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Advanced Drug Delivery Reviews (v.62, #4-5)

Editorial Board (pp. ii).

Nanotechnology solutions for infectious diseases in developing nations by Alejandro Sosnik (Theme Editor); Mansoor Amiji (Theme Editor) (pp. 375-377).

Application of nanotechnologies for improved immune response against infectious diseases in the developing world by Michael Look; Arunima Bandyopadhyay; Jeremy S. Blum; Tarek M. Fahmy (pp. 378-393).

There is an urgent need for new strategies to combat infectious diseases in developing countries. Many pathogens have evolved to elude immunity and this has limited the utility of current therapies. Additionally, the emergence of co-infections and drug resistant pathogens has increased the need for advanced therapeutic and diagnostic strategies. These challenges can be addressed with therapies that boost the quality and magnitude of an immune response in a predictable, designable fashion that can be applied for wide-spread use. Here, we discuss how biomaterials and specifically nanoscale delivery vehicles can be used to modify and improve the immune system response against infectious diseases. Immunotherapy of infectious disease is the enhancement or modulation of the immune system response to more effectively prevent or clear pathogen infection. Nanoscale vehicles are particularly adept at facilitating immunotherapeutic approaches because they can be engineered to have different physical properties, encapsulated agents, and surface ligands. Additionally, nanoscaled point-of-care diagnostics offer new alternatives for portable and sensitive health monitoring that can guide the use of nanoscale immunotherapies. By exploiting the unique tunability of nanoscale biomaterials to activate, shape, and detect immune system effector function, it may be possible in the near future to generate practical strategies for the prevention and treatment of infectious diseases in the developing world.

Keywords: Immunotherapy; Chronic disease; Vaccine; Prophylactic therapy; Nanoparticle; Biomaterials; Adjuvant; Global health

Nanotechnology solutions for mucosal immunization by Sandra Chadwick; Christina Kriegel; Mansoor Amiji (pp. 394-407).

The current prevalence of infectious diseases in many developing regions of the world is a serious burden, impacting both the general health as well as economic growth of these communities. Additionally, treatment with conventional medication becomes increasingly challenging due to emergence of new and drug resistant strains jeopardizing the progress made in recent years towards control and elimination of certain types of infectious diseases. Thus, from a public health perspective, prevention such as through immunization by vaccination, which has proven to be most effective, might be the best alternative to prevent and combat infectious diseases in these regions. To achieve this, development of wide-scale immunization programs become necessary including vaccines that can easily and widely be distributed, stored and administered. Mucosal vaccines offer great potential since they can be administered via oral or intranasal delivery route which does not require trained personnel, avoids the use of needles and improves overall patient compliance and acceptance. However, it necessitates the implementation of specific immunization strategies to improve their efficacy. Application of nanotechnology to design and create particle mediated delivery systems that can efficiently encapsulate vaccine components for protection of the sensitive payload, target the mucosal immune system and incorporate mucosal adjuvants maximizing immune response is key strategy to improve the effectiveness of mucosal vaccines.

Keywords: Mucosal vaccination; Polymeric nanoparticles; Multiple emulsions; Immune-adjuvants

Emerging nanotechnology-based strategies for the identification of microbial pathogenesis by Charalambos Kaittanis; Santimukul Santra; J. Manuel Perez (pp. 408-423).

Infectious diseases are still a major healthcare problem. From food intoxication and contaminated water, to hospital-acquired diseases and pandemics, infectious agents cause disease throughout the world. Despite advancements in pathogens' identification, some of the gold-standard diagnostic methods have limitations, including laborious sample preparation, bulky instrumentation and slow data readout. In addition, new field-deployable diagnostic modalities are urgently needed in first responder and point-of-care applications. Apart from compact, these sensors must be sensitive, specific, robust and fast, in order to facilitate detection of the pathogen even in remote rural areas. Considering these characteristics, researchers have utilized innovative approaches by employing the unique properties of nanomaterials in order to achieve detection of infectious agents, even in complex media like blood. From gold nanoparticles and their plasmonic shifts to iron oxide nanoparticles and changes in magnetic properties, detection of pathogens, toxins, antigens and nucleic acids has been achieved with impressive detection thresholds. Additionally, as bacteria become resistant to antibiotics, nanotechnology has achieved the rapid determination of bacterial drug susceptibility and resistance using novel methods, such as amperometry and magnetic relaxation. Overall, these promising results hint to the adoption of nanotechnology-based diagnostics for the diagnosis of infectious diseases in diverse settings throughout the globe, preventing epidemics and safeguarding human and economic wellness.

