Preparation and characterization of solid lipid nanoparticles encapsulated noscapine and evaluation of its protective effects against imiquimod-induced psoriasis-like skin lesions.

Psoriasis is a chronic inflammatory skin disease characterized by thickening the epidermis with erythema, scaling, and proliferation. Noscapine (NOS) has several anti-inflammatory, anti-angiogenic, and anti-fibrotic effects, but its low solubility and large size results in its lower efficacy in the clinic. In this regard, solid lipid nanoparticles (SLN) encapsulated NOS (SLN-NOS) were fabricated using the well-known response surface method based on the central composite design and modified high-shear homogenization and ultrasound method. As a result, Precirol® was selected as the best lipid base for the SLN formulation based on Hildebrand-Hansen solubility parameters, in which SLN-NOS 1 % had the best zeta potential (-35.74 ± 2.59 mV), average particle size (245.66 ± 17 nm), polydispersity index (PDI, 0.226 ± 0.09), high entrapment efficiency (89.77 %), and ICH-based stability results. After 72 h, the SLN-NOS 1 % released 83.23 % and 58.49 % of the NOS at pH 5.8 and 7.4, respectively. Moreover, Franz diffusion cell's results indicated that the skin levels of NOS for SLN and cream formulations were 46.88 % and 13.5 % of the total amount, respectively. Our pharmacological assessments revealed that treatment with SLN-NOS 1 % significantly attenuated clinical parameters, namely ear thickness, length, and psoriasis area and severity index, compared to the IMQ group. Interestingly, SLN-NOS 1 % reduced the levels of interleukin (IL)-17, tumor necrosis factor-α, and transforming growth factor-ß, while elevating IL-10, compared to the IMQ group. Histology studies also showed that topical application of SLN-NOS 1 % significantly decreased parakeratosis, hyperkeratosis, acanthosis, and inflammation compared to the IMQ group. Taken together, SLN-NOS 1 % showed a high potential to attenuate skin inflammation.

Improvement and characterization of oral absorption behavior of clofazimine by SNEDDS: Quantitative evaluation of extensive lymphatic transport.

Clofazimine, an anti-leprosy drug, has been anticipated for a candidate to treat tuberculosis, cryptosporidiosis, and coronavirus infection, but its low oral bioavailability is considered a reason for its limited activity. In the current study, we have tried to improve the oral bioavailability of clofazimine by several SNEDDS formulations and characterized the absorption behavior from various aspects. Among four SNEDDS formulations prepared, SNEDDS A, prepared with castor oil as an oil component, provided the highest bioavailability (around 61%) and SNEDDS D, prepared with Capryol 90, gave the second highest bioavailability. SNEDDS A formed the finest nanoparticles, which were maintained under gastric and intestinal luminal conditions. The comparison in oral bioavailability between the SNEDDS formulation and its corresponding preformed nanoemulsion suggested that SNEDDS A would efficiently form nanoemulsion in the gastrointestinal tract after oral administration. AUC of mesenteric lymph node concentration was the highest for SNEDDS A, which would be one of the reasons for SNEDDS A to reveal the highest oral bioavailability. A cycloheximide-treated oral absorption study and single-pass perfusion study by utilizing a vascular-luminal perfused small intestine-liver preparation clearly indicated that over 90% of clofazimine absorbed to systemic circulation should be derived from lymphatic transport for both SNEDDS A and D. Furthermore, the fraction of dose absorbed was around 65% for SNEDDS D, but SNEDDS A achieved around 94%, indicating the excellent performance of SNEDDS A.

Impact of nanoparticles on amyloid ß-induced Alzheimer's disease, tuberculosis, leprosy and cancer: a systematic review.

