AAPE proliposomes for topical atopic dermatitis treatment

Abstract

Context: Anti-inflammatory effect of advanced adipose stem cell derived protein extract (AAPE) could be improved by minimising protein degradation. Objective: To develop a proliposomal formulation of AAPE for the treatment of topical atopic dermatitis. Materials and methods: Proliposomal powder was manufactured by evaporating a solution of soy phosphatidyl choline, AAPE and Poloxamer 407 in ethanol under vacuum on sorbitol powder. Characterisation of proliposomes (zeta potential, diameter, stability and flowability) as well as in vivo efficacy in a dermatitis mouse model was investigated. Results and discussion: Reconstitution of the proliposomal powder formed liposomes of 589?±?3.6?nm diameter with zeta potential of ?51.33?±?0.36?mV. Protein stability was maintained up to 90 days at 25?°C as proliposomes. In vivo studies on atopic dermatitis mouse model showed a significant reduction in IgE levels after topical AAPE proliposome treatment. Conclusion: AAPE proliposomes maintained protein stability and showed promising results for atopic dermatitis treatment.     

Bilayer Composition,Temperature, Speciation Effects and the Role of Bilayer Chain Ordering on Partitioning of Dexamethasone and its 21-Phosphate

Purpose

Models to predict membrane-water partition coefficients (K_p) as a function of drug structure, membrane composition, and solution properties would be useful. This study explores the partitioning of dexamethasone (Dex) and its ionizable 21-phosphate (Dex-P) in liposomes varying in acyl chain length, physical state, and pH.

Methods

DMPC:mPEG DMPE, DPPC:mPEG DPPE, and DSPC:mPEG DSPE (95:5 mol%) liposomes were prepared by thin film hydration. K_p values for Dex and Dex-P were determined from pH 1.5–8 by equilibrium dialysis and equilibrium solubility (Dex).

Results

Dex K_p values at 25°C were 705?±?24, 106?±?11, and 58?±?9 in DMPC, DPPC, and DSPC, increasing to 478?±?20 in DPPC liposomes at 45°C. Both neutral and anionic species contributed to the K_p of Dex-P versus solution pH (1.5–8). A linear correlation was found between the natural logarithm of K_p and the inverse of bilayer free surface area (1/a_free) where a_free is a parameter reflecting chain ordering that depends on bilayer composition and temperature.

Conclusions

Models of the pH dependence of partitioning of ionizable compounds must include contributions of both neutral and ionized species. Bilayer free surface area may be an important variable to predict K_p of drug molecules versus lipid composition and temperature.

     

A gamma scintigraphy study to investigate uterine targeting efficiency of raloxifene-loaded liposomes administered intravaginally in New Zealand white female rabbits

Context: Raloxifene hydrochloride (RLH), a selective estrogen receptor modulator, shows antiproliferative and apoptotic effects on Leiomyoma. Its extensive first pass metabolism leads to oral bioavailability of 2%.

Objective: The aim of this investigation was to formulate RLH-loaded liposomes and study its uterine-targeting efficiency after intravaginal administration.

Materials and methods: Liposomes were prepared by thin film hydration method using 1:1 molar ratio of DSPC:Cholesterol and characterized for vesicle size, zeta potential, %entrapment efficiency, loading, drug release and transmission electron microscopy. Radiolabeling of RLH was performed with reduced technetium-99m (^99mTc). Binding affinity of ^99mTc-labeled complexes was assessed by diethylene triamine penta acetic acid (DTPA) challenge test. Biodistribution study was done in New Zealand white female rabbits by administering the formulation intravaginally.

Results and discussion: Spherical and discrete liposomes of size 119?nm were seen in TEM results. Liposomes had high entrapment efficiency of 90.96% with drug loading of 27.25%w/w. Liposomes were able to sustain the drug release for 6 days. ^99mTc-labeled complexes showed high labeling efficiency and stability both in saline and serum. DTPA challenge test confirmed low transchelation of ^99mTc-labeled complexes. Biodistribution study by gamma scintigraphy revealed the preferential uptake of the formulation by uterus when administered vaginally. Compared to plain drug, liposomes were concentrated and retained within the uterus for a longer period of time.

Conclusion: Uterine targeting of RLH-loaded liposomes indicates its potential to overcome the limitations of marketed formulation. Drug targeting to site of action anticipates dose reduction needed to elicit the therapeutic effect.     