Keywords: Pathogen detection; Deployable sensors; Toxin detection; Bacterial drug resistance; Nanosensors; Nanodiagnostics

Nanobioimaging and sensing of infectious diseases by Padmavathy Tallury; Astha Malhotra; Logan M Byrne; Swadeshmukul Santra (pp. 424-437).

New methods to identify trace amount of infectious pathogens rapidly, accurately and with high sensitivity are in constant demand to prevent epidemics and loss of lives. Early detection of these pathogens to prevent, treat and contain the spread of infections is crucial. Therefore, there is a need and urgency for sensitive, specific, accurate, easy-to-use diagnostic tests. Versatile biofunctionalized engineered nanomaterials are proving to be promising in meeting these needs in diagnosing the pathogens in food, blood and clinical samples. The unique optical and magnetic properties of the nanoscale materials have been put to use for the diagnostics. In this review, we focus on the developments of the fluorescent nanoparticles, metallic nanostructures and superparamagnetic nanoparticles for bioimaging and detection of infectious microorganisms. The various nanodiagnostic assays developed to image, detect and capture infectious virus and bacteria in solutions, food or biological samples in vitro and in vivo are presented and their relevance to developing countries is discussed.

Keywords: Abbreviations; WHO; World Health Organization; ELISA; Enzyme Linked Immuno Sorbent Assay; PCR; Polymerase Chain Reaction; NPs; nanoparticles; Qdots; quantum dots; RSV; Respiratory Syncytial Virus; FITC; Fluorescein Isothiocyanate; Zn-DPA; Zn (II)-dipicolylamine; HBV; hepatitis B virus; HCV; hepatitis C virus; Qdot-B; Qdot-barcodes; HIV; human immunodeficiency virus; FSNPS; fluorescent silica nanoparticles; FRET; Förster resonance energy transfer; FAM-SE; (5-carboxy-fluorescein succinimidyl ester); ROX-SE; (6-carboxy-X-rhodamine, succinimidyl ester); R6G-SE; (5-carboxyrhodamine 6G, succinimidyl ester); TMR-SE; (carboxytetramethylrhodamine, succinimidyl ester); OsBpy; Tris (2, 2′bipyridyl) osmium bis (hexafluorophosphate); RuBpy; Tris(bipyridine) ruthenium (II) dichloride; FNP-IIFM; fluorescent nanoparticle-based indirect immunofluorescence microscopy; Eu III; Europium; CaDPA; calcium dipicolinate; LOD; limit of detection; SEC; ₁; staphylococcal enterotoxin C; ₁; CT; cholera toxin; PA; anthrax protective agent; CCMV; cow pea chlorotic mottle virus; MRI; Magnetic Resonance Imaging; SpA; Protein A; Gd-DOTA; Gadolinium-1,4,7,10-tetraazacyclododecane tetraacetic acid; ICP-MS; inductively coupled plasma mass spectrometry; SPR; surface plasmon resonance; Au NP; gold nanoparticle; HSV-2; Herpes simplex Virus type 2; HSV-1; Herpes simplex Virus type 1; RLS; Resonance Light Scattering; ss; single stranded; HRS; Hyper-Rayleigh scattering; ds; double stranded; TEM; transmission electron microscopy; H. pyroli; Helicobacter pyroli; SERS; surface enhanced Raman scattering; SMCC; Succinimidyl-4-(N-Maleimidomethyl)Cyclohexane-1-Carboxylate; Bg; Bacillus globigii; Ova; Ovalbumin; CFU; colony forming unit; ATP; adenosine triphosphate; IR; Infra Red; SQUID; Superconducting Quantum Interference Device; MNP; magnetic nanoparticles; MALDI-MS; Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry; POA; adopted pigeon ovalbumin; MGNP; magnetic glycol nanoparticles; SPIO; superparamagnetic iron oxide; MRS; magnetic relaxation sensors; NMR; Nuclear Magnetic ResonanceFluorescent nanoparticles; Multiplexing; Viral imaging; Bacterial detection; Surface plasmon resonance; Colorimetric assay; Magnetic nanosensors; Immunomagnetic separation

Nanotechnology diagnostics for infectious diseases prevalent in developing countries by Tanya S. Hauck; Supratim Giri; Yali Gao; Warren C.W. Chan (pp. 438-448).

