as a targeted therapy. Few children progress to blast crisis on therapy. The blast crisis occurs in the marrow. Very few cases are reported in adults with isolated central nervous system (CNS) blast crisis. Here we are reporting a rare case of isolated CNS relapse in a child.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1007/s11095-020-02971-0

Evaluation of cancer therapeutics by utilizing 3D tumor models, before clinical studies, could be more advantageous than conventional 2D tumor models (monolayer cultures). The 3D systems mimic the tumor microenvironment more closely than 2D systems. The following review discusses the various 3D tumor models present today with the advantages and limitations of each. 3D tumor models replicate the elements of a tumor microenvironment such as hypoxia, necrosis, angiogenesis and cell adhesion. The review introduces application of techniques such as microfluidics, imaging and tissue engineering to improve the 3D tumor models. Despite their tremendous potential to better screen chemotherapeutics, 3D tumor models still have a long way to go before they are used commonly as tumor models in pharmaceutical industrial research.

Background: Langerhans cell histiocytosis (LCH) is a rare clonal malignancy of the monocyte-macrophage system. Patients with lesions in \"risk organs\" have significantly higher risk of mortality than patients with lesions limited to \"non-risk\" sites. The influence of early response to therapy on long-term survival in this heterogeneous multi-system disease was analyzed. Methods: During a 7-year period, we retrospectively analyzed the findings in 24 consecutive patients who required systemic chemotherapy for LCH [single system with multifocal bone involvement and multisystem involvement with or without risk organ (RO) involvement]. All patients were started on vinblastine and prednisolone. Progressive disease was treated with salvage protocols or targeted therapy. Positron emission tomography-computed tomography (PET-CT)/conventional CT based response assessment was performed at week 6 of chemotherapy, and if needed after week 12 of chemotherapy. Results: MFO bone, MS ROneg, and MS ROpos LCH was observed in 3, 4, and 17 patients, respectively. Age range of patients varied from 1 month-7 years (median = 18 months). The EFS and OS were 100% and 100% for MFO bone, 50% and 100%, respectively, for MS ROneg and 35% and 52%, respectively, for MS ROpos. OS was 93% and 100% for CR attained at 6 and 12 weeks respectively regardless of the risk status (P < 0.01). Conclusion: Rapid early response, that is, complete remission at 6 and 12 weeks was associated with significantly improved overall survival. In slow responders, early salvage with alternative regimens or targeted therapy may result in better outcomes.

PurposeCationic polymers (i.e. polyallylamine, poly-L-lysine) having primary amino groups are poor transfection agents and possess high cytotoxicity index when used without any chemical modification and usually entail specific receptor mediated endocytosis or lysosomotropic agents to execute efficient gene delivery. In this report, primary amino groups of polyallylamine (PAA, 17 kDa) were substituted with imidazolyl functions, which are presumed to enhance endosomal release, and thus enhance its gene delivery efficiency and eliminate the requirement of external lysosomotropic agents. Further, systems were cross-linked with polyethylene glycol (PEG) to prepare PAA-IAA-PEG (PIP) nanoparticles and evaluated them in various model cell lines.Materials and MethodsThe efficacy of PIP nanoparticles in delivering a plasmid encoding enhanced green fluorescent protein (EGFP) gene was assessed in COS-1, N2a and HEK293 cell lines, while their cytotoxicity was investigated in COS-1 and HEK293 cell lines. The PAA was chemically modified using imidazolyl moieties and ionically cross-linked with PEG to engineer nanoparticles. The extent of substitution was determined by ninhydrin method. The PIP nanoparticles were further characterized by measuring the particle size (dynamic light scattering and transmission electron microscopy), surface charge (zeta potential), DNA accessibility and buffering capacity. The cytotoxicity was examined using the MTT method.ResultsIn vitro transfection efficiency of synthesized nanoparticles is increased up to several folds compared to native polymer even in the presence of serum, while maintaining the cell viability over 100% in COS-1 cells. Nanoparticles possess positive zeta potential between 5.6–13 mV and size range of 185–230 nm in water. The accessibility experiment demonstrated that nanoparticles with higher degree of imidazolyl substitution formed relatively loose complexes with DNA. An acid-base titration showed enhanced buffering capacity of modified PAA.ConclusionsThe PIP nanoparticles reveal tremendous potential as novel delivery system for achieving improved transfection efficiency, while keeping the cells at ease.

