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Hypoxia in the tumor microenvironment (TME) mediates resistance to radiotherapy and contributes to poor prognosis in patients receiving radiotherapy. Here we report the design of clinically suitable formulations of hybrid manganese dioxide (MnO2) nanoparticles (MDNP) using biocompatible materials to reoxygenate the TME by reacting with endogenous H2O2. MDNP containing hydrophilic terpolymer-protein-MnO2 or hydrophobic polymer-lipid-MnO2 provided different oxygen generation rates in the TME relevant to different clinical settings. In highly hypoxic murine or human xenograft breast tumor models, we found that administering either MDNP formulation before radiotherapy modulated tumor hypoxia and increased radiotherapy efficacy, acting to reduce tumor growth, VEGF expression, and vascular density. MDNP treatment also increased apoptosis and DNA double strand breaks, increasing median host survival 3- to 5-fold. Notably, in the murine model, approximately 40% of tumor-bearing mice were tumor-free after a single treatment with MDNPs plus radiotherapy at a 2.5-fold lower dose than required to achieve the same curative treatment without MDNPs. Overall, our findings offer a preclinical proof of concept for the use of MDNP formulations as effective radiotherapy adjuvants. Cancer Res; 76(22); 6643–56. ©2016 AACR.

Summary of results of various groups treated with TMD or LMD with or without RT on short-term tumor growth rate and changes in TME.

Characterization of NPs (S1); Immunofluorescence detection and quantification of EMT6 tumor hypoxia (S2); IF detection and quantification of EMT6 tumor hypoxia (S3); Quantification of IHC images (S4); Effect of IT treatment with MDNPs alone or combined with RT on murine and human breast tumors growth (S5); Effect of IT administered MDNPs alone or in combination with RT on the growth of murine EMT6 breast tumor (S6); Effect of IV treatment with MDNPs alone or combined with RT on murine and human breast tumors growth (S7); H&E stained mammary fat pad tissues of a healthy mouse and a LMD+RT surviving mouse (S8); Effect of MDNPs treatment post irradiation (S9).

Summary of reported rates of H2O2 production by different cancer cell lines and estimated H2O2 production in a solid tumor of ~100 mm3 in volume.

Description of additional methods and procedures used in the study. Also includes Supplementary References.

Summary of experimental design and assessments for the combination treatment with MDNPs and RT.

Similarities and differences of a large-scale flapping-wing robot with fixed-wing UAVs in equations of motion, trim curves, and aerodynamic forces in forward flight are discussed in this paper and a simplified model for flapping flight is presented. Due to the high Wing to Total Weight (WTW) ratio of large-scale ornithopters, simple rigid body dynamics is not accurate enough for flight dynamics modeling. On the other hand, the multi-body dynamics associated with flapping gives little insight into the behavior of the resulting model due to complexity of equations. It is also difficult to design proper controllers for such complicated models. In this paper, the effects of different terms of multi-body equations of ornithopter on the estimated aerodynamic forces are studied via experimental flight data. A simpler but yet accurate set of equations is obtained by removing less effective terms from original relations. The presented model is in the form of normal aircraft equations plus some additional terms which can be used in different control and estimation processes. In addition, trim conditions of forward flight are extracted using several flight tests, and corresponding periodic behavior of states and forces are studied. These studies are applicable for identifying time-periodic models.

Radiation therapy (RT) is a major modality for the treatment of prostate cancer (PCa), especially castration-resistant PCa (CRPC). However, hypoxia, often seen in PCa tumors, leads to radiation-resistance. This work investigates the effect of a novel oxygen-generating polymer-lipid manganese dioxide nanoparticle (PLMDs) on improving RT outcomes in CRPC xenograft models by modulating the tumor microenvironment (TME) both before and after RT.Human PC3 and DU145 PCa cells were used to investigate clonogenic inhibition and DNA repair pathways in vitro. Tumor hypoxia and post-RT angiogenesis were evaluated in a PC3-bearing SCID mouse model. PC3 and DU145 xenografts were used to study the efficacy of PLMD in combination with single or fractionated RT.PLMD plus RT significantly inhibited clonogenic potential, increased DNA double-strand breaks, and reduced DNA damage repair in hypoxic PC3 and DU145 cells as compared to RT alone. PLMD significantly reduced hypoxia-positive areas, hypoxia induced factor 1α (HIF-1α) expression, and protein carbonyl levels (a measure of oxidative stress). Application of PLMD with RT decreased RT-induced angiogenic biomarkers by up to 3-fold. Treatment of the human CRPC xenografts with PLMD plus RT (single or fractionated doses) significantly prolonged median survival of the host compared to RT alone resulting in up to a 40% curative rate.PLMD treatment modulated TME and sensitized hypoxic human CRPC cells to RT thus enhancing the efficacy of RT. These results confirmed the potential of PLMD as an adjuvant to RT for the treatment of hypoxic CRPC.

