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Xingran Du,1,* Jianpeng Xue,2,* Mingzi Jiang,3 Shaoqing Lin,4 Yuzhen Huang,4 Kaili Deng,5 Lei Shu,5 Hanmei Xu,2 Zeqing Li,2 Jing Yao,4 Sixia Chen,4 Ziyan Shen,4 Ganzhu Feng4 1Department of Infectious Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2State Key Laboratory of Natural Medicines, The Engineering Research Center of Synthetic Polypeptide Discovery and Evaluation of Jiangsu Province, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, The First People’s Hospital of Kunshan, Suzhou, Jiangsu, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 5Department of Respiratory Medicine, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ganzhu FengDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of ChinaTel +86-025-58509837Fax +86-025-58509994Email zhu1635253@163.comBackground: The development of vaccines is a promising and cost-effective strategy to prevent emerging multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections. The purpose of this study was to prepare a multiepitope peptide nanovaccine and evaluate its immunogenicity and protective effect in BALB/c mice.Methods: The B-cell and T-cell epitopes of Omp22 from A. baumannii were predicted using bioinformatics methods and identified by immunological experiments. The optimal epitopes were conjugated in series by 6-aminocaproic acid and chemically synthesized multiepitope polypeptide rOmp22. Then, rOmp22 was encapsulated by chitosan (CS) and poly (lactic-co-glycolic) acid (PLGA) to prepare CS-PLGA-rOmp22 nanoparticles (NPs). The immunogenicity and immunoprotective efficacy of the vaccine were evaluated in BALB/c mice.Results: CS-PLGA-rOmp22 NPs were small (mean size of 272.83 nm) with apparently spherical structures, positively charged (4.39 mV) and nontoxic to A549 cells. A high encapsulation efficiency (54.94%) and a continuous slow release pattern were achieved. Compared with nonencapsulated rOmp22, CS-PLGA-rOmp22 immunized BALB/c mice induced higher levels of rOmp22-specific IgG in serum and IFN-γ in splenocyte supernatant. Additionally, lung injury and bacterial burdens in the lung and blood were suppressed, and potent protection (57.14%-83.3%) against acute lethal intratracheal A. baumannii challenge was observed in BALB/c mice vaccinated with CS-PLGA-rOmp22.Conclusion: CS-PLGA-rOmp22 NPs elicited specific IgG antibodies, Th1 cellular immunity and protection against acute lethal intratracheal A. baumannii challenge. Our results indicate that this nanovaccine is a desirable candidate for preventing A. baumannii infection.Keywords: A. baumannii, epitope vaccine, polymeric nanoparticles, PLGA, chitosan

Vitamin E belongs to the family of lipid-soluble vitamins and can be divided into two groups, tocopherols and tocotrienols, with four isomers (alpha, beta, gamma and delta). Although vitamin E is widely known as a potent antioxidant, studies have also revealed that vitamin E possesses anti-inflammatory properties. These crucial properties of vitamin E are beneficial in various aspects of health, especially in neuroprotection and cardiovascular, skin and bone health. However, the poor bioavailability of vitamin E, especially tocotrienols, remains a great limitation for clinical applications. Recently, nanoformulations that include nanovesicles, solid-lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, and polymeric nanoparticles have shown promising outcomes in improving the efficacy and bioavailability of vitamin E. This review focuses on the pharmacological properties and pharmacokinetics of vitamin E and current advances in vitamin E nanoformulations for future clinical applications. The limitations and future recommendations are also discussed in this review.

Background Successful endodontic therapy is mainly governed by the satisfactory sealing ability of the applied root canal sealer. Also, tolerability of root canal structure to accommodate the presence of a sealer participates in the efficiency of the treatment. Hence, this study was aimed to extrapolate our previous one that was concerned with the preparation and evaluation of novel nature-based root canal sealers. Our current work is focused on the evaluation of sealing ability and in vivo biocompatibility. Materials and Methods Egyptian propolis was extracted (ProE) and encapsulated in polymeric nanoparticles (ProE-loaded NPs). Two root sealers, PE sealer and PE nanosealer, were fabricated by incorporating ProE and ProE-loaded NPs, respectively. The sealing ability of the developed sealers was tested by a dye extraction method. An in vivo biocompatibility study was conducted using a subcutaneous implantation method for two and four weeks. At the same time, a model sealer (AH Plus®) was subjected to the same procedures to enable accurate and equitable results. Results The teeth treated with PE sealer exhibited weak sealing ability which did not differ from that of unfilled teeth. PE nanosealer enhanced the sealing ability similarly to the model sealer with minimal apical microleakage. Studying in vivo biocompatibility indicated the capability of the three tested sealers to induce cell proliferation and tissue healing. However, PE nanosealer had superior biocompatibility, with higher potential for cell regeneration and tissue proliferation. Conclusion PE nanosealer can be presented as an innovative root canal sealer, with enhanced sealing ability as well as in vivo biocompatibility. It can be applied as a substitute for the currently available sealers that demonstrate hazardous effects.

