Antimalarial Drug Delivery Research Articles

Antimalarial Delivery with a Ferritin-Based Protein Cage: A Step toward Developing Smart Therapeutics against Malaria.

Over the past two decades, the utilization of protein cages has witnessed exponential growth driven by their extensive applications in biotechnology and therapeutics. In the context of the recent Covid-19 pandemic, protein-cage-based scaffolds played a pivotal role in vaccine development. Beyond vaccines, these protein cages have proven valuable in diverse drug delivery applications thanks to their distinctive architecture and structural stability. Among the various types of protein cages, ferritin-based cages have taken the lead in drug delivery applications. This is primarily attributed to their ease of production, exceptional thermal stability, and nontoxic nature. While ferritin-based cages are commonly employed in anticancer drug delivery and contrast agent delivery, their efficacy in malarial drug delivery had not been explored until this study. In this investigation, several antimalarial drugs were encapsulated within horse spleen ferritin, and the binding and loading processes were validated through both experimental and computational techniques. The data unequivocally demonstrate the facile incorporation of antimalarial drugs into ferritin without disrupting its three-dimensional structure. Computational docking and molecular dynamics simulations were employed to pinpoint the precise location of the drug binding site within ferritin. Subsequent efficacy testing on Plasmodium revealed that the developed nanoconjugate, comprising the drug-ferritin conjugate, exhibited significant effectiveness in eradicating the parasite. In conclusion, the findings strongly indicate that ferritin-based carrier systems hold tremendous promise for the future of antimalarial drug delivery, offering high selectivity and limited side effects.

Nanotechnology: “Advancing Material Science and Medicine”

Nanotechnology has been a rapidly growing field of advanced science at the inception of this century. Nanotechnology of advanced materials, polymers, principally revolves around endeavours to plan materials at a sub-atomic level to accomplish alluring properties and applications at a naturally visible level. Nanotechnology can be used for the advancement of technologies, ranging from communication and information, health and medicine, future energy, environment and climate change to transport and cultural heritage, personal protective equipment (PPE), fuels, fuel cells, biosensors, disease sensors etc. Nanomaterials will lead to a new approach to manufacturing materials and devices. Faster computers, advanced pharmaceuticals, controlled drug delivery, biocompatible materials, nerve and tissue repair, crackproof surface coatings, better skin care and protection, more efficient catalysts, better and smaller sensors, even more efficient telecommunication. For example, a low risk solution using antibody modified bismuth nanoparticle, in combination with an X-ray dose equivalent to a chest X-ray specifically, has been shown to kill the common bacterium Pseudomonas aeruginosa in a set up designed to resemble a deep wound in human tissue. Nanosized gold particle could catalyse the oxidation of carbon monoxide better than anything previously known. Heparin functionalized nanoparticles have been use for targeted delivery of anti-malarial drugs. Heparin is abundant and cheap, compared to treatments that involve antibodies, an important consideration, since malaria is most common in developing countries. A bone repairing nano-particle paste has been developed that promises faster repair of fractures and breakages. DNA containing two growth genes is encapsulated inside synthetic calcium phosphate nanoparticles. In a remarkable demonstration of the extreme limits of nanoscale engineering, researchers have used the tip of a scanning tunnelling microscope to cleave and form selected chemical bonds in a complex molecule. Many medicinal and industrial endeavours have seen the use of Nanotechnology. Nanoparticles can attach to SARS COV-2 viruses, disrupting their structure and so kill the virus. These and other more recent advances in nanotechnology will be presented at this conference.