Successful delivery of anticancer drugs to intracellular targets requires different properties of the nanocarrier to overcome multiple transport barriers. However, few nanocarrier systems, to date, possess such properties, despite knowledge about the biological fate of inorganic and polymeric nanocarriers in relation to their fixed size, shape and surface properties. Herein, a polymer-lipid hybrid nanoparticle (PLN) system is described with size and shape transformability and its mechanisms of cellular uptake and intracellular trafficking are studied. Pharmaceutical lipids were screened for use in transformable PLN. Mechanisms of cellular uptake and the role of fatty acid-binding proteins in intracellular trafficking of PLN were investigated in breast cancer cells. Intra-tumoral penetration and retention of doxorubicin (DOX) were evaluated by confocal microscopy. The lead PLNs showed time-dependent size reduction and shape change from spherical to spiky shape. This transformability of PLNs and lipid trafficking pathways facilitated intracellular transport of DOX-loaded PLN (DOX-PLN) into mitochondria and nuclei. DOX-PLN significantly increased DOX penetration and retention over free DOX or non-transformable liposomal DOX particles at 4 h post-intravenous administration. Transformability of PLN and lipid-biology interplay can be exploited to design new nanocarriers for effective drug delivery to tumor cells and intracellular targets.

Background Tumor microenvironment (TME) and associated multiple factors are found to contribute to the failures in cancer therapies, including chemo- and immunotherapy. Here we report a new multimodal strategy that uses a bioreactive multifunctional hybrid polymer-lipid encapsulated manganese dioxide nanoparticle (PLMD NP) system to remodel the TME, suppress drug resistance factors, reverse immunosuppressive conditions, and enhance chemotherapy efficacy. Methods The influence of PLMD NPs on enhancing cellular uptake in EMT6 mouse breast cancer cells and tumor penetration of doxorubicin (DOX) in EMT6 orthotopic breast tumor mouse model was evaluated using confocal microscopy (n = 3-4). Immunohistochemistry was employed to examine the effect of PLMD NPs on downregulating hypoxia-induced drug resistance proteins and anticancer activity of DOX (n = 3-4). The efficacy of the combination therapy with PLMD NPS and DOX was assessed in murine EMT6 (n = 15-23) and 4T1 (n = 7) orthotopic breast tumor mouse models. Rechallenge and splenocyte transfer were performed to validate the stimulation of adaptive tumor immunity in the surviving mice. Results PLMD NPs enhanced intratumoral penetration and efficacy of DOX, and reduced intratumoral expression of P-glycoprotein, p53, and carbonic anhydrase IX by 74.5%, 38.0%, and 58.8% vs saline control, respectively. Combination treatment with PLMD NPs and DOX increased the number of tumor-infiltrated CD8+ T cells and resulted in up to 60.0% complete tumor regression. Of naive mice (n = 7) that received splenocytes from the PLMD+DOX-treated surviving mice, 57.1% completely suppressed tumor growth whereas 100% of mice that received splenocytes from DOX-treated mice (n = 3) and the control group (n = 7) showed rapid tumor growth. Conclusions The clinically suitable PLMD NPs can effectively downregulate TME-associated drug resistance and immunosuppression. The combination therapy with PLMD NPs and DOX is a multimodal and translational treatment approach for enhancing chemotherapeutic efficacy and boosting antitumor immunity.

Air-data measurements are one of the essential observations for system identification of flapping-wing unmanned aerial vehicles (UAVs). The effects of intensive high-amplitude oscillations ...