Islam Ali Abdel Raheem,1 Amro Abdul Razek,1 Abeer Abdelaziz Elgendy,1 Noha Mohamed Saleh,2 Mona Ibrahem Shaaban,3 Faten K Abd El-Hady4 1Department of Endodontics, Faculty of Dentistry, Mansoura University, Mansoura, Egypt; 2Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; 3Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; 4Chemistry of Natural and Microbial Products Department, National Research Centre, Giza, EgyptCorrespondence: Noha Mohamed SalehDepartment of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Gomhoreyah Street, Mansoura 35516, EgyptTel/fax +2 050 2247496Email nunu_ramy@yahoo.comBackground: Propolis is a unique natural adhesive product collected by honeybees. It contains a diversity of bioactive compounds with reported functional properties such as antioxidants, antibacterial, antifungal, anti-inflammatory, antiviral and anticancer activity. Dental caries is a worldwide problem that caused by microbial growth usually progress from tooth enamel to the underlying pulpal tissues and root canal. This situation could be controlled by a sequence of steps to remove microorganisms and fill root canal with a suitable long-lasting root canal sealer. Unfortunately, leachable and degradation products of the currently used sealers compromised their antimicrobial activity by inflammatory modulation associated with irritation and toxicity of periapical tissues.Materials and methods: Hence, propolis was selected to be designed as a natural root canal sealer due to its amazing functional properties. Moreover, its handling properties were enhanced and potentiated by its incorporation in polymeric nanoparticles (NPs). Frist, propolis was collected, extracted and analyzed for its bioactive compounds. After that, propolis-loaded NPs of PLGA (ProE-loaded NPs) were developed and fully characterized regarding physicochemical properties, in vitro release and in vitro cytotoxicity. Then, root canal sealers were fabricated and assayed for their antimicrobial activity. Both cytotoxicity and antimicrobial activity were compared to those of a model sealer; AH Plus®.Results: The results revealed that spherical nanoscopic NPs with narrow size distribution were obtained. ProE-loaded NPs exhibited accepted entrapment efficiency (>80) and prolonged release. In vitro cytotoxicity study confirmed the safety of ProE-loaded NPs. Also, the developed sealers showed antimicrobial activity versus bacterial strains of Enterococcus faecalis and Streptococcus mutans and antifungal activity against Candida albicans.Conclusion: ProE-loaded NPs could be incorporated in and represented as a root canal sealer with prolonged release and enhanced cytocompatibility as well as antimicrobial activities.Keywords: propolis, sealer, polymeric nanoparticles, PLGA, in vitro cytotoxicity, antimicrobial activity

Lipid-polymer hybrid nanoparticles (LPHNPs) are next-generation core-shell nanostructures, conceptually derived from both liposome and polymeric nanoparticles (NPs), where a polymer core remains enveloped by a lipid layer. Although they have garnered significant interest, they remain not yet widely exploited or ubiquitous. Recently, a fundamental transformation has occurred in the preparation of LPHNPs, characterized by a transition from a two-step to a one-step strategy, involving synchronous self-assembly of polymers and lipids. Owing to its two-in-one structure, this approach is of particular interest as a combinatorial drug delivery platform in oncology. In particular, the outer surface can be decorated in multifarious ways for active targeting of anticancer therapy, delivery of DNA or RNA materials, and use as a diagnostic imaging agent. This review will provide an update on recent key advancements in design, synthesis, and bioactivity evaluation as well as discussion of future clinical possibilities of LPHNPs.