Infectious diseases are prevalent in the developing world and are one of the developing world's major sources of morbidity and mortality. While infectious diseases can initiate in a localized region, they can spread rapidly at any moment due to the ease of traveling from one part of the world to the next. This could lead to a global pandemic. One key to preventing this spread is the development of diagnostics that can quickly identify the infectious agent so that one can properly treat or in some severe cases, quarantine a patient. There have been major advances in diagnostic technologies but infectious disease diagnostics are still based on 50-year technologies that are limited by speed of analysis, need for skilled workers, poor detection threshold and inability to detect multiple strains of infectious agents. Here, we describe advances in nanotechnology and microtechnology diagnostics for infectious diseases. In these diagnostic schemes, the nanomaterials are used as labels or barcodes while microfluidic systems are used to automate the sample preparation and the assays. We describe the current state of the field and the challenges.

Keywords: Abbreviations; AIDS; acquired immunodeficiency syndrome; BCA; bio-barcode based amplification; BCG; Bacillus Calmette–Gurin vaccine; EIA; enzyme immunoassay; ELISA; enzyme-linked immunosorbent assay; ELISPOT; enzyme-linked immunospot assay methods; HIV; human immunodeficiency virus; ICT; immunochromatographic tests; IGRA; interferon gamma release assays; LOC; lab-on-a-chip; PCR; polymerase chain reaction; POTC; point-of-care tests; PPD; purified protein derivative; PSA; prostate specific antigen; QD; quantum dot; SARS; severe acute respiratory syndrome; TB; tuberculosis; TST; tuberculin skin testInfectious diseases; Diagnostic tests; Nanotechnology; Nanomaterials; Microfluidics; Quantum dots; Metal nanoparticles; Lab on a chip

Nano/Microfluidics for diagnosis of infectious diseases in developing countries by Won Gu Lee; Yun-Gon Kim; Bong Geun Chung; Utkan Demirci; Ali Khademhosseini (pp. 449-457).

Nano/Microfluidic technologies are emerging as powerful enabling tools for diagnosis and monitoring of infectious diseases in both developed and developing countries. Miniaturized nano/microfluidic platforms that precisely manipulate small fluid volumes can be used to enable medical diagnosis in a more rapid and accurate manner. In particular, these nano/microfluidic diagnostic technologies are potentially applicable to global health applications, since they are disposable, inexpensive, portable, and easy-to-use for detection of infectious diseases. In this paper, we review recent advances in nano/microfluidic technologies for clinical point-of-care applications at resource-limited settings in developing countries.

Keywords: Abbreviations; AED; antiepileptic drug; AFM; atomic force microscopy; AIDS; acquired immunodeficiency syndrome; ART; antiretroviral therapy; CCD; charge-coupled device; ELISA; enzyme-linked immunosorbent assay; FLASH; fast lithographic activation of sheet; HIV; human immunodeficiency virus; LED; light-emitting diode; LOC; lab-on-a-chip; NMR; nuclear magnetic resonance; PCR; polymerase chain reaction; PDMS; poly (dimethylsiloxane); PMMA; polymethymetacrylate; POC; point-of-care; POCKET; portable and cost-effective; QD; quantum dot; RDT; rapid diagnostic test; RF; radio frequency; SPR; surface plasmon resonance; TB; tuberculosis; WHO; World Health OrganizationNano/Microfluidics; Infectious diseases; HIV/AIDS; Point-of-care; Diagnostics; Global health

Nanotechnology-based systems for the treatment and prevention of HIV/AIDS by José das Neves; Mansoor M. Amiji; Maria Fernanda Bahia; Bruno Sarmento (pp. 458-477).

The HIV/AIDS pandemic is an increasing global burden with devastating health-related and socioeconomic effects. The widespread use of antiretroviral therapy has dramatically improved life quality and expectancy of infected individuals, but limitations of currently available drug regimens and dosage forms, alongside with the extraordinary adapting capacity of the virus, have impaired further success. Alongside, circumventing the escalating number of new infections can only be attained with effective and practical preventative strategies. Recent advances in the field of drug delivery are providing evidence that engineered nanosystems may contribute importantly for the enhancement of current antiretroviral therapy. Additionally, groundwork is also being carried out in the field nanotechnology-based systems for developing preventative solutions for HIV transmission. This manuscript reviews recent advances in the field of nanotechnology-based systems for the treatment and prevention of HIV/AIDS. Particular attention is given to antiretroviral drug targeting to HIV reservoirs and the usefulness of nanosystems for developing topical microbicides and vaccines.