Exploring the potential of minoxidil tretinoin liposomal based hydrogel for topical delivery in the treatment of androgenic alopecia

Abstract

Purpose: Androgenic alopecia (AGA) is a condition of progressive hair loss and involves follicular miniaturization triggered mainly due to varying levels of androgen besides environmental and genetic factors, which may also play some role. Minoxidil (MXD) has been considered as most effective therapeutic moiety to treat this disorder. Another drug Tretinoin (TRET) is known for its comedolytic activity and is reported to enhance percutaneous absorption of MXD. Presently both these drugs are being utilized for treatment of androgenic alopecia (AGA) in solution form which poses several problems in terms of poor solubility of drug, frequency of application and side effects.

Materials and methods: Current work investigates liposomal hydrogel system for simultaneous delivery of MXD and TRET to overcome the limitations of existing formulation. Successful development of liposomes was commenced by thin film hydration method and various parameters affecting desired characteristics like size, morphology, entrapment efficiency; stability and ex vivo permeation were optimized. The formulated liposomes were further characterized for various physicochemical properties and evaluated for in vivo irritancy study in animals.

Results and discussion: Results suggested prepared liposomes to be stable, homogenous and capable to hold both the drugs within. Association with hydrogel enhanced the permeation of MXD through skin ex vivo but TRET retained on the skin. Liposome loaded hydrogel was found to be non-irritant to skin.

Conclusion: Overall developed system showed potential for effective and simultaneous delivery of both the drugs.     

Targeting Efficiency of Galactosylated Liposomes to Hepatocytes in Vivo: Effect of Lipid Composition

Purpose. To investigate the effects of the lipid composition of galactosylated liposomes on their targeted delivery to hepatocytes. Methods. Several types of liposomes with a particle size of about 90 nm were prepared using distearoyl-L-phosphatidylcholine (DSPC), cholesterol (Chol) and cholesten-5-yloxy-N-(4-((1-imino-2-D-thiogalactosylethyl)amino)butyl)formamide (Gal-C4-Chol), and labeled with [³H]cholesterol hexadecyl ether. Their tissue disposition was investigated in mice following intravenous injection. The binding and internalization characteristics were also studied in HepG2 cells. Results. Compared with [³H]DSPC/Chol (60:40) liposomes, [³H]D-SPC/Chol/Gal-C4-Chol (60:35:5) liposomes exhibit extensive hepatic uptake. Separation of the liver cells showed that galactosylated liposomes are preferentially taken up by hepatocytes, whereas those lacking Gal-C4-Chol distribute equally to hepatocytes and nonparenchymal cells (NPC). Increasing the molar ratio of DSPC to 90% resulted in enhanced NPC uptake of both liposomes, suggesting their uptake via a mechanism other than asialoglycoprotein receptors. DSPC/Chol/Gal-C4-Chol (60:35:5) and DSPC/Chol/Gal-C4-Chol (90:5:5) liposomes exhibited similar binding to the surface of HepG2 cells, but the former were taken up faster by the cells. Conclusions. The recognition of galactosylated liposomes by the asialoglycoprotein receptors is dependent on the lipid composition. Cholesterol-rich galactosylated liposomes, exhibiting less non-specific interaction and greater receptor-mediated uptake, are better for targeting drugs to hepatocytes in vivo.     

Determination of the Thickness of the Fixed Aqueous Layer Around Polyethyleneglycol-coated Liposomes

Abstract

The zeta potentials of adriamycin-encapsulating liposomes containing 1-(monomethoxy polyethyl-eneglycol)-2,3-dimyristoylglycerol (PEG-DMG) were measured in an isotonic solution of 10mM lactate buffer (pH 4.0) with sodium chloride and sucrose. The negativity of the zeta potentials of adriamycin-encapsulating liposomes containing PEG-DMG decreased with increases in NaCl concentration more steeply than that of adriamycin-encapsulating liposomes without PEG coating. From this observation, the electrical potential distributions near the membrane surfaces were shown to be different between adriamycin-encapsulating liposomes with and without PEG coating. Based on these zeta potential data, the thickness of the fixed aqueous layer around PEG-DMG-containing adriamycin liposomes was determined from the slope of In zeta potential versus Debye-Hiickel parameter plot. As a result, a correlation was indicated to exist between the circulation time of liposomes and the thickness of the aqueous layer around the liposomes.     