Background: Magnetic resonance image-guided radiation therapy (MRgRT) is a new-generation approach to improving treatment outcomes by allowing real-time precise tumor delineation that guides the radiation. However, the existing gadolinium-based contrast agents (GBCAs) are insufficient for MRgRT due to their severe side effects and rapid clearance from the tumor that requires multiple injections to maintain the signal. In addition, tumor hypoxia induced radiation resistance, which attenuates the RT efficacy. To date, there is no FDA-approved contrast agent with high safety and efficacy profile exhibiting both MR signal enhancement and RT sensitization capabilities. Based on our previous findings that manganese-dioxide nanoparticles (MDNP) can convert tumoral ROS (H2O2) into O2 to reduce hypoxia and sensitize RT, we propose the design of a novel tumor-targeting manganese-dioxide nanoparticle (MDNP) with dual MRI and RT enhancement functionalities. In this work, we evaluate the safety profile, biodistribution, in vivo clearance, MR contrast enhancement, and radiation sensitization effect of the MDNPs. Methods: Terpolymer-based MDNP (T-MDNP) were prepared by loading MnO2 precursor in a polymer-lipid matrix. Physicochemical properties and stability of NPs were determined by TEM, DLS, and zeta potential measurements. In vitro cellular uptake by cancer cells was measured via confocal microscopy. The biocompatibility and safety of the NPs was examined in vitro and in vivo. Tissue distribution, clearance, and tumor retention of T-MDNPs was evaluated using MRI and ICP. The tumoral MR signal enhancement by T-MDNP as a function of time was measured and compared with Gadavist™ (gadobutrol) in murine tumor models with human MDA-MB-231 breast or prostate PC3 xenografts. The ability of NPs to modulate tumor microenvironment (TME) and enhance RT efficacy was also evaluated. Results: The prepared T-MDNPs were 120 nm in size and exhibited excellent storage stability at room temperature and 4°C. The NPs showed negligible hemolysis effect suggesting their suitability for intravenous (IV) injection. As a result of in situ generation of Mn+2 ions via the reaction with tumoral ROS, a single dose of 70 μmole Mn/kg of body weight of T-MDNP increased tumor T1 signal by up to 1.4-fold and maintained it up to 4 hrs, while Gadavist™ was eliminated in about 30 min. The NPs were completely cleared from major organs in 72 hrs, as determined by MRI and ICP. Combination of NP treatments with RT resulted in significantly increased median survival time by 2-fold in human PC3 prostate model and 5-fold in human breast tumor model. Conclusions: Our results have demonstrated that the T-MDNPs are safe and effective as a dual MR contrast agent and radiation sensitizer. This system is promising for precise tumor margin delineation, maintaining MR signal in tumor for a duration needed for MRgRT, and improving RT efficacy. These properties make it an excellent candidate and the first-in-class entity that can be utilized with MRgRT. Citation Format: Charles Yen, Azhar Z. Abbasi, Chunsheng He, Mohammad Ali Amini, Hoyin Lip, Michael Rauth, Xiao Yu Wu. Theragnostic tumor-targeted manganese dioxide-loaded polymer-lipid nanoparticles for magnetic resonance image-guided radiation therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-100.

Nanotechnology has been applied extensively in drug delivery to improve the therapeutic outcomes of various diseases. Tremendous efforts have been focused on the development of novel nanoparticles and delineation of the physicochemical properties of nanoparticles in relation to their biological fate and functions. However, in the design and evaluation of these nanotechnology-based drug delivery systems, the pharmacology of delivered drugs and the (patho-)physiology of the host have received less attention. In this review, we discuss important pharmacological mechanisms, physiological characteristics, and pathological factors that have been integrated into the design of nanotechnology-enabled drug delivery systems and therapies. Firsthand examples are presented to illustrate the principles and advantages of such integrative design strategies for cancer treatment by exploiting 1) intracellular synergistic interactions of drug-drug and drug-nanomaterial combinations to overcome multidrug-resistant cancer, 2) the blood flow direction of the circulatory system to maximize drug delivery to the tumor neovasculature and cells overexpressing integrin receptors for lung metastases, 3) endogenous lipoproteins to decorate nanocarriers and transport them across the blood-brain barrier for brain metastases, and 4) distinct pathological factors in the tumor microenvironment to develop pH- and oxidative stress-responsive hybrid manganese dioxide nanoparticles for enhanced radiotherapy. Regarding the application in diabetes management, a nanotechnology-enabled closed-loop insulin delivery system was devised to provide dynamic insulin release at a physiologically relevant time scale and glucose levels. These examples, together with other research results, suggest that utilization of the interplay of pharmacology, (patho-)physiology and nanotechnology is a facile approach to develop innovative drug delivery systems and therapies with high efficiency and translational potential.