Zaina Ait Bachir,1,* YuKun Huang,1,* MuYe He,1 Lei Huang,1 XinYu Hou,1 RongJun Chen,2 Feng Gao1,3,4 1Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai, People’s Republic of China; 2Department of Chemical Engineering, Imperial College London, South Kensington Campus, London, UK; 3Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China; 4China Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: One of the most important aspects of drug delivery is extended nanoparticle (NP) residence time in vivo. Herein, we report a series of methotrexate (MTX)-loaded chitosan (CS) NPs coated with differently sized methoxy polyethylene glycol (mPEG) at different mPEG surface densities. Materials and methods: MTX was incorporated into NPs (112.8–171.2 nm in diameter) prepared from the resulting mPEG-g-CS. The NPs had a zeta potential of +7.4–35.0 mV and MTX loading efficiency of 17.1%–18.4%. MTX/mPEG-g-CS NPs showed an initial burst release of MTX followed by a sustained-release profile in PBS at pH 7.4. Results: The in vitro cellular uptake study showed that MTX accumulation in J774A.1 macrophage cells decreased with increasing the mPEG surface density or the mPEG molecular weight. The pharmacokinetic study on Sprague Dawley rats revealed an increase in AUC0–72 h (area under the plasma drug concentration–time curve over a period of 72 hours) with increasing the mPEG surface density or the mPEG molecular weight and a linear correlation between the mPEG surface density and AUC0–72 h. Conclusion: The biodistribution study on Institute of Cancer Research (ICR) mice revealed that MTX/mPEG-g-CS NPs significantly enhanced blood circulation time in the body and decreased accumulation in liver, spleen, and lung. These results suggest the potential of the mPEG-g-CS NPs as a promising candidate for drug delivery. Keywords: chitosan, PEGylation, nanoparticles, methotrexate, drug delivery systems

Frederick YK Siu,1–3 Shaotang Ye,1–3 Hui Lin,1–3 Shoujun Li1–3 1College of Veterinary Medicine, South China Agricultural University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, Guangzhou, People’s Republic of China; 3Guangdong Technological Engineering Research Center for Pet, Guangzhou, People’s Republic of China Background: Resveratrol (RES) is a natural anti-inflammatory and antioxidant compound with poor water solubility and oral bioavailability. The present study takes the advantages of nanocarriers combined with a ligand (galactose) anchoring to orally deliver RES in an attempt to improve its bioavailability and pharmacological activity. Methods: RES-loaded galactosylated nanoparticles (RES-GNPs) were prepared by solvent diffusion technique using poly(lactic-co-glycolic acid), synthesized N-oleoyl-d-galactosamine and Tween 80. RES-GNPs were characterized by particle size, morphology, entrapment efficiency (EE) and in vitro release. Oral bioavailability and in vitro anti-inflammatory activity were investigated in rats and lipopolysaccharides-induced RAW 264.7 cells, respectively. Results: The resulting RES-GNPs were 108.4 nm around in particle size with a polydispersity index of 0.217. Furthermore, RES-GNPs possessed a high EE and a slow drug release in water. After oral administration, RES-GNPs significantly enhanced the oral bioavailability of RES, up to 335.7% relative to RES suspensions. In situ single-pass intestinal perfusion and cellular uptake experiments showed that GNPs could improve the intestinal permeability and transcellular transport of RES. Moreover, the anti-inflammatory efficacy of RES-GNPs in RAW 264.7 cells model was superior to free RES and RES-GNPs. Conclusion: The results indicate that RES-GNPs can effectively promote the intestinal absorption of RES and strengthen its bioactivity, which may be a promising system for the treatment of inflammatory diseases. Keywords: resveratrol, polymeric nanoparticles, galactosylation, oral bioavailability, anti-inflammation

Pedram Rafiei, Azita Haddadi Division of Pharmacy, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada Abstract: Docetaxel is a highly potent anticancer agent being used in a wide spectrum of cancer types. There are important matters of concern regarding the drug’s pharmacokinetics related to the conventional formulation. Poly(lactide-co-glycolide) (PLGA) is a biocompatible/biodegradable polymer with variable physicochemical characteristics, and its application in human has been approved by the United States Food and Drug Administration. PLGA gives polymeric nanoparticles with unique drug delivery characteristics. The application of PLGA nanoparticles (NPs) as intravenous (IV) sustained-release delivery vehicles for docetaxel can favorably modify pharmacokinetics, biofate, and pharmacotherapy of the drug in cancer patients. Surface modification of PLGA NPs with poly(ethylene glycol) (PEG) can further enhance NPs’ long-circulating properties. Herein, an optimized fabrication approach has been used for the preparation of PLGA and PLGA–PEG NPs loaded with docetaxel for IV application. Both types of NP formulations demonstrated in vitro characteristics that were considered suitable for IV administration (with long-circulating sustained-release purposes). NP formulations were IV administered to an animal model, and docetaxel’s pharmacokinetic and biodistribution profiles were determined and compared between study groups. PLGA and PEGylated PLGA NPs were able to modify the pharmacokinetics and biodistribution of docetaxel. Accordingly, the mode of changes made to pharmacokinetics and biodistribution of docetaxel is attributed to the size and surface properties of NPs. NPs contributed to increased blood residence time of docetaxel fulfilling their role as long-circulating sustained-release drug delivery systems. Surface modification of NPs contributed to more pronounced docetaxel blood concentration, which confirms the role of PEG in conferring long-circulation properties to NPs. Keywords: poly(lactide-co-glycolide), poly(lactide-co-glycolide)–poly(ethylene glycol), polymeric nanoparticles, docetaxel, emulsification solvent evaporation, sustained release, pharmacokinetics, biodistribution