Nanotechnology is an interdisciplinary domain of science, technology and engineering that deals with nano-sized materials/particles. Usually, the size of nanoparticles lies between 1 and 100 nm. Due to their small size and large surface area-to-volume ratio, nanoparticles exhibit high reactivity, greater stability and adsorption capacity. These important physicochemical properties attract scientific community to utilize them in biomedical field. Various types of nanoparticles (inorganic and organic) have broad applications in medical field ranging from imaging to gene therapy. These are also effective drug carriers. In recent times, nanoparticles are utilized to circumvent different treatment limitations. For example, the ability of nanoparticles to cross the blood-brain barrier and having a certain degree of specificity towards amyloid deposits makes themselves important candidates for the treatment of Alzheimer's disease. Furthermore, nanotechnology has been used extensively to overcome several pertinent issues like drug-resistance phenomenon, side effects of conventional drugs and targeted drug delivery issue in leprosy, tuberculosis and cancer. Thus, in this review, the application of different nanoparticles for the treatment of these four important diseases (Alzheimer's disease, tuberculosis, leprosy and cancer) as well as for the effective delivery of drugs used in these diseases has been presented systematically. Although nanoformulations have many advantages over traditional therapeutics for treating these diseases, nanotoxicity is a major concern that has been discussed subsequently. Lastly, we have presented the promising future prospective of nanoparticles as alternative therapeutics. In that section, we have discussed about the futuristic approach(es) that could provide promising candidate(s) for the treatment of these four diseases.

Tumor targeted delivery of mycobacterial adjuvant encapsulated chitosan nanoparticles showed potential anti-cancer activity and immune cell activation in tumor microenvironment.

Targeting immunotherapeutics inside the tumor microenvironment (TME) with intact biological activity remains a pressing issue. Mycobacterium indicus pranii (MIP), an approved adjuvant therapy for leprosy has exhibited promising results in clinical trials of lung (NSCLC) and bladder cancer. Whole MIP as well as its cell wall fraction have shown tumor growth suppression and enhanced survival in mice model of melanoma, when administered peritumorally. Clinically, peritumoral delivery remains a procedural limitation. In this study, a tumor targeted delivery system was designed, where chitosan nanoparticles loaded with MIP adjuvants, when administered intravenously showed preferential accumulation within the TME, exploiting the principle of enhanced permeability and retention effect. Bio-distribution studies revealed their highest concentration inside the tumor after 6 h of administration. Interestingly, MIP adjuvant nano-formulations significantly reduced the tumor volume in the treated groups and increased the frequency of activated immune cells inside the TME. For chemoimmunotherapeutics studies, MIP nano-formulation was combined with standard dosage regimen of Paclitaxel. Combined therapy exhibited a further reduction in tumor volume relative to either of the MIP nano formulations. From this study a three-pronged strategy emerged as the underlying mechanism; chitosan and Paclitaxel have shown direct role in tumor cell death and the MIP nano-formulation activates the tumor residing immune cells which ultimately leads to the reduced tumor growth.

Solvents drive self-assembly mechanisms and inherent properties of Kraft lignin nanoparticles (<50 nm).

HYPOTHESIS: Strikingly, Kraft lignin nanoparticles (KLNPs) can substitute polluting nanoparticles in diverse applications. An attractive method for synthesizing KLNPs is Solvent shifting. We hypothesized that by a detailed understanding of the solvent properties and influence of the process parameters, one could derive new fundamental and technical information about the lignin nanoparticle formation process. EXPERIMENTS: DMSO and THF were chosen best solvents based on the Hansen solubility parameter of lignin. The four synthesis parameters such as lignin concentration, (anti-solvent) water volume, temperature, and stirring speed were used to investigate the size, polydispersity index (PDI), morphology as well as the thermal, mechanical and optical properties of KLNPsDMSO & KLNPsTHF. FINDINGS: KLNPsTHF follows the well-known nucleation and growth (NG) mechanism, resulting in spherical KLNPs (43 ± 12 nm: 0.20 PDI). Surprisingly, KLNPsDMSO follows a unique mechanism resembling spinodal decomposition (SD), which generates rare bicontinuous-to-spherical KLNPs (17 ± 8 nm: 0.20 PDI). Remarkably, we show that the difference in the KLNPs mechanism modulates their intrinsic properties, such as glass transition temperature (Tg), specific surface area (SSA), elastic modulus (EM) and optical properties. Beyond the new mechanism, our synthesis resulted in reproducible ultra-small KLNPs with an excellent % yield. Such findings have vast implications in high-performance nanocomposites.

Photonic Cellulose Films with Vivid Structural Colors: Fabrication and Selectively Chemical Response.