Manganese dioxide (MnO2) nanoparticles (NPs) were discovered in previous work to be effective in improving tumor oxygenation (hypoxia) and reducing H2O2 and acidity in the tumor microenvironment (TME) via local injection. To develop MnO2 formulations useful for clinical application, hybrid NPs are designed with tailored hydrophobicity and structure suitable for intravenous injection, with good blood circulation, biocompatibility, high tumor accumulation, and programmable oxygen generation rate. Two different hybrid NPs are constructed by embedding polyelectrolyte-MnO2 (PMD) in hydrophilic terpolymer/protein-MnO2 (TMD) or hydrophobic polymer/lipid-MnO2 (LMD) matrices. The in vitro reactivity of the MnO2 toward H2O2 is controlled by matrix material and NP structure and dependent on pH with up to two-fold higher O2 generation rate at acidic (tumor) pH than at systemic pH. The hybrid NPs are found to be safe to cells in vitro and organs in vivo and effectively decrease tumor hypoxia and hypoxia-inducible-factor-1alpha through local or systemic administration. Fast acting TMD reduces tumor hypoxia by 70% in 0.5 h by local injection. Slow acting LMD exhibits superior tumor accumulation and retention through the systemic administration and decreased hypoxia by 45%. These findings encourage a broader use of hybrid MD NPs to overcome TME factors for cancer treatment.

This work aimed to prepare a nanoemulsion preparation containing budesonide and assess its aerodynamic behavior in comparison with suspension of budesonide. In-vitro aerodynamic performance of the corresponding micellar solution (ie. nanoemulsion preparation without oil) was investigated too. Nanoemulsions of almond oil containing budesonide, as a hydrophobic model drug molecule, were prepared and optimized. Then, the effect of variation of surfactant/co-surfactant concentration on the aerodynamic properties of the nebulized aerosol was studied. The results indicated that the most physically stable formulation makes the smallest aerodynamic size. The concentration of co-surfactant was also shown to be critical in determination of aerodynamic size. Furthermore, the optimized sample, with 3% w/w almond oil, 20% w/w Tween 80+Span 80 and 2% w/w ethanol showed a smaller MMAD in comparison with the commercially available suspension and the micellar solution.

Anthracyclines, commonly employed for cancer chemotherapy, suffer from dose-limiting cardiotoxicity and poor efficacy due to multidrug resistance (MDR). We previously demonstrated that simultaneous delivery of the synergistic drugs doxorubicin (DOX) and mitomycin C (MMC) by polymer-lipid hybrid nanoparticles (PLN) circumvented MDR, increased efficacy, and reduced cardiotoxicity in immuncompromised mice superior to poly(ethylene glycol)-coated (PEGylated) lipososmal DOX (PLD). Herein it is shown that the DOX-MMC combination was also synergistic in MDR EMT6/AR1 murine breast cancer cells and that their nanoparticle formulations were able to overcome the MDR phenotype. In contrast PLD exhibited little or no effect on the MDR cells. For the first time, these differences in in vitro efficacy are shown to be strongly correlated with cellular uptake and intracellular distribution of DOX brought about by DOX formulations (e.g., free solution, PLN vs PLD). To take into consideration the role of an intact immune system and tumor stroma in the response of host and tumor to chemotherapy, use was made of nonimmunocomprised mouse models to study the dose tolerance, cardiotoxicity, and efficacy of DOX-MMC coloaded PLN (DMsPLN) compared to PLD. DMsPLN treatment at 50 mg/m(2) DOX and 17 mg/m(2) of MMC singly or once every 4 days for 4 cycles were well tolerated by the mice without elevated systemic toxicity blood markers or myocardial damage. In contrast, PLD was limited to a single treatment due to significant total weight loss. The DMsPLN treatment delayed tumor growth up to 312% and 28% in EMT6/WT and EMT6/AR1 models, respectively. This work supports the translational value of DMsPLN for the aggressive management of either naïve or anthracycline-resistant tumors.

Although a great number of studies may be found in literature about the parameters affecting the size of chitosan nanoparticles, no systematic work so far has detailed the factors affecting the polydispersity of chitosan as an important factor determining the quality of many preparations. Herein, using artificial neural networks (ANNs), four independent variables, namely, pH and concentration of chitosan solution as well as time and amplitude of sonication of the solution were studied to determine their influence on the polydispersity of solution. We found that in an ultrasound prepared nanodispersion of chitosan, all the four input parameters have reverse but non-linear relation with the polydispersity of the nanoparticles.