Background Diosmin showed poor water solubility and low bioavailability. Poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles were successfully used to improve the drugs solubility and bioavailability. Coating of PLGA nanoparticles with chitosan can ameliorate their gastric retention and cellular uptake. Methodology PLGA nanoparticles of diosmin were prepared using different drug and polymer amounts. Nanoparticles were selected based on entrapment efficiency% (EE%) and particle size measurements to be coated with chitosan. The selected nanoparticles either uncoated or coated were evaluated regarding morphology, ζ-potential, solid-state characterization, in vitro release, storage stability, and mucoadhesion. The anti-ulcer activity (AA) against ethanol-induced ulcer in rats was assessed through macroscopical evaluation, histopathological examination, immunohistochemical localization of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transmission electron microscopic examination of gastric tissues compared to free diosmin (100 mg/kg) and positive control. Results Based on EE% and particle size measurements, the selected nanoparticles, either uncoated or coated with 0.1% w/v chitosan, were based on 1:15 drug-PLGA weight ratio and 20 mg diosmin employing methylene chloride as an organic phase. Examination by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed nanoscopic spherical particles. Drug encapsulation within the selected nanoparticles was suggested by Fourier transform-infrared, differential scanning calorimetry (DSC) and X-ray diffractometry results. Chitosan-coated nanoparticles were more stable against size enlargement probably due to the higher ζ-potential. Only coated nanoparticles showed gastric retention as revealed by SEM examination of stomach and duodenum. The superior AA of coated nanoparticles was confirmed by significant reduction in average mucosal damage, the majority of histopathological changes and NF-κB expression in gastric tissue when compared to positive control, diosmin and uncoated nanoparticles as well as insignificant difference relative to normal control. Coated nanoparticles preserved the normal ultrastructure of the gastric mucosa as revealed by TEM examination. Conclusion The optimized chitosan-coated PLGA nanoparticles can be represented as a potential oral drug delivery system of diosmin.

Invasive mycoses are a major problem for immunocompromised individuals and patients in intensive care units. Morbidity and mortality rates of these infections are high because of late diagnosis and delayed treatment. Moreover, the number of available antifungal agents is low, and there are problems with toxicity and resistance. Alternatives for treating invasive fungal infections are necessary. Nanostructured systems could be excellent carriers for antifungal drugs, reducing toxicity and targeting their action. The use of nanostructured systems for antifungal therapy began in the 1990s, with the appearance of lipid formulations of amphotericin B. This review encompasses different antifungal drug delivery systems, such as liposomes, carriers based on solid lipids and nanostructure lipids, polymeric nanoparticles, dendrimers, and others. All these delivery systems have advantages and disadvantages. Main advantages are the improvement in the antifungal properties, such as bioavailability, reduction in toxicity, and target tissue, which facilitates innovative therapeutic techniques. Conversely, a major disadvantage is the high cost of production. In the near future, the use of nanosystems for drug delivery strategies can be used for delivering peptides, including mucoadhesive systems for the treatment of oral and vaginal candidiasis.