Recent advances in structural-color cellulose nanocrystal (CNC) materials have been made toward chemical sensing applications; however, such materials lack sufficient color chroma for naked-eye observation, and their selective recognition to given chemicals as well as the corresponding mechanism has rarely been reported. Here, a dopamine-infiltration and post-polymerization approach is proposed to construct vivid structural-color composite films. The chiral nematic structure of CNC enables the structural coloration, while the strong light absorption of the polymeric co-phase, polydopamine (PDA) enhances the color chroma and visibility. By controlling the PDA amount, the composite films can detect organic solvents quantitatively and selectively via visible color changes. From the viewpoint of the compatibility and similitude principle, notably, a critical solubility parameter distance (R0) between PDA and "active" solvents is defined with a three-dimensional Hansen solubility sphere; this well constructs a rule for the sensing selectivity of the chemochromic composite films. The findings pave the foundation for the design of colorimetric sensors with specifically testing objects.

Effect of XlogP and hansen solubility parameters on the prediction of small molecule modified docetaxel, doxorubicin and irinotecan conjugates forming stable nanoparticles.

Small molecule-chemotherapeutic drug conjugate nanoparticles (SMCDC NPs) has a great advantage in improving drug loading. However, the factors which influence these conjugates forming stable nanoparticles (NPs) are currently unclear. In our previous studies, we synthesized a series of fatty acid-paclitaxel conjugates and suggested that the changes in the hydrophobic parameters (XlogP), solubility parameters and crystallinity of these fatty acid-paclitaxel conjugates were the key factors for affecting these small molecule-chemotherapeutic drug conjugates (SMCDCs) forming stable NPs in water. Here, we selected clinically widely used chemotherapeutic drug (docetaxel (DTX), doxorubicin (DOX) and irinotecan (Ir)) as model drug, and chose three straight-chain fatty acids (acetic acid (Ac), hexanoic acid (HA) and stearic acid (SA)) and one branched small molecule (N-(tert-butoxycarbonyl) glycine (B-G)) to synthesize 12 SMCDCs. Our results indicated that our prediction criterions obtained from paclitaxel conjugates were also appropriated for these synthesized SMCDCs. We suggested that the present studies expanded the scope of application of the above-mentioned influencing factors, provided research ideas for the rational design of SMCDC forming NPs and a basis for screening NPs with good anticancer activity.

Novel drug delivery strategies and gene therapy regimen as a promising perspective for management of psoriasis.

Psoriasis is an autoimmune disorder; however, an exact underlying mechanism responsible for psoriasis is yet not known. A hypothesis put forward is an abnormal proliferation of keratinocytes due to faulty signals brought about by T-cells. Due to the lack of evidence of the exact cause, a variety of treatments have been used of which topical therapy is usually the first option in most patients. Topical therapy has several shortcomings and barriers of drug delivary which may be effectively overcome using novel drug carrier systems which exhibit maximum penetration, controlled release, reduced irritancy and, overall, a better efficacy. Thus, novel treatment strategies based on gene therapy such as antisensing nucleotide, silencing RNA complex, stem cell therapy and antibody-based therapy are being envisaged. This review article discusses the concepts and background of current novel delivery systems and gene therapy tools for effective management of psoriasis.

High-Throughput Synthesis and Screening of Rapidly Degrading Polyanhydride Nanoparticles.

Combinatorial techniques can accelerate the discovery and development of polymeric nanodelivery devices by pairing high-throughput synthesis with rapid materials characterization. Biodegradable polyanhydrides demonstrate tunable release, high cellular internalization, and dose sparing properties when used as nanodelivery devices. This nanoparticle platform shows promising potential for small molecule drug delivery, but the pace of understanding and rational design of these nanomedicines is limited by the low throughput of conventional characterization. This study reports the use of a high-throughput method to synthesize libraries of a newly synthesized, rapidly eroding polyanhydride copolymer based on 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) and sebacic acid (SA) monomers. The high-throughput method enabled efficient screening of copolymer microstructure, revealing weak block-type and alternating architectures. The high-throughput method was adapted to synthesize nanoparticle libraries encapsulating hydrophobic model drugs. Drug release from these nanoparticles was rapid, with a majority of the payload released within 3 days. Drug release was dramatically slowed at acidic pH, which could be useful for oral drug delivery. Rhodamine B (RhoB) release kinetics generally followed patterns of polymer erosion kinetics, while Coomassie brilliant blue (CBB) released the fastest from the slowest degrading polymer chemistry and vice versa. These differences in trends between copolymer chemistry and release kinetics were hypothesized to arise from differences in mixing thermodynamics. A high-throughput method was developed to synthesize polymer-drug film libraries and characterize mixing thermodynamics by melting point depression. Rhodamine B had a negative χ for all copolymers with <30 mol % CPTEG tested, indicating a tendency toward miscibility. By contrast, CBB χ increased, eventually becoming positive near 15:85 CPTEG:SA, with increasing CPTEG content. This indicates an increasing tendency toward phase separation in CPTEG-rich copolymers. These in vitro results screening polymer-drug interactions showed good agreement with in silico predictions from Hansen solubility parameter estimation and were able to explain the observed differences in model drug release trends.