New delivery systems to improve the bioavailability of resveratrol

Introduction: Resveratrol (RSV) has been one of the most extensively studied polyphenols in the last 10 years, owing to its numerous and potent therapeutic activities, namely its high antioxidant properties. However, RSV's bioavailability is compromised by its physicochemical properties, such as low stability, increased oxidation on heat and light exposure, low water solubility and also its high hepatic uptake. Moreover, results obtained in human pharmacokinetic studies have shown a low amount of intact RSV in the systemic circulation, which does not justify its therapeutic activities, raising doubts about RSV's potential. RSV is already available as a nutritional supplement, although its translation to the clinic is not straightforward, owing to the lack of clinical data.

Areas covered: In this review, formulations that are being used for delivery of RSV are discussed. New delivery systems are presented as valid alternatives to circumvent the limitations of the physicochemical characteristics and pharmacokinetics of RSV. In this way, they are compared with classical formulations with regard to improving RSV protection and bioavailability.

Expert opinion: Despite promising results in preclinical settings, the applicability of RSV to humans has met with only limited success, largely owing to its inefficient systemic delivery and consequently its low bioavailability. To achieve an optimal response of RSV, new strategies are still required to enhance its bioavailability and reduce its perceived toxicity.     

Development and optimization of curcumin-loaded mannosylated chitosan nanoparticles using response surface methodology in the treatment of visceral leishmaniasis

Objective: The study aims at formulation and optimization of macrophage-targeted curcumin-loaded mannosylated chitosan nanoparticles (Cur-MCNPs) of curcumin (CUR) to improve its therapeutic potential in the treatment of visceral leishmaniasis (VL).

Methods: Response surface methodology (RSM) using central composite design was employed to study the effect of formulation factors on physicochemical-dependent characteristics. Chitosan was coupled with d-mannose, by reductive amination, to prepare a mannosylated chitosan, a conjugate polymer and a subsequent formulation of Cur-MCNPs. Optimized formulation prepared using RSM was evaluated for in vitro release kinetics at physiological pH 7.4 and endosomal macrophage pH 4.5; in vivo pharmacokinetic profile and targeting potential were evaluated by fluorescence microscopy.

Results: Optimized Cur-MCNPs exhibited spherical and smooth surface with a mean particle size of 215 nm, polydispersity index of 0.381, zeta potential of + 24.37 mV and % entrapment efficiency of 82.12%. The pharmacokinetic study of optimized Cur-MCNPs showed significant improvement in the value of mean resident time (39.38 h) compared to free CUR solution (0.30 h) (p < 0.05). In vivo uptake study indicated that endocytosis took place effectively within the macrophages of reticuloendothelial system.

Conclusions: Thus, Cur-MCNPs could be considered as a promising delivery strategy towards active targeting of CUR to macrophages for the effective treatment of VL.     

Enhancement of the antibacterial activity of ampicillin by liposome encapsulation

Abstract

This study showed that encapsulation of ampicillin (Amp) in liposomes prepared with synthetic lecithins enhanced its antibiotic activity against both Amp-sensitive and Amp-resistant Escherichia coli. This was demonstrated by growth inhibition of E. coli in the presence of the liposomal preparations containing Amp. Growth inhibition was also seen in the presence of exogenous β-lactamase. Adsorption of Amp onto the surface of the liposomes did not result in enhanced activity of the drug against E. coli. The encapsulation efficiency of Amp in liposomes prepared by the Bangham method (BM) was greatly affected by the phospholipids used. The efficiency increased with a rise in the phase transition temperature (T_c) of the phospholipid, the maximum encapsulation of Amp being obtained with distearoylphosphatidylcholine (DSPC). The entrapment efficiency of Amp with the reverse phase evaporation method (REV) was largely superior to that with the BM method. Kinetic studies using DSPC liposomes prepared by the REV and BM protocols demonstrated that Amp-loaded liposomes contained 60 and 72% of drug, respectively, after 24 h at 37°C.     

Adsorption of chitin derivatives onto liposomes: Optimization of adsorption conditions

Abstract

A 2′ factorial design is used to optimize the adsorption conditions of the hydrophilic anionic polyelectrolytes, Carboxymethylchitin (CMC) and Carboxymethyl/Glycolchitin (CO) onto liposomes at physiological ionic strength (I) and pH using phosphate buffered saline (PBS, I= 154mM, pH = 7.4). Positive ([+]) or high surface affinity liposomes (DSPC:CHOL:DMTAP, 5:4:1), and Neutral ([N]) or low surface affinity liposomes (DSPC:CHOL, 1:1) were used as adsorption surfaces. Results of the calculations of the main effects indicate that polymer molecular weight (mwt), Surface Affinity (S), Number of Adsorption Shots (Sh), Temperature (T), and the combinations mwt ×S, mwt ×Sh are the most important process parameters. Results of a study conducted at T = 37 °C show that no loss occurs from the positive surface at the highest particle concentratiqn, N_p = 4.043 × 10¹¹. Finally, the extent of polymer-induced particle aggregation PTIS decreased when the diameter of the uncoated liposomes is doubled from 0.22 to 0.45m. These results are as expected, given the stiffness and the dimensions of the macromolecules.     