Purpose Artificial neural networks (ANNs) are used to optimize a formulation of poly(lactic acid) (PLA) nanoparticles containing hydrophobic drug molecules through a study of the critical parameters affecting nanoparticle size.

The pharmacokinetic properties of chitosan nanoparticles have been shown to mainly depend on its particle size. The aim of this study was to concurrently evaluate and model the effective parameters, namely, chitosan concentration, buffer pH, amplitude and time of sonication, on the particle size of chitosan nanoparticles. Chitosan solutions were prepared and sonicated with different values for the above mentioned parameters. The data were then modeled using artificial neural networks (ANNs). The results illustrated that all four input parameters affect the size of prepared chitosan nanoparticles. While a reverse effect was observed between the size and the buffer pH as well as time and amplitude of sonication, the concentration was found to directly influence the particle size. The optimum condition to obtain the minimum size of nanoparticles in the range of 50-200 nm was found to be high values of pH and sonication time (i.e. approximately 4.9 and 500 s, respectively) and amplitude values of more than ~55.

Hypoxia in the tumor microenvironment (TME) mediates resistance to radiotherapy and contributes to poor prognosis in patients receiving radiotherapy. Here we report the design of clinically suitable formulations of hybrid manganese dioxide (MnO2) nanoparticles (MDNP) using biocompatible materials to reoxygenate the TME by reacting with endogenous H2O2. MDNP containing hydrophilic terpolymer-protein-MnO2 or hydrophobic polymer-lipid-MnO2 provided different oxygen generation rates in the TME relevant to different clinical settings. In highly hypoxic murine or human xenograft breast tumor models, we found that administering either MDNP formulation before radiotherapy modulated tumor hypoxia and increased radiotherapy efficacy, acting to reduce tumor growth, VEGF expression, and vascular density. MDNP treatment also increased apoptosis and DNA double strand breaks, increasing median host survival 3- to 5-fold. Notably, in the murine model, approximately 40% of tumor-bearing mice were tumor-free after a single treatment with MDNPs plus radiotherapy at a 2.5-fold lower dose than required to achieve the same curative treatment without MDNPs. Overall, our findings offer a preclinical proof of concept for the use of MDNP formulations as effective radiotherapy adjuvants. Cancer Res; 76(22); 6643–56. ©2016 AACR.

This review discusses the reports of alternative dosage forms to suspension formulations of hydrophobic drugs for nebulisers. Suspensions for nebulisers, although widely used over recent years, have several limitations which have led to pharmaceutical researchers looking for alternative, better performing preparations. Particular attention has been directed towards the use of nanoparticles as carriers of hydrophobic active ingredients. Several nanoformulations have been prepared and compared in vitro and/or in vivo with the corresponding microsuspension formulation. It is also clear that future studies in this field should address the parallel important aspects of safety and economical aspects of nanoparticualte formulations.

Chitosan was isolated and purified from the mycelia of Rhizomucor miehei and Mucor racemosus. To characterize the extracted materials, their FTIR spectra were compared with that of shrimp chitosan. Final degree of deacetylation which determined by (1)H NMR was obtained as 98.6% for chitosan from R. miehei (named as C1) and 97.1% for chitosan from M. racemosus (named as C2), respectively. To investigate the antimicrobial properties of the isolated fungal chitosans, minimum inhibitory concentration (MIC) values were performed against twelve strains of bacteria and fungi. Data obtained generally showed that the antibacterial and antifungal activities of the purified fungal chitosans were more effective against Escherichia coli, Pseudomonas aeroginosa, Candida albicans and Candida glabrata in comparison to the shrimp chitosan. Taken together, the results suggest that the use of the fungal chitosan could be of interest as a suitable alternative source to shrimp chitosan.