Keywords: Abbreviations; AcLDL; acetylated low-density lipoprotein; AF; amniotic fluid; AF/BP; amniotic fluid/blood plasma concentration ration (determined at birth); AIDS; acquired immune deficiency syndrome; AUC; 0–24; _h; area under the curve (0–24; h); b.i.d.; twice daily; BBB; blood-brain barrier; BCS; biopharmaceutics classification system; BMEC; brain-microvascular endothelial cells; CBP; cord blood plasma; CBP/BP; cord blood plasma/blood plasma concentration ration (determined at birth); CNS; central nervous system; CSF; cerebrospinal fluid; CSF/BP; cerebrospinal fluid/blood plasma concentration ratio; DCs; dendritic cells; DC-SIGN; dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin; EMF; electromagnetic field; FGT/BP; female genital tract/blood plasma concentration ratio; fMLF; N; -formyl-methionyl-leucyl-phenylalanine; GALT; gut-associated lymphoid tissues; HAART; highly active antiretroviral therapy; HIV; human immunodeficiency virus; HJV; hemagglutinating virus of Japan (Sendai virus); HLA-DR; human leukocyte antigen DR-1; IC; ₅₀; 50% inhibitory concentration; ID; intradermal; IM; intramuscular; IN; intranasal; IP; intraperitoneal; ISCOM; immunostimulating complex; IVag; intravaginal; LCs; Langerhans cells; LN/BP; lymph node/blood plasma concentration ratio; NNRTI; non-nucleoside reverse transcriptase inhibitors; NRTIs; nucleoside reverse transcriptase inhibitors; NtRTI; nucleotide reverse transcriptase inhibitors; PEG; poly(ethylene glycol); PEG-PLA; PEGylated-poly(; L; -lactide); PEI; poly(ethyleneimine); PEO–PCL; poly(ethylene oxide)-modified poly(epsilon-caprolactone); PHCA; polyhexylcyanoacrylate; PIs; protease inhibitors; PLA; poly(; L; -lactide); PLGA; poly(; D,L; -lactide-; co; -glycolide); PMBCs; peripheral blood mononuclear cells; PPI; poly(propyleneimine); RANTES; regulated on activation normal T cell expressed and secreted chemokine; RES; reticulo-endothelial system; RTIs; reverse transcriptase inhibitors; SC; subcutaneous; SHIV; simian human immunodeficiency virus; SIV; simian immunodeficiency virus; SLNs; solid lipid nanoparticles; Sm/BP; semen/blood plasma concentration ratio; t.i.d.; three times a day; t; _1/2; plasma half-life; TAT peptide; HIV-1 trans-activating transcriptor peptide; Th1; type 1; T helper cells; Th2; type 2; T helper cellsAntiretroviral therapy; Drug carriers; Drug targeting; HIV reservoir sites; Macrophages; Lymphatic system; Central nervous system; Microbicides; Vaccines

Non-polymeric nano-carriers in HIV/AIDS drug delivery and targeting by Umesh Gupta; Narendra K. Jain (pp. 478-490).

Development of an effective drug delivery approach for the treatment of HIV/AIDS is a global challenge. The conventional drug delivery approaches including Highly Active Anti Retroviral Therapy (HAART) have increased the life span of the HIV/AIDS patient. However, the eradication of HIV is still not possible with these approaches due to some limitations. Emergence of polymeric and non-polymeric nanotechnological approaches can be opportunistic in this direction. Polymeric carriers like, dendrimers and nanoparticles have been reported for the targeting of anti HIV drugs. The synthetic pathways as well polymeric framework create some hurdles in their successful formulation development as well as in the possible drug delivery approaches. In the present article, we have discussed the general physiological aspects of the infection along with the relevance of non-polymeric nanocarriers like liposomes, solid lipid nanoparticles (SLN), ethosomes, etc. in the treatment of this disastrous disease.

Keywords: Nanotechnology; AIDS; Nanocarrier in Anti HIV; Liposomes

Pure drug and polymer based nanotechnologies for the improved solubility, stability, bioavailability and targeting of anti-HIV drugs by Puneet Sharma; Sanjay Garg (pp. 491-502).

The impact of human immunodeficiency virus (HIV) infection has been devastating with nearly 7400 new infections every day. Although, the advent of highly active antiretroviral therapy (HAART) has made a tremendous contribution in reducing the morbidity and mortality in developed countries, the situation in developing countries is still grim with millions of people being infected by this disease. The new advancements in the field of nanotechnology based drug delivery systems hold promise to improve the situation. These nanoscale systems have been successfully employed in other diseases such as cancer, and therefore, we now have a better understanding of the practicalities and technicalities associated with their clinical development. Nanotechnology based approaches offer some unique opportunities specifically for the improvement of water solubility, stability, bioavailability and targeting of antiretroviral drugs. This review presents discussion on the contribution of pure drug and polymer based nanotechnologies for the delivery anti-HIV drugs.