Enhanced Tumor Targeting of Doxorubicin by Ganglioside GMl-bearing Long-circulating Liposomes

Abstract

Doxorubicin (DXR) was encapsulated in long-circulating liposomes, composed of ganglioside GM1 (GM1)/distearoylphosphatidylcholine (DSPC)/cholesterol (CH) (0.13:1:1 in molar ratio) and sized to approximately 100 nm in mean diameter, with 98% entrapping efficiency by the transmembrane pH gradient method. Free DXR, DXR-DSPC/CH and DXR-GM1/DSPC/CH liposomes were injected intravenously into Colon 26 tumor-bearing Balb/c mice via the tail vein at a dose of 5.0 mg DXR/kg. DXR-GM1/DSPC/CH liposomes gave a higher blood level of the drug than did DXR-DSPC/CH liposomes or free DXR up to 24 hours after injection, and the area under the blood concentration-time curve (AUC) for DXR-GM1/DSPC/CH liposomes was 1.5 or 526 times higher than that for DXR-DSPC/CH liposomes or free DXR, respectively. DXR-GM1/DSPC/CH liposomes gave a decreased DXR concentration in the reticuloendothelial system (RES) of the liver and the spleen. Both liposomal formulations effectively reduced the DXR concentration in the heart as compared with that in the case of free DXR. At 6 hours after i.v. injection, DXR-GM1/DSPC/CH liposomes provided an approximately 3.3- or 9-fold higher peak DXR level in the tumor as compared with DXR-DSPC/CH liposomes or the free drug, respectively. These high tumor levels of DXR appear to reflect the prolonged residence time of the liposomes. The results suggest that encapsulation of DXR in GM1-bearing long-circulating liposomes will be useful for cancer chemotherapy.     

Formulation,characterization, in vitro and in vivo evaluation of castor oil based self-nano emulsifying levosulpiride delivery systems

Context: Levosulpiride (LSP) is a hydrophobic benzamide derivative used in the treatment of schizophrenia. SNEDDS were extensively practiced for systemic delivery of poorly aqueous soluble drugs to achieve maximum bioavailability.

Objective: The present study was focussed on the formulation, optimisation and evaluation of LSP SNEDDS using castor oil, for enhancement of drug absorption and bioavailability.

Materials and methods: Pseudo-ternary phase diagram was plotted to identify the range of SNEDDS components. Twenty formulations were designed, prepared and characterised by its particle size, zeta potential, viscosity, and stability. In vitro dissolution data modelling was performed. Microscopy, FTIR and in vivo bioavailability studies were conducted for optimum formulation.

Results, discussion and conclusion: F18 containing castor oil, 0.9?mL; PEG 600, 1.36?mL and Tween 80, 2.74?mL was found to be optimum. The optimised formulation had shown uniform globule size, no interactions of LSP with SNEDDS components and higher pharmacokinetic parameters than that of commercial preparation.     

The effect of PEG coating on in vitro cytotoxicity and in vivo disposition of topotecan loaded liposomes in rats

Amphoteric drugs encapsulated in PEGylated liposomes may not show superior therapeutic antitumor activity due to increased leakage rate of these drugs in presence of PEG-lipids. In order to investigate the effect of PEG coating on in vitro and in vivo characteristics of topotecan loaded liposomes, an amphoteric anticancer drug, PEGylated and conventional liposomes were prepared by lipid film hydration method. Various properties of the prepared nanoliposomes such as encapsulation efficiency, size, zeta potential, physical stability as well as the chemical stability of lactone form of topotecan, cytotoxicity and topotecan pharmacokinetics were evaluated. In vitro cytotoxic activity was evaluated on murine Lewis lung carcinoma (LLC) and human mammary adenocarcinoma (BT20) cells. Pharmacokinetic was evaluated in Wistar rats after i.v. injection of topotecan, formulated in PBS pH 7.4 or in conventional or in PEGylated liposomes. The conventional liposome (CL) formulation was composed of DSPC/cholesterol/DSPG (molar ratio; 7:7:3), while for PEGylated liposome the composition was DSPC/cholesterol/DSPG/DSPE-PEG(2000) (molar ratio; 7:7:3:1.28). The size of both liposomes was around 100 nm with polydispersity index of about 0.1. In comparison with free drug, liposomal topotecan showed more stability for topotecan lactone form in vitro. Compared to free topotecan, PEGylated and conventional liposomes improved cytotoxic effect of topotecan against the two cancer cell line studied. The results of pharmacokinetic studies in rats showed that both CL and PEGylated liposomal formulations increased the concentration of total topotecan in plasma, however, initial concentration and the values of AUC, MRT and t(1/2 beta) were much higher (P<0.001) for PEGylated liposomal drug than for conventional one or free drug. PEGylated liposome resulted in a 52-fold and 2-fold increases in AUC(0-infinity) compared with that of free topotecan and CL, respectively. These results indicated that PEG modified liposome might be an effective carrier for topotecan.     