Background: Immunogenic cell death (ICD) is a cell death modality which triggers an immune response against dead-cell antigens, particularly when they derive from cancer cells. ICD has been reported to be highly induced by anthracycline drugs, such as doxorubicin (DOX), via facilitating tumor antigen presentation to and activation of T cells. However, these immunogenic effects may be compromised due to the immunosuppressive tumor microenvironment (TME), such as excess ROS, particularly H2O2, produced by tumor cells and dysfunctional macrophages in the tumor. We hypothesize that modulating immunosuppressive factors in the TME can enhance tumor response to chemotherapy and boost immunity. Specifically, polymer-lipid encapsulated manganese dioxide nanoparticles (PLMD NPs) are used to reduce tumor hypoxia and ROS by scavenging H2O2 and generating oxygen. Antitumor immunity against the cancer cells can be enhanced by the combination therapy with PLMD and DOX. Methods: PLMD NPs were prepared by dispersing MnO2 precursor particles in melted lipid and polymer in a surfactant-containing aqueous medium. The efficacy of the combination treatment was evaluated in immunocompetent mice-bearing orthotopic murine EMT6 breast tumor. The mice were treated by intravenous (IV) injection of free DOX alone, or 4 h after PLMD NP IV injection. A re-challenge study was performed by re-inoculating EMT6 cells in cured mice 120 days after the initial treatments. to validate the presence of adaptive anti-tumor immunity in the animals treated with PLMD+DOX combination, splenocyte transfer study was carried out. Ex-vivo imaging techniques were used to measure the number of infiltrated CD8+ T cells into the tumor and polarization of the M2 to M1 macrophages. Results: The PLMD+DOX combination treatment resulted in the median survival time by ~ 5.6-fold as compared to DOX alone, and led to 60% cure rate (9 out of 15 mice). This combination therapy also generated anti-tumor immunity against tumor re-inoculation in 88% of surviving mice and provided anti-tumor immunity in naïve mice that received splenocyte transfer with 57% of mice without tumor growth after inoculation. Ex-vivo studies resulted a 400% increase in the number of intratumoral CD8+ T cells, 5 days after PLMD+DOX treatment, while DOX alone treatment showed only 150% increase when compared to saline treatment. Moreover, M1 macrophages-related CD86 positive cells were found up-regulated by 51% while a significant loss of M2 marker CD163 (-47%) was observed in PLMD+DOX-treated tumors compared to DOX alone-treated ones. Conclusions: The present work demonstrated that clinically suitable PLMD NPs can effectively downregulate TME-associated immunosuppression factors and boost DOX efficacy. The PLMD NPs and DOX combination therapy presents a multimodal and a translational treatment approach to enhancing DOX-induced ICD and boosting anti-tumor immunity. Citation Format: Mohammad Ali Amini, Azhar Abbasi, Ping Cai, Hoyin Lip, Jason Li, Claudia Gordijo, Li Zhang, Michael Rauth, Xiao Yu Wu. Boosting doxorubicin-induced immunogenic cell death by using tumor microenvironment modulating nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5218.

Chitosan nanoparticles were prepared using ultrasonication methodology at specific amplitudes and times of sonication. Subsequently, small interfering RNA (siRNA) was added to the solution at predetermined values of nitrogen to phosphorous ratio (N/P), and stirring time. Employing response surfaces generated from a statistical model, the effect of sonication time and amplitude, stirring time, and N/P ratio was studied on the particle size, polydispersity, and loading efficiency of prepared siRNA/chitosan nanoparticles. It was found that to obtain the smallest size, amplitude and time of sonication as well as stirring time should be kept at ∼45%, 165 seconds, and 50 minutes, respectively. Minimum polydispersity values were also obtained at similar values of sonication time/amplitude and stirring time in addition to N/P values of ∼28. Also, the maximum proportion of siRNA loading was observed at approximate values of 300 seconds, 80% and 280 for sonication time, amplitude, and N/P ratio, respectively. The optimum conditions (i.e., to prepare a sample with minimum values of particle size and polydispersity index and maximum values of loading efficiency) were determined as 60.6, 30.0 (seconds), 28.0, and 12.5 (minutes) for amplitude, time of sonication, N/P, and stirring time, respectively. In this scrutiny, the predicted values of optimum formulation were 456 nm size, 89.6% loading efficiency, and 0.4 polydispersity index.