Transdermal antimalarial drug delivery to improve poor adherence to antimalarials: A new light at the end of the tunnel

Malaria, a perilous disease caused by Plasmodium parasites and characterized by a substantial mortality rate, has persistently posed as a global health challenge. Conventional antimalarial formulations, although effective, grapple with issues surrounding their bioavailability and palatability, and potentially hampering patient adherence and inadvertently fueling drug resistance and poor treatment outcomes. This paper meticulously delves into the predicaments associated with prevailing antimalarial delivery methods – oral, intravenous, and intramuscular. The paper navigates through the compelling merits of the transdermal pathway, drawing inspiration from its triumphant deployment in other medical realms. The investigation extends to encompass preclinical inquiries dedicated to exploring the transdermal administration of antimalarials. Transdermal antimalarials have shown complete suppression and elimination of Plasmodium parasites, as suggested by the preclinical studies. These preclinical studies emerge as a beacon of hope, exhibiting heightened bioavailability, enhanced safety margins, and notable cost-effectiveness when compared with oral antimalarials. Moreover, this innovative avenue for drug delivery not only offers convenience but also holds the potential to be a transformative solution to the adherence problems of traditional antimalarials, which currently afflicts standard therapeutic options.

Knowledge and practices of private pharmacy auxiliaries on malaria in Abidjan, Côte d’Ivoire

BackgroundThe emergence of resistance to artemisinin derivatives in Southeast Asia constitutes a serious threat for other malaria endemic areas, particularly in Côte d’Ivoire. To delay this resistance, the application of the control measures recommended by the National Malaria Control Programme (NMCP) for a correct management, in the private pharmacies, is a necessity. The purpose of this study was, therefore, to assess the level of knowledge and practices of private pharmacy auxiliary in Abidjan about the management of malaria.MethodsA descriptive cross-sectional study was conducted from April to November 2015. It included auxiliaries of private pharmacies in Abidjan. Data collection material was a structured an open pretested questionnaire. Data analysis was carried out using Package for Social Science (SPSS) software version 21.1. Chi square test was used to compare proportions for a significance threshold of 0.05 for the p value.ResultsA total, 447 auxiliaries from 163 private pharmacies were interviewed. It was noted that the auxiliaries had a good knowledge of clinical signs of uncomplicated malaria (99.1%), biological examinations (54.6% for the thick film and 40.7% for rapid diagnostic tests (RDTs) and anti-malarial drugs (99.3% for artemether + lumefantrine, AL). The strategies of vector control (long-lasting insecticide-treated mosquito nets (LLITNs, Repellent ointments, cleaning gutters, elimination of larvae breeding site and intermittent preventive treatment with sulfadoxine–pyrimethamine (IPTp-SP) in pregnant women were also known by the auxiliaries, respectively 99.8% and 77.4%. However, the malaria pathogen (25.1%) and the NMCP recommendations (e.g. use of AL or AS + AQ as first-line treatment for uncomplicated malaria and IPTp-SP in pregnant women) were not well known by the auxiliaries (28.2% and 26.9% for uncomplicated and severe malaria). Concerning the practices of the auxiliaries, 91.1% offered anti-malarial drugs to patients without a prescription and 47.3% mentioned incorrect dosages. The combination artemether + lumefantrine was the most recommended (91.3%). The delivery of anti-malarial drugs was rarely accompanied by advice on malaria prevention, neither was it carried out on the result of an RDT.ConclusionThe epidemiology and the NMCP recommendations for the diagnostic and therapeutic management of malaria, are not well known to auxiliaries, which may have implications for their practices. These results show the need to sensitize and train private pharmacy auxiliaries, and also to involve them in NMCP activities.

Nanotechnology in the Health Realm

Nonotechnology has been a rapidly growing field of advanced science in recent times. Nanotechnology has found many applications in treating infectious diseases induced by viruses, bacteria, protozoan, fungi etc. Nanoparticles are effective against a virus, since a virion is of the same dimension as a nanoparticle. Nanoparticles can attach to SARS COV-2 viruses, disrupting their structure and so kill the virus. A low risk solution using antibody modified bismuth nanoparticle, in combination with an X-ray dose equivalent to a chest X-ray specifically, has been shown to kill the common bacterium Pseudomonas aeruginosa in a set up designed to resemble a deep wound in human tissue. Heparin functionalized nanoparticles have been use for targeted delivery of antimalarial drugs. Heparin is abundant and cheap, compared to treatments that involve antibodies, an important consideration, since malaria is most common in developing countries. A bone repairing nano-particle paste has been developed that promises faster repair of fractures and breakages. DNA containing two growth genes is encapsulated inside synthetic calcium phosphate nanoparticles. Many medicinal endeavours have seen the use of Nanotechnology. These and other more recent advances in nanotechnology will be presented at this conference

Formulation and characterization of liposomes containing drug absorption enhancers for optimized anti-HIV and antimalarial drug delivery.