Keywords: HIV; Polymer; Nanoparticle; Nanocrystal; Polymeric micelle; Dendrimer

Nanotechnology applications for improved delivery of antiretroviral drugs to the brain by Ho Lun Wong; Niladri Chattopadhyay; Xiao Yu Wu; Reina Bendayan (pp. 503-517).

Human immunodeficiency virus (HIV) can gain access to the central nervous system during the early course of primary infection. Once in the brain compartment the virus actively replicates to form an independent viral reservoir, resulting in debilitating neurological complications, latent infection and drug resistance. Current antiretroviral drugs (ARVs) often fail to effectively reduce the HIV viral load in the brain. This, in part, is due to the poor transport of many ARVs, in particular protease inhibitors, across the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSBF). Studies have shown that nanocarriers including polymeric nanoparticles, liposomes, solid lipid nanoparticles (SLN) and micelles can increase the local drug concentration gradients, facilitate drug transport into the brain via endocytotic pathways and inhibit the ATP-binding cassette (ABC) transporters expressed at the barrier sites. By delivering ARVs with nanocarriers, significant increase in the drug bioavailability to the brain is expected to be achieved. Recent studies show that the specificity and efficiency of ARVs delivery can be further enhanced by using nanocarriers with specific brain targeting, cell penetrating ligands or ABC-transporters inhibitors. Future research should focus on achieving brain delivery of ARVs in a safe, efficient, and yet cost-effective manner.

Keywords: Abbreviations; ABC transporter; ATP-binding cassette membrane transporter; AIDS; acquired immunodeficiency syndrome; apoE; apolipoprotein E; ARVs; antiretroviral drugs; BBB; blood-brain barrier; BCSFB; blood-cerebro spinal fluid barrier; CD4; cluster of differentiation 4; CNS; central nervous system; CSF; cerebrospinal fluid; HAART; highly active antiretroviral therapy; HAD; human immunodeficiency virus-associated dementia; hCMEC/D3; human brain microvessel endothelial cell line; HIV; human immunodeficiency virus; HIVE; human immunodeficiency virus encephalitis; LDL; low-density lipoprotein; MCMD; minor cognitive/motor disorder; MMA-SPM; methylmethacrylate-sulfopropylmethacrylate; MRP; multidrug resistance-associated proteins; NNRT; non-nucleoside reverse transcriptase inhibitors; NRTI; nucleoside reverse transcriptase inhibitor; PBCA; poly(butyl cyanoacryalate); PEG; polyethylene glycol; PIs; HIV protease inhibitors; PIL; PEGylated immunoliposomes; P-gp; P-glycoprotein; PLA; polylactide; PLGA; poly(D,L-lactide-co-glycolide); SLN; solid lipid nanoparticles; Tat; transcriptional activator; Vpr; viral protein RHuman immunodeficiency virus; Brain delivery; Antiretroviral; Nanotechnology; Blood-brain barrier; ATP-binding cassette membrane transporters

Surface modifications of nanocarriers for effective intracellular delivery of anti-HIV drugs by Simi Gunaseelan; Krishnan Gunaseelan; Manjeet Deshmukh; Xiaoping Zhang; Patrick J. Sinko (pp. 518-531).

A variety of nanocarriers such as bioconjugates, dendrimers, liposomes, and nanoparticles have been widely evaluated as potential targeted drug delivery systems. Passive targeting of nanoscale carriers is based on a size-flow-filtration phenomenon that is usually limited to tumors, the reticular endothelial system, and possibly lymph nodes (LNs). In fact, targeting the delivery of drugs to pivotal physiological sites such as the lymph nodes has emerged as a promising strategy in treating HIV disease. Ligands for specific cell surface receptors can be displayed on nanocarriers in order to achieve active targeting. The approach has been extensively used preclinically in cancer where certain receptors are over-expressed at various stages of the disease. Unfortunately, markers of HIV infection are lacking and latently infected cells do not show any signs of infection on their surface. However, the disease naturally targets only a few cell types. The HIV receptor CD4, coreceptors (CCR5 and CXCR4), and some receptors relatively specific for macrophages provide potentially valuable surface targets for drug delivery to all susceptible cells in patients infected by HIV. This review focuses on nanoscale targeting with an emphasis on surface modifications of drug delivery nanocarriers for active targeting. A number of related issues, including HIV biology, targets, pharmacokinetics, and intracellular fate as well as literature-cited examples of emerging surface-modified targeted carrier systems are discussed.