Formulation development of lipid nanoparticles: Improved lipid screening and development of tacrolimus loaded nanostructured lipid carriers (NLC).

Lipid nanoparticles are well-known nanocarriers for improved drug delivery. Their formulation development typically involves three formulations steps. In the first part a suitable lipid mixture which enables a high loading capacity and high encapsulation efficacy of the active needs to be identified (lipid screening). In the second step suitable stabilizers that enable the production of small-sized lipid nanoparticles with narrow size distribution and sufficient physical stability need to be identified (stabilizer screening, optimization of production parameters) and in the third step the biopharmaceutical efficacy needs to be evaluated. Based on the results obtained the formulations will require further optimization. The classical formulation development of lipid nanoparticles and especially the classical lipid screening is tedious. Therefore, in this study, a novel approach for the lipid screening that was based on the determination of the Hansen solubility parameters was evaluated and the results obtained were compared to the results from the classical model. Tacrolimus was used as a model drug. Results showed that both lipid screenings led to similar results, indicating that the new approach can be used for future developments. The optimized formulation was composed of a lipid matrix system that contained waxes, triglycerides and monoacylglycerols with various carbon chain lengths (C8, C10, C16, C18) and enabled an encapsulation efficiency of ~99%. The stabilizer screening showed that surfactants with high HLB values, lower molecular weight, and shorter alkyl chain length tended to form smaller particles with narrower size distribution and better physical stability. The most suitable surfactant was found to be a caprylyl/capryl glucoside (Plantacare® 810), a PEG-free stabilizer, that is extremely mild for atopic skin. It led to particle sizes of about 200 nm and a zeta potential well above |30| mV. The optimized formulation contained 0.1% tacrolimus and possessed good physical stability. In conclusion, an optimized method for the selection of lipids that results in a limited number of experiments could be established and tacrolimus loaded lipid nanoparticles with similar drug load as a marketed formulation was successfully developed in this study.

Physicochemical stimuli as tuning parameters to modulate the structure and stability of nanostructured lipid carriers and release kinetics of encapsulated antileprosy drugs.

To unveil the effect of electrolyte concentration, pH and polymer addition on Tween 80 stabilized nanostructured lipid carriers (NLCs, based on dialkyldimethylammonium bromides DxDAB and Na oleate), an in-depth scattering analysis was performed. Dynamic and static light scattering (DLS/SLS) and small-angle neutron scattering (SANS) techniques along with zeta potential studies were exploited to understand the structural evolution and physical stability of NLCs. In these experiments, we varied the salt concentration, pH, and the admixture of Pluronic F127 in order to elucidate their effect on NLC morphologies. In most cases, two populations of different sizes are present which differ by one order of magnitude. The antileprosy drugs (ALD) Rifampicin and Dapsone were encapsulated in NLCs and the vector properties were assessed for a series of DxDAB (where x = 12, 14, 16 and 18) NLCs. The influence of composition on the entrapment and release behavior of NLCs was investigated: The size of NLCs correlates with the release rate of the incorporated drug. The interaction of drug-loaded NLCs with bovine serum albumin was studied to understand the release of ALD in the plasma.

Epitope imprinting of Mycobacterium leprae bacteria via molecularly imprinted nanoparticles using multiple monomers approach.