Most of the current clinically used anti-HIV and antimalarial drugs have low bioavailability, either due to poor solubility and permeability, rapid clearance from anatomical reservoirs and poor retention at their site of action (e.g. due to the p-glycoprotein efflux system), and extreme first-pass metabolism (e.g. by the cytochrome P450 enzymes). Hence, new approaches such as the incorporation of drug absorption enhancers (DAEs) (also referred to as bioenhancers) into dosage forms, and exploration of nanocarriers such as liposomes as novel dosage forms, are needed and may provide a viable means that could improve the bioavailability of both anti-HIV and antimalarial drugs. Liposomes loaded with efavirenz or mefloquine in combination with drug absorption enhancers, as well as placebo dosage forms, were prepared using a thin-lipid film hydration technique and characterized for their particle size and zeta potentials, entrapment efficiency, in vitro drug release, and in vitro drug permeability. Liposomes were further investigated for their biocompatibility (safety) using H-4-II-E liver cells in vitro. Drug-loaded liposomes prepared using l-α-phospatidylcholine, dioleoyl (DOPC) and cholesterol (CHOL) (1:1mol/mol) as well as liposomes made of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), CHOL, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) (4:6:26mol/mol/mol) exhibited the best results in terms of their entrapment efficiency, particle size, zeta potential, in vitro drug release, and permeability. DSPC:CHOL:DPPC liposomes released EFV-based formulations better than DPPC:CHOL liposomes for immediate release behaviour. DOPC:CHOL liposomes produced a controlled release and more drug was released in the presence of DAEs for both EFV (0.4-fold higher) and MQ-based (sevenfold higher) formulations in the first 2h. However, these liposomes were less biocompatible (< 50% cell viability) with liver cells. DOPC:CHOL and DSPC:CHOL:DPPC liposomes could provide a useful nano-formulation platform, which could ensure drug loading, followed by sustained release of both anti-HIV and antimalaria drugs.

Fabrication and evaluation of artemether loaded polymeric nanorods obtained by mechanical stretching of nanospheres

The objective of the present study was to prepare and evaluate artemether-loaded poly (lactic-co-glycolic acid) (PLGA) nanorods by mechanical stretching of nanospheres. Artemether-loaded PLGA nanospheres were prepared by the standard nanoprecipitation method. To prepare the nanorods, nanospheres (129 nm) were embedded in polyvinyl alcohol film. The film was stretched by using an in-house fabricated film stretching apparatus in one dimension at the rate of 10 mm/min in acetone or silicon oil. Nanorods were recovered by dissolving the film in Milli-Q-water after stretching. The effect of film thickness (100 µm vs 150 µm), the ratio of lactide to glycolide in PLGA (50:50 vs 75:25), extent of stretching (2x vs 4x), on the aspect ratio of the nanorods was studied. A sustained release of artemether was observed from both nanospheres and nanorods with almost 85% drug release at the end of 72 h. In cytotoxicity study, almost 90% cell viability was found when THP-1 cells were treated with artemether, nanospheres, and nanorods equivalent to 0.001 to 100 µg/mL of artemether. At all the concentrations of artemether, nanorods showed less haemolysis of RBCs than the nanospheres. Artemether-loaded PLGA nanorods could be successfully prepared by the film stretching method for intravenous delivery of antimalarial drugs.