羟基喜树碱脂质体的制备及质量评价研究

目的:制备羟基喜树碱(HCPT)脂质体,并对其质量进行评价.方法:采用薄膜分散-高压乳匀法制备羟基喜树碱脂质体;用激光粒度分析仪测定其Zeta电位、粒径大小;考察其在0.9%NaCl溶液、水、5%葡萄糖溶液中8 h的稳定性;用凝胶柱层析法考察包封率;采用薄膜透析法考察体外释药性质.结果:羟基喜树碱脂质体Zeta电位为(-33.1±1.3) mV,平均粒径(182.5±5.6) nm,8 h内在水、5%葡萄糖溶液中稳定性良好;包封率(91.2±1.2)%;体外释药曲线符合Higuchi方程Q=1.291 6t1/2 0.309 8,r=0.980 3.结论:本试验制备的羟基喜树碱脂质体稳定性好,大小均匀, 包封率高,并具有延缓药物释放的性质.     

Improvements of cellular stress response on resveratrol in liposomes

Resveratrol (RSV) has proven potential in prophylaxis and treatment of various disorders mediated by free radicals and oxidative stress. RSV solubility, stability, and cytotoxicity must be regulated for satisfactory bioavailability. Here, RSV was loaded into liposomes, characterized by PCS and TEM and evaluated on HEK293 cell line by metabolic activity assay, electron paramagnetic resonance, and fluorescence microscopy.RSV at 10 μM induced changes in cell metabolic activity and significantly improved antioxidative capacity. At 100 μM it showed concentration-dependent cytotoxicity. Oligolamellar liposomes with mean diameter 84 nm, polydispersity index 0.2, and zeta potential −40 mV showed high entrapment of RSV and rapid cellular internalization. Cell stress caused by UV-B irradiation diminished cell metabolic activity by 50%. RSV loaded into them showed no cytotoxicity at 100 μM and stimulated cellular metabolic and antioxidant activity levels to eliminate the harmful effect of the stress. Localization of RSV within liposomal bilayer is crucial for stimulation of cell-defense system, prevention of RSV cytotoxicity, and its long-term stability. In summary, evidence of different metabolic activity using free RSV and LIP–RSV is presented indicating that liposome-mediated uptake of RSV is more effective for improvement of the cell-stress response.     

Intraocular distribution of topically applied hydrophilic and lipophilic substances in rat eyes

Purpose: Topical administration is the preferred route of drug delivery for ophthalmic ailments. However, poor permeation through ocular surface and significant systemic absorption, makes the topical drug delivery challenging. Furthermore, distribution of topically delivered drugs varies with their physicochemical properties and the type of formulation used. Hence, this study was done to understand the pattern of ocular drug distribution of topically applied hydrophilic and lipophilic substances in two different formulations.

Methods: 5-Carboxyfluorescein and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate were used as representative candidates for hydrophilic and lipophilic substances, respectively. They were formulated in solution and liposomes. Single drop of either formulation containing hydrophilic or lipophilic substance was instilled topically, unilaterally to rat eyes. Subsequently, rats were sacrificed at 10, 30 and 120?min post-instillation. Eyes were cryosectioned and examined under confocal microscope to determine the fluorescence intensity in ocular tissues.

Results: Corneal permeation of hydrophilic and lipophilic substances in both formulations peaked at 30?min post-instillation. Liposomal–lipophilic dye and non-liposomal–hydrophilic dye showed better corneal distribution. Fluorescence was absent in contralateral eyes of non-liposomal–hydrophilic dye-treated animals but was present in contralateral eyes of liposomal–hydrophilic dye-treated animals. Fluorescence in contralateral eyes of liposomal–lipophilic dye-treated animals was significantly higher compared to non-liposomal–lipophilic dye-treated animals.