Mycobacterium leprae causes endemic disease leprosy which becomes chronic if not treated timely. To expedite this 'timely diagnosis', and that also at an early stage, here an attempt is made to fabricate an epitope-imprinted sensor. A molecularly imprinted polymer nanoparticles modified electrochemical quartz crystal microbalance sensor was developed for sensing of Mycobacterium leprae bacteria through its epitope sequence. Multiple monomers, 3-sulphopropyl methacrylate potassium salt, benzyl methacrylate and 4-aminothiophenol were utilized to imprint this bacterial epitope. Imprinted nanoparticles were electropolymerized on gold coated quartz electrode. The sensor was able to show specific binding towards the blood samples of infected patients, even in the presence of 'matrix' and other plasma proteins such as albumin and globulin. Even other peptide sequences, similar to epitope sequences only with two amino acid mismatches were also unable to show any binding. Sensor withstood analytical tests viz. selectivity, specificity, matrix effect, detection limit (0.161 nM), quantification limit (and 0.536 nM), reproducibility (RSD 2.01%). Hence a diagnostic tool for bacterium causing leprosy is successfully fabricated in a facile manner which will broaden the clinical access and efficient population screening can be made feasible.

Modification of bacterial nanocellulose properties through mutation of motility related genes in Komagataeibacter hansenii ATCC 53582.

Bacterial nanocellulose (BNC) produced by Komagataeibacter hansenii has received significant attention due to its unique supernetwork structure and properties. It is nevertheless necessary to modify bacterial nanocellulose to achieve materials with desired properties and thus with broader areas of application. The aim here was to influence the 3D structure of BNC by genetic modification of the cellulose producing K. hansenii strain ATCC 53582. Two genes encoding proteins with homology to the MotA and MotB proteins, which participate in motility and energy transfer, were selected for our studies. A disruption mutant of one or both genes and their respective complementation mutants were created. The phenotype analysis of the disruption mutants showed a reduction in motility, which resulted in higher compaction of nanocellulose fibers and improvement in their mechanical properties. The data strongly suggest that these genes play an important role in the formation of BNC membrane by Komagataeibacter species.

Fingerstick test quantifying humoral and cellular biomarkers indicative for M. leprae infection.

OBJECTIVES: New user-friendly diagnostic tests for detection of individuals infected by Mycobacterium leprae (M. leprae), the causative pathogen of leprosy, can help guide therapeutic and prophylactic treatment, thus positively contributing to clinical outcome and reduction of transmission. To facilitate point-of-care testing without the presence of phlebotomists, the use of fingerstick blood (FSB) rather than whole blood-derived serum is preferred. This study is a first proof-of-principle validating that previously described rapid serum tests detecting antibodies and cytokines can also be used with FSB. METHODS: Quantitative detection of previously identified biomarkers for leprosy and M. leprae infection, anti-M. leprae PGL-I IgM antibodies (αPGL-I), IP-10 and CRP, was performed with lateral flow (LF) strips utilizing luminescent up-converting reporter particles (UCP) and a portable reader generating unbiased read-outs. Precise amounts of FSB samples were collected using disposable heparinized capillaries. Biomarker levels in paired FSB and serum samples were determined using UCP-LF test strips for leprosy patients and controls in Bangladesh, Brazil, South-Africa and the Netherlands. RESULTS: Correlations between serum and FSB from the same individuals for αPGL-I, CRP and IP-10 were highly significant (p < .0001) even after FSB samples had been frozen. The αPGL-I FSB test was able to correctly identify all multibacillary leprosy patients presenting a good quantitative correlation with the bacterial index. CONCLUSIONS: Reader-assisted, quantitative UCP-LF tests for the detection of humoral and cellular biomarkers for M. leprae infection, are compatible with FSB. This allows near-patient testing for M. leprae infection and immunomonitoring of treatment without highly trained staff. On site availability of test-result concedes immediate initiation of appropriate counselling and treatment. Alternatively, the UCP-LF format allows frozen storage of FSB samples compatible with deferred testing in central laboratories.

Antitumor activity of the bioreductive prodrug 3-(2-nitrophenyl) propionic acid-paclitaxel nanoparticles (NPPA-PTX NPs) on MDA-MB-231 cells: in vitro and in vivo.