Nanotechnology and Nanoparticles in Contemporary Sciences

Nonotechanology has been a rapidly growing field of advanced science at the inception of this century. Many problematic endeavours in sciences have been successfully overcome using nanoparticles. For example, a low risk solution using antibody modified bismuth nanoparticle, in combination with an X-ray dose equivalent to a chest X-ray specifically, has been shown to kill the common bacterium Pseudomonas aeruginosa in a set up designed to resemble a deep wound in human tissue. Nanosized gold particle could catalyse the oxidation of carbon monoxide better than anything previously known. Heparin functionalized nanoparticles have been use for targeted delivery of anti-malarial drugs. Heparin is abundant and cheap compared to treatments that involve antibodies, an important consideration, since malaria is most common in developing countries. A bone repairing nano-particle paste has been developed that promises faster repair of fractures and breakages. DNA containing two growth genes is encapsulated inside synthetic calcium phosphate nanoparticles. In a remarkable demonstration of the extreme limits of nanoscale engineering, researchers have used the tip of a scanning tunnelling microscope to cleave and form selected chemical bonds in a complex molecule. Many medicinal and industrial endeavours have seen the use of Nanotechnology. These and other more recent advances in nanotechnology will be presented at this conference

Active Case Finding for Malaria: A 3-Year National Evaluation of Optimal Approaches to Detect Infections and Hotspots Through Reactive Case Detection in the Low-transmission Setting of Eswatini.

BackgroundReactive case detection (RACD) is a widely practiced malaria elimination intervention whereby close contacts of index cases receive malaria testing to inform treatment and other interventions. However, the optimal diagnostic and operational approaches for this resource-intensive strategy are not clear.MethodsWe conducted a 3-year prospective national evaluation of RACD in Eswatini, a malaria elimination setting. Loop-mediated isothermal amplification (LAMP) was compared to traditional rapid diagnostic testing (RDT) for the improved detection of infections and for hotspots (RACD events yielding ≥1 additional infection). The potential for index case–, RACD-, and individual-level factors to improve efficiencies was also evaluated.ResultsAmong 377 RACD events, 10 890 participants residing within 500 m of index cases were tested. Compared to RDT, LAMP provided a 3-fold and 2.3-fold higher yield to detect infections (1.7% vs 0.6%) and hotspots (29.7% vs 12.7%), respectively. Hotspot detection improved with ≥80% target population coverage and response times within 7 days. Proximity to the index case was associated with a dose-dependent increased infection risk (up to 4-fold). Individual-, index case–, and other RACD-level factors were considered but the simple approach of restricting RACD to a 200-m radius maximized yield and efficiency.ConclusionsWe present the first large-scale national evaluation of optimal RACD approaches from a malaria elimination setting. To inform delivery of antimalarial drugs or other interventions, RACD, when conducted, should utilize more sensitive diagnostics and clear context-specific operational parameters. Future studies of RACD’s impact on transmission may still be needed.

Artesunate-heparin conjugate based nanocapsules with improved pharmacokinetics to combat malaria

Artesunate-heparin conjugate (ART-HEP) based nanocapsules as drug delivery vehicle was developed for intracellular release of ART in malaria therapy. Owing both hydrophobic and hydrophilic moieties, the conjugate was successfully self-assembled into artesunate-heparin nanocapsules (ART-HEP-NCPs) with lower critical micelle concentration (CMC) of about 20 µg/mL. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed that ART-HEP-NCPs has an average hydrodynamic diameter of 112.1 nm with a negatively charged surface (−11.2 mV) and typical micellar nanostructure, respectively. Interestingly, such modification achieved high drug loading efficiency (DLE) of ART (29.3 wt%), which is significantly higher than already reported conventional ART-loaded nanoparticles. The nanocapsules demonstrated lower in vitro ART release under neutral physiological environment (33.81%) but higher release rate was observed in simulated acidic microenvironment (92.74%) in 70 h test. This behavior of ART-HEP-NCPs will facilitate the intracellular release of ART under slightly acidic parasitic food vacuole for effective antimalarial effect. Storage stability and hemolytic studies exhibited that ART-HEP based nanocapsules were stable and safe for intravenous (i.v) injection. Notably, ART-HEP-NCPs has promising internalization into Plasmodium infected red blood cells (iRBCs) and also displayed in vitro inhibitory effect against P. falciparum 3D7 with half-maximal inhibitory concentration (IC50) of 10.16 nM, which was slightly higher than free ART (IC50 6.27 nM). This expected slightly lower inhibitory effect of polymeric prodrug could be ascribed to the gradual release of ART from the polymer chain over time. More importantly, the in vivo pharmacokinetics study indicated that the nanoscale characteristic of nanocapsules substantially contributed to the extended circulation of ART in blood. In conclusion, such multifunctional ART-HEP-NCPs with higher ART loading and extended half-life could be a promising platform for targeted antimalarial drug delivery.