Keywords: Abbreviations; 3TC; lamivudine; AIDS; acquired immunodeficiency syndrome; AUC; area under the curve; AZT; zidovudine; AZTP; azidothymidine palmitate; BBB; blood brain barrier; BMMs; bone marrow-derived macrophages; CHO; chinese hampster ovary; CNS; central nervous system; CPP; cell penetrating peptide; DCs; dendritic cells; d4T; stavudine; ddC; 2′,3′-dideoxycytidine; ddCTP; 2′,3′-dideoxycytidine-5-triphosphate; ddI; dideoxyinosine; ddITP; dideoxyinosine (didanosine) triphosphate; DIG; digoxigenin; DPPC; dipalmitoyl phosphatidyl choline; EC; effective concentration; ED; effective dose; EFV; efavirenz; EPR; enhanced permeability and retention; Fc; fragment crystallization; FDA; food and drug administration; FDCs; follicular dendritic cells; FIV; feline immunodeficiency virus; FLT; fluorothymidine; fMLF; N-formyl-methione-leucine-phenyl alanine; GALT; gut-associated lymphoid tissue; gp120; glycoprotein120; HAART; highly active antiretroviral therapy; HIV; human immunodeficiency virus; HSA; human serum albumin; IDV; indinavir; IP; intraperitoneal; IV; intravenous; LDL; low density lipoprotein; LNs; lymph nodes; M/M; monocytes/macrophages; MN-G; mannosylated gelatin; MPPI; mannosylated poly(propyleneimine); MPS; mononuclear phagocyte system; N; B-DNJ; N; -Butyldeoxynojirimycin; NNRTI; non-nucleoside reverse transcriptase inhibitors; NP; nanoparticle; NRTI; nucleoside reverse transcriptase inhibitor; PB; peptide-based; PBCA; polybutylcyanoacrylate; PBMC; peripheral blood mononuclear cells; PCL; poly(epsilon-caprolactone); PEG; polyethylene glycol; PEO; poly(ethylene oxide); PHCA; polyhexacyanoacrylate; PI; protease inhibitor; PLA; poly lactic acid; PMNL; polymorphonuclear leucocytes; PPI; poly(propyleneimine); RES; reticular endothelial system; R.I.CK-Tat9; retro-inverso-cysteine-lysine-Tat nonapeptide; RTV; ritonavir; SC; subcutaneous; SQV; saquinavir; Tat; trans-activating transcriptorHIV/AIDS; Anti-HIV drugs; Nanocarriers; Surface modification; Macrophages; Intracellular delivery

Nano-microbicides: Challenges in drug delivery, patient ethics and intellectual property in the war against HIV/AIDS by Lisa C. du Toit; Viness Pillay; Yahya E. Choonara (pp. 532-546).

As we continue to be embroiled in the global battle against the human immunodeficiency virus (HIV), there has been an ongoing evolution in the understanding of the molecular mode of sexual transmission of HIV. This has gone hand-in-hand with a paradigm shift and research focus on the development of microbicides — compounds designed for vaginal (and possibly rectal) administration that are envisaged to put safe, affordable and accessible protection into the hands of women. However, an effective microbicide is not yet available; innovative approaches for the design of topical vaginal microbicides are urgently needed. The potential of the advancing field of nanomedicine has been earmarked in the increasing efforts to address the major health problems of the developing world. In this review, advances in the design of innovative microbicide nanocarriers and nano-enabled microbicides, henceforth referred to as ‘nano-microbicides’, are presented; elaborating on nanotechnology's role in the antiviral arena. The role of nanotechnology in the antiviral arena and the unique issues facing the generation of intellectual property relating to nano-microbicides in the ongoing global ‘tug-of-war’ of ‘patients versus patents’ are also explicated.

Keywords: Human immunodeficiency virus; Microbicide; Drug delivery systems; Dendrimer; Nanoparticle; Nano-enabled; Intellectual property; Patents

New old challenges in tuberculosis: Potentially effective nanotechnologies in drug delivery by Alejandro Sosnik; Ángel M. Carcaboso; Romina J. Glisoni; Marcela A. Moretton; Diego A. Chiappetta (pp. 547-559).