BACKGROUND: 3-(2-Nitrophenyl) propionic acid-paclitaxel (NPPA-PTX) is a paclitaxel (PTX) bioreductive prodrug synthesized by our lab. We hypothesize that NPPA-PTX can self-assemble to form nanoparticles (NPs). MATERIALS AND METHODS: In the present research, the theoretical partition coefficient (XlogP) and Hansen solubility parameters of NPPA-PTX were calculated. NPPA-PTX nanoparticles prepared by NPPA-PTX and DSPE-PEG (NPPA-PTX:DSPE-PEG =1:0.1, w/w) (NPPA-PTX@PEG NPs) were prepared and characterized. The cellular uptake, in vitro antitumor activity, in vivo targeting effect, tumor distribution, in vivo antitumor activity, and safety of NPPA-PTX@PEG NPs were investigated. RESULTS: Our results indicate that NPPA-PTX can self-assemble to form NPPA-PTX@PEG NPs. Both the cellular uptake and safety of NPPA-PTX@PEG NPs were higher than those of Taxol. NPPA-PTX@PEG NPs could target tumor tissues by a passive targeting effect. In tumor tissues, NPPA-PTX@PEG NPs could completely transform into active PTX. The in vivo antitumor activity of NPPA-PTX@PEG NPs was confirmed in MDA-MB-231 tumor-bearing nude mice. CONCLUSION: The bioreductive prodrug NPPA-PTX could self-assemble to form NPs. The safety and antitumor activity of NPPA-PTX@PEG were confirmed in our in vitro and in vivo experiments. The NPPA-PTX@PEG NPs developed in this study could offer a new way of preparing bioreductive prodrug, self-assembled NPs suitable for antitumor therapy.

Comparative genomics of the Komagataeibacter strains-Efficient bionanocellulose producers.

Komagataeibacter species are well-recognized bionanocellulose (BNC) producers. This bacterial genus, formerly assigned to Gluconacetobacter, is known for its phenotypic diversity manifested by strain-dependent carbon source preference, BNC production rate, pellicle structure, and strain stability. Here, we performed a comparative study of nineteen Komagataeibacter genomes, three of which were newly contributed in this work. We defined the core genome of the genus, clarified phylogenetic relationships among strains, and provided genetic evidence for the distinction between the two major clades, the K. xylinus and the K. hansenii. We found genomic traits, which likely contribute to the phenotypic diversity between the Komagataeibacter strains. These features include genome flexibility, carbohydrate uptake and regulation of its metabolism, exopolysaccharides synthesis, and the c-di-GMP signaling network. In addition, this work provides a comprehensive functional annotation of carbohydrate metabolism pathways, such as those related to glucose, glycerol, acetan, levan, and cellulose. Findings of this multi-genomic study expand understanding of the genetic variation within the Komagataeibacter genus and facilitate exploiting of its full potential for bionanocellulose production at the industrial scale.

Development and evaluation of topical formulations for a novel skin whitening agent (AP736) using Hansen solubility parameters and PEG-PCL polymers.

AP736 itself is a novel skin whitening agent reported to exhibit anti-melanogenic and tyrosinase inhibitory activity. However, formulating a topical product has been difficult because AP736 is insoluble in water as well as in many oils. In this study, we aimed to develop a new topical delivery system in which AP736 is not only physically stable, but also suitably delivered to the skin. By calculating each HSP (Hansen Solubility Parameters), ethylenedioxy moiety-containing compounds could be easily selected for the formulation ingredients of AP736. Although diethylene glycol monoethyl ether with the highest solubility of AP736 enalbes to make AP736-incorporated water-in-oil emulsions well, the recrystallization of AP736 was observed in oil-in-water emulsions. Therefore, we fabricated polymeric nanoparticles (PNPs) in order to encapsulate AP736 to prevent its recrystallization. We used three different PEG-PCL polymers with various chain lengths and ethylenedioxy moiety-containing surfactants (i.e. Choleth) for fabricating PNPs. The prepared PNPs had a mean particle size from 50 nm to 200 nm. Most of PNPs showed the good encapsulation efficiency up to 90%. In particular, Choleth-24 had a significant role in encapsulating AP736 in PNPs. After encapsulation of AP736, no significant changes were observed in the sizes of tested PNPs within 4 weeks. Further, the recrystallization of AP736 was not observed in oil-in-water emulsions after 24 weeks of storage at 40 °C. In vitro permeation study using Strat-M showed that PNPs containing Choleth-24 has the faster release pattern compared to PNPs using Tween 80 and saturated in D.I. water. These results are demonstrating that PNPs might be an effective vehicle for stabilization in oil-in-water emulsions and topical application of AP736.