Micelle carriers based on dendritic macromolecules containing bis-MPA and glycine for antimalarial drug delivery.

Biomaterials for antimalarial drug transport still need to be investigated in order to attain nanocarriers that can tackle essential issues related to malaria treatment, e.g. complying with size requirements and targeting specificity for their entry into Plasmodium-infected red blood cells (pRBCs), and limiting premature drug elimination or drug resistance evolution. Two types of dendritic macromolecule that can form vehicles suitable for antimalarial drug transport are herein explored. A new hybrid dendritic-linear-dendritic block copolymer based on Pluronic® F127 and amino terminated 2,2'-bis(glycyloxymethyl)propionic acid dendrons with a poly(ester amide) skeleton (HDLDBC-bGMPA) and an amino terminated dendronized hyperbranched polymer with a polyester skeleton derived from 2,2'-bis(hydroxymethyl)propionic acid (DHP-bMPA) have provided self-assembled and unimolecular micelles. Both types of micelle carrier are biocompatible and exhibit appropriate sizes to enter into pRBCs. Targeting studies have revealed different behaviors for each nanocarrier that may open new perspectives for antimalarial therapeutic approaches. Whereas DHP-bMPA exhibits a clear targeting specificity for pRBCs, HDLDBC-bGMPA is incorporated by all erythrocytes. It has also been observed that DHP-bMPA and HDLDBC-bGMPA incorporate into human umbilical vein endothelial cells with different subcellular localization, i.e. cytosolic and nuclear, respectively. Drug loading capacity and encapsulation efficiencies for the antimalarial compounds chloroquine, primaquine and quinacrine ranging from 30% to 60% have been determined for both carriers. The resulting drug-loaded nanocarriers have been tested for their capacity to inhibit Plasmodium growth in in vitro and in vivo assays.

Interactions of Artefenomel (OZ439) with Milk during Digestion: Insights into Digestion-Driven Solubilization and Polymorphic Transformations.

Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of crystalline drug in suspension during in vitro intestinal lipolysis of milk containing OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid-state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissolution of the free base form 1 and recrystallization of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addition of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although crystalline precipitates of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant reduction in crystalline OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures by the digested milk lipids. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for coadministration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.

Synthesis and in vitro drug release studies on substituted polyphosphazene conjugates of lumefantrine.

&lt;p class="Default"&gt;&lt;span&gt;The present study pertains to the delivery of antimalarial drug (Lumifantrine). In this, polyphosphazene has been used in the synthesis of polyphosphazene-linked conjugates of Lumifantrine. These polymer-linked Conjugates have been synthesized and characterized by modern analytical techniques. The &lt;em&gt;in-vitro&lt;/em&gt; drug release of Lumifantrine drug conjugates: &lt;em&gt;p&lt;/em&gt;-Amino benzoic acid ester substituted polyphosphazene drug conjugate &lt;strong&gt;(15)&lt;/strong&gt; and Glycine methyl ester substituted polyphosphazene drug conjugate &lt;strong&gt;(21) &lt;/strong&gt;have been found to be 6.00 % and 5.96% (pH 1.2), 88.52% and 79.86% (pH 7.4), respectively. These drug conjugate may prove an effective delivery system for the treatment of malaria.&lt;/span&gt;&lt;/p&gt;

