An Available Strategy for Nasal Brain Transport of Nanocomposite Based on PAMAM Dendrimers via In Situ Gel

Huichao Xie; Lingjun Li; Yue Sun; Yuzhen Wang; Shuang Gao; Yuan Tian; Xuemei Ma; Chengcheng Guo; Fumin Bo; Li Zhang

doi:10.3390/nano9020147

An Available Strategy for Nasal Brain Transport of Nanocomposite Based on PAMAM Dendrimers via In Situ Gel

Nanomaterials ◽

10.3390/nano9020147 ◽

2019 ◽

Vol 9 (2) ◽

pp. 147 ◽

Cited By ~ 8

Author(s):

Huichao Xie ◽

Lingjun Li ◽

Yue Sun ◽

Yuzhen Wang ◽

Shuang Gao ◽

...

Keyword(s):

Targeted Delivery ◽

Drug Carriers ◽

Pamam Dendrimer ◽

Pamam Dendrimers ◽

In Situ Gel ◽

Transport Efficiency ◽

Plastic Fluid ◽

The Brain

Polyamidoamine (PAMAM) dendrimers are efficient drug carriers. The presence of a physiological pathway for nasal brain transport provides a potential path for direct brain-targeted delivery of dendrimer nanocomposites. In this study, we synthesized PAMAM dendrimer composites with a nanoscale size; the particle size of PAE (Paeonol)/mPEG (the heterofunctional PEG polymer with a methoxy)-PAMAM G5.NHAc and mPEG-PAMAM G5.NH2-FITC were 72.41 ± 11.58 nm and 96.51 ± 7.77 nm, and the zeta potential of PAE/mPEG-PAMAM G5.NHAc and mPEG-PAMAM G5.NH2-FITC were + 0.57 ± 0.11 mv and + 9.60 ± 0.41 mv, respectively. The EE% and DL% of PAE in PAE/mPEG-PAMAM G5.NHAc were 53.77% and 13.92%, respectively. PAE/mPEG-PAMAM G5.NHAc/DGG ionic-sensitive in situ gel was prepared, the viscosity of solution and gel state were 112 ± 3.2 mPa and 1403 ± 38.5 mPa, respectively. The in vitro goat mucoadhesive strength of the gel was 4763.36 ± 85.39 dyne/cm2. In situ gel system was proven to be a non-Newtonian pseudo-plastic fluid with shear thinning, thixotropy and yield stress. The optimal model of PAE released from PAE/mPEG-PAMAM G5.NHAc and PAE/mPEG-PAMAM G5.NHAc/DGG were the Higuchi equation and the Korsmeyer-Peppas equation, respectively. The cytotoxicity of the nanocomposites showed a concentration-dependence, and the cell viabilities of PAE/mPEG-PAMAM G5.NHAc were both higher than 95% between 0.0001 μM and 10 μM. mPEG-PAMAM G5.NH2-FITC was efficiently taken up by cells and exhibited strong fluorescence in the cytoplasm and nucleus. Significant accumulation of nanocomposites was observed in the brain after administration of the in situ gel group, and maximum accumulation was reached at 12 h. A small amount of accumulation was observed in the nanocomposite solution group only at 2 h. Therefore, the direct nasal brain transport efficiency of PAMAM dendrimer nanocomposites can be significantly improved after combining with in situ gel. PAMAM dendrimer nanocomposite/DGG is a potential drug delivery system for nasal brain transport.

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Targeting Breast Cancer Cells with G4 PAMAM Dendrimers and Valproic Acid Derivative Complexes

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200423073812 ◽

2020 ◽

Vol 20 (15) ◽

pp. 1857-1872

Author(s):

Alberto M. Muñoz ◽

Manuel J. Fragoso-Vázquez ◽

Berenice P. Martel ◽

Alma Chávez-Blanco ◽

Alfonso Dueñas-González ◽

...

Keyword(s):