Nanosystems as modulators of intestinal dapsone and clofazimine delivery.

The aim of this work was to assess the feasibility of drug nanosystems combination for oral therapy of multibacillary leprosy. The anti-leprotic drugs dapsone (DAP) and clofazimine (CLZ) were incorporated within polymeric nanosystems and studied per se and in combination. DAP was loaded in Eudragit L100 nanoparticles (NPs-DAP) while CLZ was loaded in (poly(lactic-co-glycolic acid) (NPs-CLZ). The nanosystems exhibited around 200 nm in size and a drug loading of 12% for each drug. In vitro cytotoxicity on intestinal Caco-2 cells revealed that after 8 h incubation, DAP alone and within NPs were not toxic up to 100 µg mL-1, while CLZ per se was toxic, reducing cell viability to 30% at 50 µg mL-1. Caco-2 exposed to the combination of NPs-DAP (100 µg mL-1) and NPs-CLZ (50 µg mL-1) exhibited 80% of viability. Caco-2 monolayer permeability assays revealed that DAP and CLZ in the nanosystems per se or in NPs-DAP/ NPs-CLZ combination crossed the intestinal barrier. No significant differences were observed between the single nanosystems or in combination with the apparent permeability values and the amount of permeated drug. Thus, the NPs-DAP/NPs-CLZ combination seems to be a promising platform to deliver both drugs in association, representing an important step towards the improvement of multibacillary leprosy therapy.

Overcoming clofazimine intrinsic toxicity: statistical modelling and characterization of solid lipid nanoparticles.

The aim of this work was to develop solid lipid nanoparticles (SLNs) loaded with clofazimine (CLZ) (SLNs-CLZ) to overcome its intrinsic toxicity and low water solubility, for oral drug delivery. A Box-Behnken design was constructed to unravel the relations between the independent variables in the selected responses. The optimized SLNs-CLZ exhibited the following properties: particle size ca 230 nm, zeta potential of -34.28 mV, association efficiency of 72% and drug loading of 2.4%, which are suitable for oral delivery. Further characterization included Fourier transformed infrared spectroscopy that confirmed the presence of the drug and the absence of chemical interactions. By differential scanning calorimetry was verified the amorphous state of CLZ. The storage stability studies ensured the stability of the systems over a period of 12 weeks at 4°C. In vitro cytotoxicity studies evidenced no effect of both drug-loaded and unloaded SLNs on MKN-28 gastric cells and on intestinal cells, namely Caco-2 and HT29-MTX cells up to 25 µg ml-1 in CLZ. Free CLZ solutions exhibited IC50 values of 16 and 20 µg ml-1 for Caco-2 and HT29-MTX cells, respectively. It can be concluded that the optimized system, designed considering important variables for the formulation of poorly soluble drugs, represents a promising platform for oral CLZ delivery.

Effect of XlogP and Hansen Solubility Parameters on Small Molecule Modified Paclitaxel Anticancer Drug Conjugates Self-Assembled into Nanoparticles.

Small molecule modified anticancer drug conjugates (SMMDCs) can self-assemble into nanoparticles (NPs) as therapeutic NP platforms for cancer treatment. Here we demonstrate that the XlogP and Hansen solubility parameters of paclitaxel (PTX) SMMDCs is essential for SMMDCs self-assembling into NPs. The amorphous state of PTX SMMDCs will also affect SMMDCs self-assembling into NPs. However, the antitumor activity of these PTX SMMDCs NPs decreased along with their XlogP values, indicating that a suitable XlogP value for designing the SMMDCs is important for self-assembling into NPs and for possessing antitumor activity. For higher level XlogP SMMDCs, a degradable linker should be considered in the design of SMMDCs to overcome the problem of lower antitumor activity. It is preferable that the hydrophilic groups in the SMMDCs should be present on the surface of self-assembling NPs.