Control of Malaria by Bio-Therapeutics and Drug Delivery Systems

Malaria is a ubiquitous disease that can affect more than 40% of the world’s population who live with some risk of contracting this disease. The World Health Organization (WHO) has recently highlighted the high spread of this disease in Sub-Saharan Africa. Despite the considerable fall in mortality rate over the past decade, the development of resistance against main treatment strategies still exists. This problem has provoked scientific efforts to develop various treatment strategies including use of vaccines, drug delivery systems, and biotherapeutics approaches. A vaccination strategy is being implemented to trigger direct clearance of the causative parasites from the human host. However, the complex life-cycle of Plasmodium parasites with continuous antigenic mutations has partly hindered this approach so far. The application of different types of drug delivery systems for the delivery of antimalarial drugs is also being considered in order to improve the efficacy, pharmacokinetics, tolerability, and reduce toxicity of existing anti-malarial drugs. A third approach has emerged from the high success of antibodies to treat complex diseases like cancer and autoimmune diseases. Various antibody engineering methods and formats have been proposed to tackle the notable sophisticated lifecycle of malaria. Within the malaria research field, the characteristics of these diverse treatment strategies, individually, are broadly acknowledged. This review article considers the current status of these approaches and the future outlook.

Recent advances in nanomedicine for antimalarial drug delivery

Recent advances in nanomedicine for antimalarial drug delivery

Solvents effects on crystallinity and dissolution of β-artemether

β-artemether (ARM) is a widely used anti-malarial drug isolated from the Chinese antimalarial plant, Artemisia annua. The solvent effects on crystal habits and dissolution of ARM were thoroughly investigated and discussed herein. The ARM was recrystallized in nine different solvents of varied polarity, namely, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, trichloromethane, ethyl acetate, acetone and hexane by solvent evaporation method. The obtained crystals were morphologically characterized using scanning electron microscope (SEM). The average sizes of crystals were 1.80–2.64 μm calculated from microscopic images using Image-Pro software. No significant change in chemical structure was noticed after recrystallization and the specific band at 875 cm−1 wavenumber (C–O–O–C) confirmed the presence of most sensitive functional group in the ARM chemical structure. The existence and production of two polymorphic forms, polymorph A and polymorph B, was confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The data suggested that the fabrication of polymorph B can be simply obtained from the recrystallization of ARM in a specific solvent. Significant effects of solvent polarity, crystals shapes and sizes on drug dissolution were noticed during in vitro dissolution test. The release kinetics were calculated and well fitted by the Higuchi and Hixon–Crowell models. The ARM-methanol and ARM-hexane showed highest and slowest dissolution, respectively, due to the effects of solvent polarity and crystal morphologies. Overall, proper selection of the solvents for the final crystallization of ARM helps to optimize dissolution and bioavailability for a better delivery of anti-malarial drug.

Adaptation of targeted nanocarriers to changing requirements in antimalarial drug delivery

The adaptation of existing antimalarial nanocarriers to new Plasmodium stages, drugs, targeting molecules, or encapsulating structures is a strategy that can provide new nanotechnology-based, cost-efficient therapies against malaria. We have explored the modification of different liposome prototypes that had been developed in our group for the targeted delivery of antimalarial drugs to Plasmodium-infected red blood cells (pRBCs). These new models include: (i) immunoliposome-mediated release of new lipid-based antimalarials; (ii) liposomes targeted to pRBCs with covalently linked heparin to reduce anticoagulation risks; (iii) adaptation of heparin to pRBC targeting of chitosan nanoparticles; (iv) use of heparin for the targeting of Plasmodium stages in the mosquito vector; and (v) use of the non-anticoagulant glycosaminoglycan chondroitin 4-sulfate as a heparin surrogate for pRBC targeting. The results presented indicate that the tuning of existing nanovessels to new malaria-related targets is a valid low-cost alternative to the de novo development of targeted nanosystems.

An amphiphilic graft copolymer-based nanoparticle platform for reduction-responsive anticancer and antimalarial drug delivery