Tuberculosis (TB) is the second most deadly infectious disease. Despite potentially curative pharmacotherapies being available for over 50years, the length of the treatment and the pill burden can hamper patient lifestyle. Thus, low compliance and adherence to administration schedules remain the main reasons for therapeutic failure and contribute to the development of multi-drug-resistant (MDR) strains. Pediatric patients constitute a high risk population. Most of the first-line drugs are not commercially available in pediatric form. The design of novel antibiotics attempts to overcome drug resistance, to shorten the treatment course and to reduce drug interactions with antiretroviral therapies. On the other hand, the existing anti-TB drugs are still effective. Overcoming technological drawbacks of these therapeutic agents as well as improving the effectiveness of the drug by targeting the infection reservoirs remains the central aims of Pharmaceutical Technology. In this framework, nanotechnologies appear as one of the most promising approaches for the development of more effective and compliant medicines. The present review thoroughly overviews the state-of-the-art in the development of nano-based drug delivery systems for encapsulation and release of anti-TB drugs and discusses the challenges that are faced in the development of a more effective, compliant and also affordable TB pharmacotherapy.

Keywords: Abbreviations; AUC; Area-Under-the-Curve; BCS; Biopharmaceutic Classification System; CD; cyclodextrins; CFU; Colony Forming Units; CMC; Critical Micellar Concentration; DMSO; Dimethyl sulfoxide; DOTS; Directly Observed Therapy, Short course; DDS; Drug Delivery Systems; ETB; Ethambutol; FDC; Fixed Dose Combinations; HIV; Human Immunodeficiency Virus; HLB; Hydrophilic–Lipophilic Balance; HP; hydroxypropylated derivatives; HPβCD; hydroxypropyl-β-cyclodextrin; INH; Isoniazid; i.t.; intratracheal; IV; intravenous; MBSA; maleylated bovine serum albumin; MDR; multidrug-resistant; MIC; Minimum Inhibitory Concentration; MMAD; mass median aerodynamic diameter; OSA; O; -steroyl amylopectin; PAMAM; polyamidoamines; PBCA; poly(n-butylcyanoacrylate); PCL; poly(ε-caprolactone); PEG; poly(ethylene glycol); PEO–PPO; poly(ethylene oxide)–poly(propylene oxide); PIBCA; poly(isobutylcyanoacrylate); PLA; poly(lactic acid); PLGA; poly(lactic-; co; -glycolic acid); PNP; Polymeric nanoparticles; PPI; polypropylene imine; PYZ; Pyrazinamide; RAMEB; randomly methylated β-CD; RES; reticulo-endothelial system; RIF; Rifampicin; SLN; Solid lipid nanoparticles; TB; Tuberculosis; TRIPS; Trade Related Aspects of Intellectual Property Rights; WHO; World Health Organization; XDR-TB; Extremely Drug-resistant TuberculosisTuberculosis; Pharmaceutical nanotechnology; Polymeric and non-polymeric nanoparticles; Polymeric micelles and liposomes; Complexation; Local delivery to the lung; Targeting to alveolar macrophages

Nanotechnology applied to the treatment of malaria by Santos-Magalhaes Nereide Stela Santos-Magalhães; Vanessa Carla Furtado Mosqueira (pp. 560-575).

Despite the fact that we live in an era of advanced technology and innovation, infectious diseases, like malaria, continue to be one of the greatest health challenges worldwide. The main drawbacks of conventional malaria chemotherapy are the development of multiple drug resistance and the non-specific targeting to intracellular parasites, resulting in high dose requirements and subsequent intolerable toxicity. Nanosized carriers have been receiving special attention with the aim of minimizing the side effects of drug therapy, such as poor bioavailability and the selectivity of drugs. Several nanosized delivery systems have already proved their effectiveness in animal models for the treatment and prophylaxis of malaria. A number of strategies to deliver antimalarials using nanocarriers and the mechanisms that facilitate their targeting to Plasmodium spp.-infected cells are discussed in this review. Taking into account the peculiarities of malaria parasites, the focus is placed particularly on lipid-based (e.g., liposomes, solid lipid nanoparticles and nano and microemulsions) and polymer-based nanocarriers (nanocapsules and nanospheres). This review emphasizes the main requirements for developing new nanotechnology-based carriers as a promising choice in malaria treatment, especially in the case of severe cerebral malaria.