Multidrug resistance (MDR) is a main cause of chemotherapy failure in cancer treatment. It is associated with complex cellular and molecular mechanisms including overexpression of drug efflux transporters, increased membrane rigidity, and impaired apoptosis. Numerous efforts have been made to overcome efflux transporter-mediated MDR using nanotechnology-based approaches. However, these approaches fail to surmount plasma membrane rigidity that attenuates drug penetration and nanoparticle endocytosis. Here, a “one-two punch” nanoparticle approach is proposed to coordinate intracellular biointeraction and bioreaction of a nanocarrier material docosahexaenoic acid (DHA) and an anticancer prodrug mitomycin C (MMC) to enhance mitochondrion-targeted toxicity. Incorporation of DHA in solid polymer-lipid nanoparticles first reduces the membrane rigidity in live cancer cells thereby increasing nanoparticle cellular uptake and MMC accumulation. Subsequent intracellular MMC bioreduction produces free radicals that in turn react with adjacent DHA inducing significantly elevated mitochondrial lipid peroxidation, leading to irreversible damage to mitochondria. Preferential tumor accumulation of the nanoparticles and the synergistic anticancer cytotoxicity remarkably inhibit tumor growth and prolonged host survival without any systemic toxicity in an orthotopic MDR breast tumor model. This work suggests that combinatorial use of biophysical and biochemical properties of nanocarrier materials with bioreactive prodrugs is a powerful approach to overcoming multifactorial MDR in cancer.

Multifunctional nanoparticles (NPs) have found important applications in diagnosis, chemotherapy, and image-guided surgery of tumors. In this work, we have developed polymeric theranostic NPs (PTNPs) containing the anticancer drug docetaxel (DTX), a fluorescent dye, and magnetic manganese oxide (MnO) NPs for dual modal imaging and chemotherapy. PTNPs ~150 nm in diameter were synthesized by co-loading hydrophobic DTX and MnO NPs ~5 nm in diameter, into the matrix of a fluorescent dye-labeled amphiphilic polymer. The PTNPs enabled high loading efficiency and sustained in vitro release of DTX. Energy-dependent cellular uptake and extended cytoplasmic retention of the PTNPs in MDA-MB-231 human breast cancer cells were observed by fluorescence microscopy examination. DTX-loaded PTNPs exhibited higher cytotoxicity than free DTX with a 3 to 4.4-fold decrease in drug dose required for 50% cell growth inhibition. The hydrophilic backbone of the amphiphilic polymer improved the fluidity of PTNPs which enhanced the longitudinal relaxivity (r1) of loaded MnO NPs by 2.7-fold with r1=2.4mM(-1)s(-1). Whole body fluorescence imaging (FI) and magnetic resonance imaging (MRI) showed significant accumulation and prolonged retention of PTNPs in orthotopic MDA-MB-231 breast tumors. These results suggest that the new amphiphilic polymer-based PTNP system, able to simultaneously deliver a poorly soluble anticancer drug, enhance MRI contrast, and stain tumor tissue by fluorescence, is a good candidate for cancer theranostic applications.

The aim of this study is to prepare a nanosuspension of budesonide for respiratory delivery using nebuliser by optimising its particle size and characterising its in vitro deposition behaviour. PLA (poly lactic acid)-budesonide nanosuspension (BNS) was prepared using high-pressure emulsification/solvent evaporation method. To optimise particle size, different parameters such as PLA concentration, sonication time, and amplitude were investigated. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and scanning electron microscope (SEM) analyses were performed to characterise the prepared PLA-budesonide nanoparticles. The in vitro aerodynamic characteristics of the PLA-BNS using a jet nebuliser were estimated and compared with that of commercially available suspension formulation of budesonide. Budesonide-loaded PLA nanoparticles with fine particle size (an average size of 224-360 nm), narrow size distribution, and spherical and smooth surface were prepared. The optimum condition for preparation of fine particle size for aerosolisation was found to be at PLA concentration of 1.2 mg/ml and amplitude of 70 for 75 s sonication time. The in vitro aerosolisation performance of PLA-BNS compared to that of commercial budesonide indicated that it has significantly (p 0.05) smaller mass median aerodynamic diameter (MMAD) value with an enhancement in fine particle fraction (FPF) value. Improving the in vitro deposition of budesonide, PLA-BNS could be considered as a promising alternative suspension formulation for deep lung delivery of the drug using nebuliser.

Nasal vaccination is a promising, needle-free alternative route for parenteral vaccination. This study introduces a simple, scalable nasal vaccine delivery formulation for Foot and Mouth Disease virus (FMDv) using chitosan (CS) nanoparticles and assesses the potential of fungal CS for use as nanocarriers for mucosal vaccines. Fungal CS was extracted from fungal biomass and physiochemically characterized. FMDv-loaded CS nanoparticles, prepared using an ionic gelation technique, were characterized for particle size, zeta potential, morphology, loading efficiency and virus particle release. The immunogenicities of nasally applied FMDv-loaded fungal or commercial shrimp CS were compared with intraperitoneally administered fluid vaccine in guinea pigs. The nanoparticles had varied sizes (221.9-281.2 nm), positive electrical charge (+7 to +13 mV) and excellent antigen-loading capacity (93-97%). In vitro release studies revealed a biphasic virus particle release for all CS nanoparticles. Higher serum titers were developed with CS formulations than with free virus and were comparable with the titers for intraperitoneally administered fluid vaccine. Significantly higher IgA levels were found after the administration of nasal vaccine than after fluid vaccine or free virus. Overall, CS-FMDv nanoparticles stimulated humoral and mucosal immunity following intranasal administration. Fungal CS polymers were potent mucosal immunoadjuvants and showed promise as alternative sources of CS for mucosal vaccine formulations.