Salma E El-Habashy, Ahmed N Allam, Amal H El-Kamel Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt Abstract: Nanoparticles (NPs) have long gained significant interest for their use in various drug formulations in order to increase bioavailability, prolong drug release, and decrease side effects of highly toxic drugs. The objective of this investigation was to evaluate the potential of ethyl cellulose-based NPs (EC-NPs) to modulate the release and reduce ulcerogenicity of piroxicam (PX) after oral administration. PX-loaded EC-NPs were prepared by solvent evaporation technique using different stabilizers at three concentration levels. Morphological examination of selected formulas confirmed the formation of spherical NPs with slightly porous surface. Formulation containing poloxamer-stabilized EC-NPs (P188/0.2), having a particle size of 240.26±29.24nm, polydispersity index of 0.562±0.030, entrapment efficiency of 85.29%±1.57%, and modulated release of PX (88% after 12hours), was selected as the optimum formulation. Differential scanning calorimetry demonstrated the presence of PX in an amorphous form in the NPs. Fourier-transform infrared spectroscopy revealed the possible formation of hydrogen bond and the absence of chemical interaction. In vivo study, evaluation of pharmacokinetic parameters, evaluation of gastric irritation potential, and histological examination were conducted after administration of the selected formulation. Time to reach maximum plasma concentration, tmax, of poloxamer-stabilized EC-NPs was significantly higher than that of Feldene® 20mg capsules (P≤0.001). Encapsulation of the acidic, gastric offender PX into NPs managed to significantly suppress gastric ulceration potential in rats (P≤0.05) as compared to that of PX suspension. A reduction of 66% in mean ulcer index was observed. In conclusion, poloxamer-stabilized EC-NPs (P188/0.2) had a significant potential of offsetting deleterious side effects common in PX use. Keywords: polymeric nanoparticles, poloxamer, NSAIDs, pharmacokinetics, gastric irritation&nbsp

Since the dawn of civilization, it has been understood that pathogenic microorganisms cause infectious conditions in humans, which at times, may prove fatal. Among the different virulent properties of microorganisms is their ability to form biofilms, which has been directly related to the development of chronic infections with increased disease severity. A problem in the elimination of such complex structures (biofilms) is resistance to the drugs that are currently used in clinical practice, and therefore, it becomes imperative to search for new compounds that have anti-biofilm activity. In this context, nanotechnology provides secure platforms for targeted delivery of drugs to treat numerous microbial infections that are caused by biofilms. Among the many applications of such nanotechnology-based drug delivery systems is their ability to enhance the bioactive potential of therapeutic agents. The present study reports the use of important nanoparticles, such as liposomes, microemulsions, cyclodextrins, solid lipid nanoparticles, polymeric nanoparticles, and metallic nanoparticles, in controlling microbial biofilms by targeted drug delivery. Such utilization of these nanosystems has led to a better understanding of their applications and their role in combating biofilms.

Nanotechnology has recently gained increased attention for its capability to effectively diagnose and treat various tumors. Nanocarriers have been used to circumvent the problems associated with conventional antitumor drug delivery systems, including their nonspecificity, severe side effects, burst release and damaging the normal cells. Nanocarriers improve the bioavailability and therapeutic efficiency of antitumor drugs, while providing preferential accumulation at the target site. A number of nanocarriers have been developed; however, only a few of them are clinically approved for the delivery of antitumor drugs for their intended actions at the targeted sites. The present review is divided into three main parts: first part presents introduction of various nanocarriers and their relevance in the delivery of anticancer drugs, second part encompasses targeting mechanisms and surface functionalization on nanocarriers and third part covers the description of selected tumors, including breast, lungs, colorectal and pancreatic tumors, and applications of relative nanocarriers in these tumors. This review increases the understanding of tumor treatment with the promising use of nanotechnology.

To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Nanodrug systems have been employed to improve the efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profile of pharmaceutical substances. In particular, functionalized nanodrug systems can offer enhanced bioavailability of orally taken drugs, prolonged half-life of injected drugs (by reducing immunogenicity), and targeted delivery to specific tissues. Thus, nanodrug systems might lower the frequency of administration while providing maximized pharmacological effects and minimized systemic side effects, possibly leading to better therapeutic compliance and clinical outcomes. In spite of these attractive pharmacokinetic advantages, recent attention has been drawn to the toxic potential of nanodrugs since they often exhibit in vitro and in vivo cytotoxicity, oxidative stress, inflammation, and genotoxicity. A better understanding of the pharmacokinetic and safety characteristics of nanodrugs and the limitations of each delivery option is necessary for the further development of efficacious nanodrugs with high therapeutic potential and a wide safety margin. This review highlights the recent progress in nanodrug system development, with a focus on the pharmacokinetic advantages and safety challenges.