Valproic Acid ◽

Cell Lines ◽

Water Solubility ◽

Md Simulations ◽

Pamam Dendrimer ◽

Pamam Dendrimers ◽

Force Microscopy ◽

Micromolar Concentration ◽

Atomic Force

Background: Our research group has developed some Valproic Acid (VPA) derivatives employed as anti-proliferative compounds targeting the HDAC8 enzyme. However, some of these compounds are poorly soluble in water. Objective: Employed the four generations of Polyamidoamine (G4 PAMAM) dendrimers as drug carriers of these compounds to increase their water solubility for further in vitro evaluation. Methods: VPA derivatives were subjected to Docking and Molecular Dynamics (MD) simulations to evaluate their affinity on G4 PAMAM. Then, HPLC-UV/VIS, 1H NMR, MALDI-TOF and atomic force microscopy were employed to establish the formation of the drug-G4 PAMAM complexes. Results: The docking results showed that the amide groups of VPA derivatives make polar interactions with G4 PAMAM, whereas MD simulations corroborated the stability of the complexes. HPLC UV/VIS experiments showed an increase in the drug water solubility which was found to be directly proportional to the amount of G4 PAMAM. 1H NMR showed a disappearance of the proton amine group signals, correlating with docking results. MALDI-TOF and atomic force microscopy suggested the drug-G4 PAMAM dendrimer complexes formation. Discussion: In vitro studies showed that G4 PAMAM has toxicity in the micromolar concentration in MDAMB- 231, MCF7, and 3T3-L1 cell lines. VPA CF-G4 PAMAM dendrimer complex showed anti-proliferative properties in the micromolar concentration in MCF-7 and 3T3-L1, and in the milimolar concentration in MDAMB- 231, whereas VPA MF-G4 PAMAM dendrimer complex didn’t show effects on the three cell lines employed. Conclusion: These results demonstrate that G4 PAMAM dendrimers are capableof transporting poorly watersoluble aryl-VPA derivate compounds to increase its cytotoxic activity against neoplastic cell lines.

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Cells Transfected with the Basic Fibroblast Growth Factor Gene Fused to a Signal Sequence Are Invasive In Vitro and In Situ in the Brain

Neurosurgery ◽

10.1227/00006123-199504000-00020 ◽

1995 ◽

Vol 36 (4) ◽

pp. 780-788 ◽

Cited By ~ 14

Author(s):

Stephen Gately ◽

Ana-Maria C. Tsanaclis ◽

Shingo Takano ◽

Michael Klagsbrun ◽

Steven Brem

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Basic Fibroblast Growth Factor ◽

Signal Sequence ◽

Fibroblast Growth ◽

Factor Gene ◽

Growth Factor Gene ◽

The Brain

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DEVELOPMENT AND CHARACTERIZATION OF IN SITU GEL OF XANTHAN GUM FOR OPHTHALMIC FORMULATION CONTAINING BRIMONIDINE TARTRATE

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i7.25221 ◽

2018 ◽

Vol 11 (7) ◽

pp. 277 ◽

Cited By ~ 3

Author(s):

Vazir Ashfaq Ahmed ◽

Divakar Goli

Keyword(s):

Drug Release ◽

Xanthan Gum ◽

Gelation Time ◽

Gel Strength ◽

Eye Drops ◽

In Situ Gel ◽

23 Factorial Design ◽

Brimonidine Tartrate

Objective: The goal of this study was to develop and characterize an ion-activated in situ gel-forming brimonidine tartrate, solution eye drops containing xanthan gum as a mucoadhesive polymer.Method: Sol-gel formulation was prepared using gellan gum as an ion-activated gel-forming polymer, xanthan gum as mucoadhesive agent, and hydroxypropyl methyl cellulose (HPMC E50LV) as release retardant polymer. Phenylethyl alcohol is used as preservatives in borate buffer. The 23 factorial design was employed to optimize the formulation considering the concentration of gelrite, xanthan gum and HPMC as independent variables, gelation time, gel strength, and mucoadhesive force (N). Gelation time , gel strength, mucoadhesive force (N), viscosity (cP) and in vitro percentage drug release were chosen as dependent variables. The formulation was characteristics for pH, clarity, isotonicity, sterility, rheological behavior, and in vitro drug release, ocular irritation, and ocular visualization.Result: Based on desirability index of responses, the formulation containing a concentration of gelrite (0.4%), xanthan gum (0.21%), and HPMC (HPMC E50 (0.24%) was found to be the optimized formulation concentration developed by 23 factorial design. The solution eye drops resulted in an in situ phase change to gel-state when mixed with simulated tear fluid. The gel formation was also confirmed by viscoelastic measurements. Drug release from the gel followed non-fickian mechanism with 88% of drug released in 10 h, thus increased the residence time of the drug.Conclusion: An in situ gelling system is a valuable alternative to the conventional system with added benefits of sustained drug release which may ultimately result in improved patient compliance.