Background The physicochemical properties of nanoparticles (NPs) influence their biological outcomes. Methods We assessed the effects of an amorphous silica coating on the pharmacokinetics and pulmonary effects of CeO 2 NPs following intratracheal (IT) instillation, gavage and intravenous injection in rats. Uncoated and silica-coated CeO 2 NPs were generated by flame spray pyrolysis and later neutron-activated. These radioactive NPs were IT-instilled, gavaged, or intravenously (IV) injected in rats. Animals were analyzed over 28 days post-IT, 7 days post-gavage and 2 days post-injection. Results Our data indicate that silica coating caused more but transient lung inflammation compared to uncoated CeO 2 . The transient inflammation of silica-coated CeO 2 was accompanied by its enhanced clearance. Then, from 7 to 28 days, clearance was similar although significantly more 141 Ce from silica-coated (35 %) was cleared than from uncoated (19 %) 141 CeO 2 in 28 days. The protein coronas of the two NPs were significantly different when they were incubated with alveolar lining fluid. Despite more rapid clearance from the lungs, the extrapulmonary 141 Ce from silica-coated 141 CeO 2 was still minimal (<1 %) although lower than from uncoated 141 CeO 2 NPs. Post-gavage, nearly 100 % of both NPs were excreted in the feces consistent with very low gut absorption. Both IV-injected 141 CeO 2 NP types were primarily retained in the liver and spleen. The silica coating significantly altered the plasma protein corona composition and enhanced retention of 141 Ce in other organs except the liver. Conclusion We conclude that silica coating of nanoceria alters the biodistribution of cerium likely due to modifications in protein corona formation after IT and IV administration.

Cationic polymers (i.e. polyallylamine, poly-L-lysine) having primary amino groups are poor transfection agents and possess high cytotoxicity index when used without any chemical modification and usually entail specific receptor mediated endocytosis or lysosomotropic agents to execute efficient gene delivery. In this report, primary amino groups of polyallylamine (PAA, 17 kDa) were substituted with imidazolyl functions, which are presumed to enhance endosomal release, and thus enhance its gene delivery efficiency and eliminate the requirement of external lysosomotropic agents. Further, systems were cross-linked with polyethylene glycol (PEG) to prepare PAA-IAA-PEG (PIP) nanoparticles and evaluated them in various model cell lines. The efficacy of PIP nanoparticles in delivering a plasmid encoding enhanced green fluorescent protein (EGFP) gene was assessed in COS-1, N2a and HEK293 cell lines, while their cytotoxicity was investigated in COS-1 and HEK293 cell lines. The PAA was chemically modified using imidazolyl moieties and ionically cross-linked with PEG to engineer nanoparticles. The extent of substitution was determined by ninhydrin method. The PIP nanoparticles were further characterized by measuring the particle size (dynamic light scattering and transmission electron microscopy), surface charge (zeta potential), DNA accessibility and buffering capacity. The cytotoxicity was examined using the MTT method. In vitro transfection efficiency of synthesized nanoparticles is increased up to several folds compared to native polymer even in the presence of serum, while maintaining the cell viability over 100% in COS-1 cells. Nanoparticles possess positive zeta potential between 5.6-13 mV and size range of 185-230 nm in water. The accessibility experiment demonstrated that nanoparticles with higher degree of imidazolyl substitution formed relatively loose complexes with DNA. An acid-base titration showed enhanced buffering capacity of modified PAA. The PIP nanoparticles reveal tremendous potential as novel delivery system for achieving improved transfection efficiency, while keeping the cells at ease.