Clinical effectiveness of imatinib mesylate in cancer treatment is compromised by its off-target cardiotoxicity. In the present study, we have developed physically stable imatinib mesylate-loaded poly(lactide-co-glycolide) nanoparticles (INPs) that could sustainably release the drug, and studied its efficacy by in vitro anticancer and in vivo cardiotoxicity assays. MTT (methylthiazolyldiphenyl-tetrazolium bromide) assay revealed that INPs are more cytotoxic to MCF-7 breast cancer cells compared to the equivalent concentration of free imatinib mesylate. Wistar rats orally administered with 50 mg/kg INPs for 28 days showed no significant cardiotoxicity or associated changes. Whereas, increased alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels, and reduced white blood cell, red blood cell, and hemoglobin content were observed in the animals administered with free drug. While the histological sections from hearts of animals that received INPs did not show any significant cardiotoxic symptoms, loss of normal architecture and increased cytoplasmic vacuolization were observed in the heart sections of animals administered with free imatinib mesylate. Based on these results, we conclude that nano-encapsulation of imatinib mesylate increases its efficacy against cancer cells, with almost no cardiotoxicity., GM and CJS were supported by the Fundação para a Ciência e a Tecnologia (FCT), Portugal, by grants SFRH/ BD/72809/2010 and SFRH/BPD/89493/2012, respectively. The present work was also supported by the FCT projects PTDC/AGR-GPL/119211/2010 and UID/AGR/04033/2013.

Use of biodegradable polymers for biomedical applications has increased in recent decades due to their biocompatibility, biodegradability, flexibility, and minimal side effects. Applications of these materials include creation of skin, blood vessels, cartilage scaffolds, and nanosystems for drug delivery. These biodegradable polymeric nanoparticles enhance properties such as bioavailability and stability, and provide controlled release of bioactive compounds. This review evaluates the classification, synthesis, degradation mechanisms, and biological applications of the biodegradable polymers currently being studied as drug delivery carriers. In addition, the use of nanosystems to solve current drug delivery problems are reviewed.

Erica Locatelli,1 Larraitz Gil,2 Liron Limor Israel,3 Lorena Passoni,4,5 Maria Naddaka,1 Andrea Pucci,1 Torsten Reese,6 Vanessa Gomez-Vallejo,2 Paolo Milani,5,7 Michela Matteoli,4,8 Jordi Llop,2 Jean Paul Lellouche,3 Mauro Comes Franchini11Department of Industrial Chemistry “Toso Montanari”. University of Bologna, Italy; 2Radiochemistry Department, Molecular Imaging Unit, CIC biomaGUNE, San Sebastián, Guipúzcoa, Spain; 3Department of Chemistry, Nanomaterials Research Centre, Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan, Israel; 4Department of Medical Biotechnology and Translational Medicine, University of Milano, Italy; 5Fondazione Filarete, Milano, Italy; 6Imaging Department, Molecular Imaging Unit, CIC biomaGUNE, San Sebastián, Guipúzcoa, Spain; 7CIMAINA and Department of Physics, University of Milano, Italy; 8Humanitas Clinical and Research Center, Rozzano, ItalyAbstract: A novel nanocarrier system was designed and developed with key components uniquely structured at the nanoscale for early cancer diagnosis and treatment. In order to perform magnetic resonance imaging, hydrophilic superparamagnetic maghemite nanoparticles (NPs) were synthesized and coated with a lipophilic organic ligand. Next, they were entrapped into polymeric NPs made of biodegradable poly(lactic-co-glycolic acid) linked to polyethylene glycol. In addition, resulting NPs have been conjugated on their surface with a 2,2'-(7-(4-((2-aminoethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ligand for subsequent 68Ga incorporation. A cell-based cytotoxicity assay has been employed to verify the in vitro cell viability of human pancreatic cancer cells exposed to this nanosystem. Finally, in vivo positron emission tomography-computerized tomography biodistribution studies in healthy animals were performed.Keywords: maghemite nanoparticles, organic coating, polymeric nanoparticles, magnetic resonance imaging, radiolabeling, positron emission tomography