Introduction Tumor hypoxia is a poor prognostic factor in a number of malignancies such as prostate cancer (PCa). Clinically relevant hypoxic levels are detected in 30-90% PCa with oxygen concentrations below that required for half-maximal radiosensitivity, thus making radiotherapy (RT) ineffective alone [10]. Recently our lab has created pharmaceutically acceptable bioreactive hybrid manganese dioxide nanoparticles (MDNPs) and demonstrated their ability to modulate tumor microenvironment (TME) by reacting with H2O2 and protons and producing O2 in hypoxic tumors, as well as to enhance radiation response of tumor. Methods Lipid encapsulated and polymer stabilizedMDNPs (LMD NPs) were prepared by dispersing MnO2 precursor particles in melted lipid and polymer and then characterized for the particle size and zeta potential. In-vitro oxygen generation of LMD NPs was examined by measuring oxygen saturation level (sO2) in the blood using photoacoustic (PA) imaging method with addition of LMD NPs and H2O2. Biodistribution of LMD NPs in PCa tumor-bearing mice was evaluated by using a Xenogen IVIS Spectrum Imaging System following IV injection of ICG labeled NPs through the tail vein. Mice were monitored non-invasively for up to 24 hours. To investigate the effect of combination of MDNPs and radiation therapy on tumor growth delay and survival, PCa tumor-bearing mice were treated intravenously with LMD NPs with saline as a control. Four hour post injection, 10 Gy radiation dose was given at the site of the tumor. Mice were monitored every 2 days by measuring tumor size using a caliper. Mice were sacrificed when the tumor size reached 500 mm3. Results PA imaging demonstrated a controlled and prolonged generation of O2 in the blood with maximum oxygen saturation (90-95%) being reached within 60 min after incubation with LMD NPs and H2O2. The biodistribution and ex-vivo images of the resected organs showed that LMD NPs accumulated in the prostate tumor sites within 1 h post i.v. injection and remained in the tumor for at least 24 h. The ex vivo optical data of excised tissue showed a significant uptake of LMD nanoparticles by prostate tumor 24 hpost particle administration. The combination of LMD NPs treatment with single dose 10 Gy RT inhibited tumor growth by 24% at 5 days post treatment, whereas the tumor size increased about 47% in mice treated with RT alone. LMD NPs plus RT also improved survival rate of the cancerous mice for up to 53 days, which was about 3.3-fold enhancement in the mean survival rate compared to saline plus RT treatment (30 days). Conclusion The new bioreactive MnO2 NPs exhibited desirable oxygen- generating profile and high tumor accumulation and retention after systemic administration. This work has demonstrated, in a preclinical prostate tumor model, that the combination of LMD NPs with radiation therapy is a promising treatment approach for solid tumor.. Citation Format: Mohammad Ali Amini, Azhar Z. Abbasi, Claudia R. Gordijo1, Ping Cai, Andrew M. Rauth, Robert G. Bristow, Xiao Yu Wu. Hybrid bioactive nanoparticles for modulating prostate tumor microenvironment and enhancing radiation therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 745.

The purpose of this study was to find an artificial neural networks model for determining major factors impacting the stability of an acetaminophen nanosuspansion that was prepared using nanoprecipitation in microfluidic reactors. Four variables, namely concentration of surfactant, solvent and antisolvent flow rate and solvent temperature were used as input variables and time of sedimentation of nanoparticles was considered as output variable. The particle size of optimized formulation was measured by transmission electron microscope and dynamic light scattering. Comparing the 3D graphs from the model showed that antisolvent flow rate and temperature have direct relation with time of sedimentation, whereas solvent flow rate generally has reverse relation with the time of sedimentation. Concentration of surfactant was found to be the most important factor in determining the stability of nanosuspension.