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IN SITU GEL AS PLATFORM FOR KETOCONAZOLE SLOW RELEASE DOSAGE FORM

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2018v10i5.27849 ◽

2018 ◽

Vol 10 (5) ◽

pp. 76

Author(s):

Methaq Hamad Sabar ◽

Iman Sabah Jaafar ◽

Masar Basim Mohsin Mohamed

Keyword(s):

Drug Release ◽

Guar Gum ◽

Polymer Concentration ◽

Hydroxypropyl Methylcellulose ◽

In Vitro Release ◽

High Viscosity ◽

In Situ Gel ◽

Alginate Concentration

Objective: The aim of this study was to formulate ketoconazole (keto) as oral floating in situ gel to slow the release of keto in the stomach.Methods: Sodium alginate (Na alginate) was used as a primary polymer in the preparation of the in situ gel and was supported by the following polymers: guar gum (GG), hydroxypropyl methylcellulose (HPMC) K4M, K15M and carbapol 940 as viscosity enhancing agents. As a consequence, and to complete the gelation process of above formulations was by adding the calcium carbonate (CaCO3). The in situ gels were investigated by the following tests: floating lag time, floating duration, viscosity, drug content, in vitro gelling studies and in vitro release study.Results: The study showed that the faster release was obtained with F1 which contained Na alginate alone. Additionally, reduction in Na alginate concentration resulted in significant increase in drug release. It was also noted that the increase in GG (viscosity enhancing polymer) concentration resulted in non-significant decrease in percent drug release and the reduction in CaCO3 concentration led to significant increase in drug release. Moreover, the release of drug was also affected by grade of viscosity enhancing polymer, the faster release was observed with the formula which contained a polymer of low viscosity (HPMC K4M) and an opposite result was with the high viscosity polymer (HPMCK15M).Conclusion: This study showed the formulation of Na alginate with GG and CaCO3, led to gain floating in situ gel and a sustained release of keto.

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Nanocubosomal based in situ gel loaded with natamycin for ocular fungal diseases: development, optimization, in-vitro, and in-vivo assessment

Drug Delivery ◽

10.1080/10717544.2021.1965675 ◽

2021 ◽

Vol 28 (1) ◽

pp. 1836-1848

Author(s):

Khaled M. Hosny ◽

Waleed Y. Rizg ◽

Hala M. Alkhalidi ◽

Walaa A. Abualsunun ◽

Rana B. Bakhaidar ◽

...

Keyword(s):

Fungal Diseases ◽

In Situ Gel ◽

In Vivo Assessment

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FORMULATION AND IN-VITRO EVALUATION OF ZOLMITRIPTAN IN SITU GEL FOR NASAL ADMINISTRATION

INDIAN DRUGS ◽

10.53879/id.50.12.p0054 ◽

2013 ◽

Vol 50 (12) ◽

pp. 54-58

Author(s):

P. H Patil ◽

◽

V. S Belgamwar ◽

D. A Patel ◽

S. J. Surana

Keyword(s):

Evaluation Studies ◽

Methyl Cellulose ◽

Nasal Delivery ◽

Nasal Administration ◽

Histopathological Study ◽

In Situ Gel ◽

In Vitro Evaluation ◽

Effective Delivery

The aim of present investigation was formulation and in-vitro evaluation of in situ gel for the nasal delivery of zolmitriptan. The in situ gel was prepared by temperature induced gelation technique using Pluronic with mucoadhesive polymer hydroxy propyl methyl cellulose K4 M in different ratios. The in situ gels so prepared were characterized and from the evaluation studies, batch PH2 was optimized and further subjected for stability studies at 30±2°C and 60±5% RH for 90 days. These formulations retained good stability at accelerated conditions and also did not show any remarkable damage to nasal mucosa in histopathological study. Owing to these properties it can be used as an effective delivery system for the nasal route.

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DEVELOPMENT AND INVESTIGATION OF TIMOLOL MALEATE AND TRAVOPROST COMBINATION NIOSOMAL IN SITU GELLING SYSTEM FOR THE TREATMENT OF GLAUCOMA

INDIAN DRUGS ◽

10.53879/id.52.07.10193 ◽

2015 ◽

Vol 52 (07) ◽

pp. 33-35

Author(s):

A Dubey ◽

◽

P Prabhu ◽

N Nair ◽

K Beladiya ◽

...

Keyword(s):

In Vitro Release ◽

Entrapment Efficiency ◽

Timolol Maleate ◽

In Situ Gel ◽

Vesicle Size ◽

Gelling Time ◽

In Situ Gelling ◽

Vitro Release

The aim of the present investigation was to develop a combination of timolol maleate and travoprost niosomal in situ gelling system for the treatment of glaucoma. Niosomes were prepared by thin film hydration technique using rotary flash evaporator. A 32 factorial design was utilized to study the effect of the molar ratio of Span 60 (X1) and cholesterol (X2) on vesicle size, drug entrapment efficiency and in vitro release study. On the basis of vesicle size, maximum entrapment efficiency and in vitro release of drug, best formulations were selected for the preparation of niosomal in situ gel (Drop). On the basis of gelling time and viscosity, optimized ratio of the polymers was selected for the desired preparation. Selected niosomal batches were dispersed in carbopol 940 and HPMC K4M polymer solution (combination IF6) to form in situ gel niosomal formulations (Drop). The gelling time of the niosomal in situ gel (NIF1) was found to be the best (+++) and the viscosity was found to be 1190 cP. Zeta potential, average size analysis, polydispersibility index value was found to be -45.1 mV, 256.5 nm, 0.228 respectively. In vitro drug release was found to be within the range of 50.23 ± 0.54 to 60.23 ± 0.33% over the period of 6 h. IOP lowering activity of best formulation (NIF1) showed more significant and sustained effect than the marketed eye drops. Best formulation (NIF1) was found to be stable, sterile, non irritant and isotonic. Hence niosomal in situ gelling combination system may have the potential of bringing better application than the conventional ocular therapy with improved ocular bioavailability and increased patient compliance.