Bo Li1, Hui Xu2, Zhen Li1, Mingfei Yao1, Meng Xie1, Haijun Shen1, Song Shen1, Xinshi Wang1, Yi Jin11College of Pharmaceutical sciences, Zhejiang University, Hangzhou, 2No. 202 Hospital of People's Liberation Army, Shenyang, ChinaBackground: Multidrug resistance (MDR) mediated by the overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), remains one of the major obstacles to effective cancer chemotherapy. In this study, lipid/particle assemblies named LipoParticles (LNPs), consisting of a dimethyldidodecylammonium bromide (DMAB)-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticle core surrounded by a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) shell, were specially designed for anticancer drugs to bypass MDR in human breast cancer cells that overexpress P-gp.Methods: Doxorubicin (DOX), a chemotherapy drug that is a P-gp substrate, was conjugated to PLGA and encapsulated in the self-assembled LNP structure. Physiochemical properties of the DOX-loaded LNPs were characterized in vitro. Cellular uptake, intracellular accumulation, and cytotoxicity were compared in parental Michigan Cancer Foundation (MCF)-7 cells and P-gp-overexpressing, resistant MCF-7/adriamycin (MCF-7/ADR) cells.Results: This study found that the DOX formulated in LNPs showed a significantly increased accumulation in the nuclei of drug-resistant cells relative to the free drug, indicating that LNPs could alter intracellular traffic and bypass drug efflux. The cytotoxicity of DOX loaded-LNPs had a 30-fold lower half maximal inhibitory concentration (IC50) value than free DOX in MCF-7/ADR, measured by the colorimetric cell viability (MTT) assay, correlated with the strong nuclear retention of the drug.Conclusion: The results show that this core-shell lipid/particle structure could be a promising strategy to bypass MDR.Keywords: chemotherapy, drug delivery, polymeric nanoparticles, multidrug resistance

The current treatment for coronary restenosis following balloon angioplasty involves the use of a mechanical or a drug-eluting stent. Despite the high usage of commercially-available drug-eluting stents in the cardiac field, there are a number of limitations. This review will present the background of restenosis, go briefly into the molecular and cellular mechanisms of restenosis, the use of mechanical stents in coronary restenosis, and will provide an overview of the drugs and genes tested to treat restenosis. The primary focus of this article is to present a comprehensive overview on the use of nanoparticulate delivery systems in the treatment of restenosis both in-vitro and in-vivo. Nanocarriers have been tested in a variety of animal models and in human clinical trials with favorable results. Polymer-based nanoparticles, liposomes, and micelles will be discussed, in addition to the findings presented in the field of cardiovascular drug targeting. Nanocarrier-based delivery presents a viable alternative to the current stent based therapies.

Sima Singh,1,* Niranjan G Kotla,2,* Sonia Tomar,3 Balaji Maddiboyina,4 Thomas J Webster,5,6 Dinesh Sharma,7 Omprakash Sunnapu2 1Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 2Technologies for the Advancement of Science, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, Karnataka, 3Department of Pharmaceutics, Ram Gopal College of Pharmacy, Rohtak, Haryana, 4Department of Pharmaceutics, Maharishi Markandeshwar University, Mullana, Ambala, Haryana, India; 5Department of Chemical Engineering, Northeastern University, Boston, MA, USA; 6Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia; 7Ranbaxy Laboratory Ltd, Gurgaon, Haryana, India *These authors contributed equally tothis work Abstract: Targeted drug delivery plays a significant role in disease treatment associated with the colon, affording therapeutic responses for a prolonged period of time with low side effects. Colorectal cancer is the third most common cancer in both men and women with an estimated 102,480 cases of colon cancer and 40,340 cases of rectal cancer in 2013 as reported by the American Cancer Society. In the present investigation, we developed an improved oral delivery system for existing anticancer drugs meant for colon cancer via prebiotic and probiotic approaches. The system comprises three components, namely, nanoparticles of drug coated with natural materials such as guar gum, xanthan gum (that serve as prebiotics), and probiotics. The natural gums play a dual role of protecting the drug in the gastric as well as intestinal conditions to allow its release only in the colon. In vitro results obtained from these experiments indicated the successful targeted delivery of 5-fluorouracil to the colon. Electron microscopy results demonstrated that the prepared nanoparticles were spherical in shape and 200nm in size. The in vitro release data indicated that the maximum release occurs at pH 7.2 and 7.4 with 93% of the drug released in the presence of 4% (w/v) of rat cecal content. In vivo results conclude a practical mechanism to maintain the integrity and intactness of the intestinal/colonic microflora, in the face of a “chemical attack” by oral colon-targeted drug delivery for colon cancer treatment. Keywords: colon-specific drug delivery system, polymeric nanoparticles, probiotics, 5-fluorouracil