Keywords: Abbreviations; ACT; artimisinin-based combination therapy; AE1; anion transport protein; AM; artemether; AS; artesunate; AT; atovaquone; AUC; area under the curve; CD; cyclodextrin; CHEMS; cholesteylhemesuccinate; CHOL; cholesterol; C; _max; plasma maximum concentration; CQ; chloroquine; CQR; chloroquine resistance; CRT; chloroquine resistance transporter; CSA; chondroitin sulfate A; CTP; phosphocholine cytidylyl transferase; DFO; desferrioxamine; DHA; dihydroartemisinin; DHFR; dihydrofolate reductase inhibitor; DHPS; dihydrofolate synthesis inhibitor; DMPC; dimyristoylphosphatidylcholine; DPPC; dipalmitoylphosphatidylcholine; DPPG; dipalmitoylphosphatidylglycerol; DPPE; dipalmitoylphosphatidyletanolamine; DPPE–PEG; dipalmitoylphosphatidyletanolamine conjugated to poly(ethyleneglycol); DSPC; distearoylphosphatidylcholine; DSPE; distearoylphosphatidyletanolamine; ECC; encoded erythrocyte choline carrier; ECG; electrocardiogram; ED; ₅₀; effective dose to kill 50% of parasites; EPC; egg phosphatidylcholine; Hf; halofantrine; HIV; human immunodeficiency virus; HSPC; hydrogenated soya phosphatidylcholine; IPT; intermittent preventive treatment in pregnancy; IRS; indoor residual spraying of insecticide; LD; ₅₀; lethal dose for 50% of animals; LD; ₁₀₀; acute lethal dose; Lf; lumefantrine; LLIN; long-lasting insecticidal nets; LUVs; large unilamellar vesicles; MHC; major histocompatibility complex; MLVs; multilamellar vesicles; MPS; mononuclear phagocyte system; NaDC; sodium deoxycholate; Nanoject; AM-NLC; NanOsorb; solid microemulsion pre-concentrate; NC; nanocapsules; NE; nanoemulsions; NLC; nanostructured lipid carriers; N-LCT; long chain triglycerides; NPPs; new permeability pathways; NS; nanospheres; O/W; oil-in-water emulsion; PA; phosphatydic acid; PBS; phosphate buffer solution; PC; phosphatidylcholine; PCL; poly-ε-caprolactone; PE; phosphatidyletanolamine; PEG; poly(ethyleneglycol); PG; phosphatidylglycerol; PVP; polyvynilpyrolidone; Pgh1; P-glycoprotein homologue 1; PLA; poly(lactic acid); PLGA; poly(lactic-co-glycolic acid); PQ; primaquine; PS; phosphatidylserine; QN; quinine; RBCs; red blood cells; SLNs; solid lipid nanoparticles; SMEDDS; self-microemulsifying drug delivery systems; TDR; Diseases Research Programme of the World Health Organization; Tf; Transferrin; TQ; Tafenoquine; WHO; World Health Organization; W/O/W; water-in-oil-in-water emulsionMalaria; Nanocarriers; Liposomes; Nanocapsules; Nanoparticles; Antimalarials

Nanotechnological approaches against Chagas disease by Eder Lilia Romero; Maria Jose Morilla (pp. 576-588).

Over several thousand years, the flagellated Trypanosome cruzi–causative agent of Chagas disease–developed a complex life cycle between the reduviidae vectors and its human hosts. Due to their silent and hidden location, the intracellular amastigotes are mainly responsible for the nearly 50,000 annual deaths caused by the chronic chagasic cardiomyopathy. Chagas disease is the most important parasitic disease in the Americas, though treatments have not evolved towards a more efficient pharmacotherapy that (i) eradicates the scarce amastigotes present at the indeterminate/chronic form and (ii) employs less toxic drugs than benznidazole or nifurtimox. Nano-drug delivery systems (nanoDDS) represent useful means to selectively deliver the drug to intracellular targets. However, preclinical research in Chagas must be extended in order to improve the chances of a clinical implementation. The stages involved in this process are (i) selection of the appropriate drug for a specific parasite, (ii) development of a drug-loaded nanoDDS structure that displays the adequate pharmacokinetics, biodistribution and intracellular transit and (iii) selection of the right parasite form to target and the right stage of the disease for the treatment to be started. In this review we will critically overview the few research works published in the last 20years in the context of nanotechnology and Chagas diseases and highlight the gaps in knowledge towards the design of more efficient medicines to address this endemic.

Keywords: Abbreviations; LD50; lethal dose 50; IC50; inhibitory concentration 50; MIC; minimal inhibitory concentration; IV; intravenous; SC; subcutaneous; RES; reticuloendothelial systemChagas disease; Amastigotes; Drug delivery; Liposomes; Nanoparticles

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Advanced Drug Delivery Reviews (v.62, #4-5)

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Advanced Drug Delivery Reviews (v.62, #4-5)