Medical applications of anticancer and antimalarial drugs often suffer from low aqueous solubility, high systemic toxicity, and metabolic instability. Smart nanocarrier-based drug delivery systems provide means of solving these problems at once. Herein, we present such a smart nanoparticle platform based on self-assembled, reduction-responsive amphiphilic graft copolymers, which were successfully synthesized through thiol-disulfide exchange reaction between thiolated hydrophilic block and pyridyl disulfide functionalized hydrophobic block. These amphiphilic graft copolymers self-assembled into nanoparticles with mean diameters of about 30-50 nm and readily incorporated hydrophobic guest molecules. Fluorescence correlation spectroscopy (FCS) was used to study nanoparticle stability and triggered release of a model compound in detail. Long-term colloidal stability and model compound retention within the nanoparticles was found when analyzed in cell media at body temperature. In contrast, rapid, complete reduction-triggered disassembly and model compound release was achieved within a physiological reducing environment. The synthesized copolymers revealed no intrinsic cellular toxicity up to 1 mg mL(-1). Drug-loaded reduction-sensitive nanoparticles delivered a hydrophobic model anticancer drug (doxorubicin, DOX) to cancer cells (HeLa cells) and an experimental, metabolically unstable antimalarial drug (the serine hydroxymethyltransferase (SHMT) inhibitor (±)-1) to Plasmodium falciparum-infected red blood cells (iRBCs), with higher efficacy compared to similar, non-sensitive drug-loaded nanoparticles. These responsive copolymer-based nanoparticles represent a promising candidate as smart nanocarrier platform for various drugs to be applied to different diseases, due to the biocompatibility and biodegradability of the hydrophobic block, and the protein-repellent hydrophilic block.

Synthesis and Evaluation of Substituted Poly(organophosphazenes) as a Novel Nanocarrier System for Combined Antimalarial Therapy of Primaquine and Dihydroartemisinin.

The synthesis and evaluation of novel biodegradable poly(organophosphazenes) (3-6) namely poly[bis-(2-propoxy)]phosphazene (3) poly[bis(4-acetamidophenoxy)]phosphazene (4)poly[bis(4-formylphenoxy)]phosphazene (5) poly[bis(4-ethoxycarbonylanilino)]phosphazene (6) bearing various hydrophilic and hydrophobic side groups for their application as nonocarrier system for antimalarial drug delivery is described. The characterization of polymers was carried out by IR, (1)H-NMR and (31)P-NMR. The molecular weights of these novel polyphosphazenes were determined using size exclusion chromatography with a Waters 515 HPLC Pump and a Waters 2414 refractive index detector. The degradation behavior was studied by 200mg pellets of polymers in phosphate buffers pH5.5, 6.8 and 7.4 at 37°C. The degradation process was monitored by changes of mass as function of time and surface morphology of polymer pellets. The developed combined drugs nanoparticles formulations were evaluated for antimalarial potential in P. berghei infected mice. These polymers exhibited hydrolytic degradability, which can afford applications to a variety of drug delivery systems. On the basis of these results, the synthesized polymers were employed as nanocarriers for targeted drug delivery of primaquine and dihydroartemisinin. The promising in vitro release of both the drugs from nanoparticles formulations provided an alternative therapeutic combination therapy regimen for the treatment of drug resistant malaria. The nanoparticles formulations tested in resistant strain of P. berghei infected mice showed 100% antimalarial activity. The developed nanocarrier system provides an alternative combination regimen for the treatment of resistant malaria.

Controlled release studies of antimalarial 1, 3, 5-trisubstituted-2-pyrazolines from biocompatible chitosan–heparin Layer-by-Layer (LbL) self assembled thin films

Herein we report the in-vitro controlled release properties of 1, 3, 5-trisubstituted-2-pyrazolines through Layer-by-Layer (LbL) self assembled thin films fabricated from chitosan and heparin sodium salt as biocompatible polyelectrolytes. This study was carried out as a preliminary step towards the applicability of LbL technique in prophylactic drug delivery of antimalarial drugs. The growth of LbL self assembly was monitored by UV–Visible spectrophotometry and Quartz Crystal Microbalance (QCM). The loading as well as in-vitro release studies (in phosphate buffer saline at pH 7.4) were carried out using UV–Visible spectroscopy. Three compounds having good antimalarial activity were tested and the release rate was found inversely proportional to the hydrophobicity of the drug. Pzln-4 has shown best release among all the three compounds (up to 780min) followed by Pzln-5 and Pzln-8. The release trend was that of a fast release up to first 2h followed by a steady release. Kinetic fitting of the data confirmed the process of drug release followed a pseudo second order kinetics (R2≥0.99). A large value of rate constant (k) revealed a faster release. Pzln-4 has shown smallest value of k corresponding to slowest release among all the three compounds.