Chemotherapy, a major strategy for cancer treatment, lacks the specificity to localize the cancer therapeutics in the tumor site, thereby affecting normal healthy tissues and advocating toxic adverse effects. Nanotechnological intervention has greatly revolutionized the therapy of cancer by surmounting the current limitations in conventional chemotherapy, which include undesirable biodistribution, cancer cell drug resistance, and severe systemic side effects. Nanoparticles (NPs) achieve preferential accumulation in the tumor site by virtue of their passive and ligand-based targeting mechanisms. Polymer-based nanomedicine, an arena that entails the use of polymeric NPs, polymer micelles, dendrimers, polymersomes, polyplexes, polymer–lipid hybrid systems, and polymer–drug/protein conjugates for improvement in efficacy of cancer therapeutics, has been widely explored. The broad scope for chemically modifying the polymer into desired construct makes it a versatile delivery system. Several polymer-based therapeutic NPs have been approved for clinical use. This review provides an insight into the advances in polymer-based targeted nanocarriers with focus on therapeutic aspects in the field of oncology., Video abstract

Ha Na Woo1*, Hye Kyung Chung2*, Eun Jin Ju1, Joohee Jung1,3, Hye-Won Kang4, Sa-Won Lee4, Min-Hyo Seo4, Jin Seong Lee5, Jung Shin Lee1,6, Heon Joo Park7, Si Yeol Song1,8, Seong-Yun Jeong1, Eun Kyung Choi1,2,81Institute for Innovative Cancer Research, 2Center for Development and Commercialization of Anti-cancer Therapeutics, Asan Medical Center, Seoul, 3College of Pharmacy, Duksung Women's University, Seoul, 4Department of Parenteral Delivery Program, Samyang Pharmaceuticals R&D, Daejeon, 5Department of Radiology and Research Institute of Radiology, 6Department of Internal Medicine, Asan Medical Center, Seoul, 7Department of Microbiology, College of Medicine, Inha University, Inchon, 8Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea*These authors contributed equally to this studyAbstract: Nanoparticles are useful delivery vehicles for promising drug candidates that face obstacles for clinical applicability. Sirolimus, an inhibitor of mammalian target of rapamycin has gained attention for targeted anticancer therapy, but its clinical application has been limited by its poor solubility. This study was designed to enhance the feasibility of sirolimus for human cancer treatment. Polymeric nanoparticle (PNP)–sirolimus was developed as an injectable formulation and has been characterized by transmission electron microscopy and dynamic light scattering. Pharmacokinetic analysis revealed that PNP–sirolimus has prolonged circulation in the blood. In addition, PNP–sirolimus preserved the in vitro killing effect of free sirolimus against cancer cells, and intravenous administration displayed its potent in vivo anticancer efficacy in xenograft tumor mice. In addition, PNP–sirolimus enhanced the radiotherapeutic efficacy of sirolimus both in vitro and in vivo. Clinical application of PNP–sirolimus is a promising strategy for human cancer treatment.Keywords: sirolimus, polymeric nanoparticle, anticancer, radiotherapy

Shann S Yu1,2, Cheryl M Lau1, Susan N Thomas3, W Gray Jerome4, David J Maron5, James H Dickerson2,6, Jeffrey A Hubbell3, Todd D Giorgio1,2,7,81Department of Biomedical Engineering, Vanderbilt University, Nashville, 2Vanderbilt Institute of Nanoscale Science and Engineering, Nashville, TN, USA; 3Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland, 4Department of Pathology, Vanderbilt University Medical Center, Nashville, 5Vanderbilt Heart and Vascular Institute, Nashville, 6Department of Physics and Astronomy, Vanderbilt University, Nashville, 7Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, 8Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USAAbstract: The assessment of macrophage response to nanoparticles is a central component in the evaluation of new nanoparticle designs for future in vivo application. This work investigates which feature, nanoparticle size or charge, is more predictive of non-specific uptake of nanoparticles by macrophages. This was investigated by synthesizing a library of polymer-coated iron oxide micelles, spanning a range of 30–100 nm in diameter and -23 mV to +9 mV, and measuring internalization into macrophages in vitro. Nanoparticle size and charge both contributed towards non-specific uptake, but within the ranges investigated, size appears to be a more dominant predictor of uptake. Based on these results, a protease-responsive nanoparticle was synthesized, displaying a matrix metalloproteinase-9 (MMP-9)-cleavable polymeric corona. These nanoparticles are able to respond to MMP-9 activity through the shedding of 10–20 nm of hydrodynamic diameter. This MMP-9-triggered decrease in nanoparticle size also led to up to a six-fold decrease in nanoparticle internalization by macrophages and is observable by T2-weighted magnetic resonance imaging. These findings guide the design of imaging or therapeutic nanoparticles for in vivo targeting of macrophage activity in pathologic states.Keywords: macrophage targeting, poly(ethylene glycol) (PEG), poly(propylene sulfide) (PPS), iron oxides, opsonization