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Boosting the Brain Delivery of Atazanavir through Nanostructured Lipid Carrier-Based Approach for Mitigating NeuroAIDS

Pharmaceutics ◽

10.3390/pharmaceutics12111059 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1059

Author(s):

Saif Ahmad Khan ◽

Saleha Rehman ◽

Bushra Nabi ◽

Ashif Iqubal ◽

Nida Nehal ◽

...

Keyword(s):

Targeted Delivery ◽

Drug Loading ◽

Entrapment Efficiency ◽

Fold Increase ◽

Pharmacokinetic Studies ◽

Nanostructured Lipid Carrier ◽

Brain Delivery ◽

The Brain

Atazanavir (ATZ) presents poor brain availability when administered orally, which poses a major hurdle in its use as an effective therapy for the management of NeuroAIDS. The utilization of nanostructured lipid carriers (NLCs) in conjunction with the premeditated use of excipients can be a potential approach for overcoming the limited ATZ brain delivery. Methods: ATZ-loaded NLC was formulated using the quality by design-enabled approach and further optimized by employing the Box–Behnken design. The optimized nanoformulation was then characterized for several in vitro and in vivo assessments. Results: The optimized NLC showed small particle size of 227.6 ± 5.4 nm, high entrapment efficiency (71.09% ± 5.84%) and high drug loading capacity (8.12% ± 2.7%). The release pattern was observed to be biphasic exhibiting fast release (60%) during the initial 2 h, then trailed by the sustained release. ATZ-NLC demonstrated a 2.36-fold increase in the cumulative drug permeated across the rat intestine as compared to suspension. Pharmacokinetic studies revealed 2.75-folds greater Cmax in the brain and 4-fold improvement in brain bioavailability signifying the superiority of NLC formulation over drug suspension. Conclusion: Thus, NLC could be a promising avenue for encapsulating hydrophobic drugs and delivering it to their target site. The results suggested that increase in bioavailability and brain-targeted delivery by NLC, in all plausibility, help in improving the therapeutic prospects of atazanavir.

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Investigating the ocular toxicity potential and therapeutic efficiency of in situ gel nanoemulsion formulations of brinzolamide

Toxicology Research ◽

10.1093/toxres/tfaa066 ◽

2020 ◽

Vol 9 (4) ◽

pp. 578-587

Author(s):

Sima Talaei ◽

Mohammad Mehdi Mahboobian ◽

Mojdeh Mohammadi

Keyword(s):

Intraocular Pressure ◽

Membrane Surface ◽

Chorioallantoic Membrane ◽

In Situ Gel ◽

Toxicity Potential ◽

Vessel Injury ◽

Hen’S Egg

Abstract Glaucoma is an ocular disease i.e. more common in older adults with elevated intraocular pressure and a serious threat to vision if it is not controlled. Due to the limitations regarding the conventional form of brinzolamide (Azopt®), two optimum formulations of in situ gel nanoemulsion were developed. To ensure the safety and efficacy of developed formulations for ocular drug delivery, the current study was designed. MTT assay was carried out on the human retinal pigmentation epithelial cells. To investigate the irritation potential of the chosen formulations, hen’s egg test-chorioallantoic membrane as a borderline test between in vivo and in vitro methods has been done. The modified Draize method was utilized to evaluate eye tolerance against the selected formulations. Intraocular pressure was measured by applying the prepared formulations to the eyes of normotensive albino rabbits in order to assess the therapeutic efficacy. Based on MTT test, cell viability for NE-2 at 0.1% and NE-1 at 0.1 and 0.5% concentrations was acceptable. The results of the hen’s egg test-chorioallantoic membrane test indicated no sign of vessel injury on the chorioallantoic membrane surface for both formulations. Also, during 24 h, both formulations were well-tolerated by rabbit eyes. The pharmacodynamics effects of formulations had no difference or were even higher than that of suspension in case of adding lower concentration (0.5%) of brinzolamide to the formulations. With regard to the results of the mentioned methods, our advanced formulations were effective, safe, and well-tolerated, thus can be introduced as an appropriate vehicle for ocular delivery of brinzolamide.

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