Conclusions: Topically applied liposomal formulation of lipophilic substance provides higher corneal concentration of drug with lesser systemic absorption compared to its solution. For hydrophilic substance, topical use of solution provides greater corneal concentration compared to liposomes which is more likely to be absorbed systemically.     

Bioavailability enhancement of ondansetron after nasal administration of Caesalpinia pulcherrima-based microspheres

Abstract

Context: Natural polymers have attracted a great deal of attention for use as potential carriers in site-specific delivery over past decades. Mucoadhesive microspheres are useful tools for nasal drug delivery.

Objectives: To prepare and evaluate mucoadhesive microspheres as mode for nasal delivery of ondansetron using Caesalpinia pulcherrima galactomannan (CPG).

Materials and methods: Conventional spray-dried CPG nasal microspheres loaded with ondansetron for intranasal drug delivery in order to avoid the first pass metabolism with improved therapeutic efficiency in treatment of nausea and vomiting as an alternative therapy to parenterals. Developed microspheres were evaluated for characteristics like particle size, entrapment efficiency, zeta potential, swelling ability, in-vitro mucoadhesion, in-vitro drug release, DSC, XRD study and histopathological evaluation of tissue. CPG-based ondansetron microspheres were studied in rabbits for screening nasal absorption potential of nasal formulation.

Results: Developed nasal microspheres possess entrapment efficiency of 80–89%, higher mucoadhesion of 72–84% across goat nasal mucosa. In-vivo study showed that microspheres based on mucoadhesive polymer were able to promote quick drug absorption as well as enhanced bioavailability of drug.

Discussion: Histopathological studies evaluated biocompatible and nontoxic nature of CPG in nasal cavity. Developed mucoadhesive microspheres by nasal route showed enhancement of bioavailability as compared to oral route in rabbits.

Conclusion: CPG-based mucoadhesive microspheres can successfully deliver ondansetron intranasally, sustain its effect, avoid first pass effect, an alternative route of administration to injection and thus enhance systemic bioavailability of ondansetron hydrochloride.     

Development and evaluation of carboplatin-loaded PCL nanoparticles for intranasal delivery

Context: The study was aimed to develop a polymeric nanoparticle formulation of anticancer drug carboplatin using biodegradable polymer polycaprolactone (PCL). The formulation is intended for intranasal administration to treat glioma anticipating improved brain delivery as nasal route possess direct access to brain and nanoparticles have small size to overcome the mucosal and blood–brain barrier.

Objective: Development and evaluation of carboplatin-PCL nanoparticles for brain delivery by nasal route.

Methodology: Carboplatin-loaded PCL nanoparticles (CPCs) were prepared by double emulsion-solvent evaporation technique and characterized by particle size, zeta potential, entrapment efficiency, scanning electron microscopy and differential scanning calorimetry. The CPCs were assessed for in vitro release kinetics, ex vivo permeation and in situ nasal perfusion. Cytotoxic potential of CPCs in vitro was evaluated on LN229 human glioblastoma cells.

Results and discussion: The optimized formulation of carboplatin-PCL nanoparticle CPC-08 with particle size of 311.6?±?4.7?nm and zeta potential ?16.3?±?3.7?mV exhibited percentage entrapment efficiency of 27.95?±?4.21. In vitro drug release showed initial burst release followed by slow and continues release indicating biphasic pattern. The ex vivo permeation pattern through sheep nasal mucosa also exhibited a similar release pattern as for in vitro release studies. In situ nasal perfusion studies in Wistar rats demonstrate that CPCs show better nasal absorption than carboplatin solution. In vitro cytotoxicity studies on LN229 cells showed an enhancement in cytotoxicity by CPCs compared to carboplatin alone.

Conclusion: CPC-08 effectively improves nasal absorption of carboplatin and can be used for intranasal administration of carboplatin for improved brain delivery.     

In vitro evaluation and biodistribution of HER2-targeted liposomes loaded with an 125I-labelled DNA-intercalator

Background: Increasing attention is currently focussed on the issue of finding strategies for the delivery of Auger-electron-emitting radionuclides into tumor cell nuclei.

Purpose: In this study, we investigated tumor-cell uptake and cell-killing ability in vitro as well as in vivo biodistribution of an ¹²⁵I-labelled anthracycline derivative administered by means of HER2-targeted liposomes.

Methods: Anthracycline derivative Comp1 was radiolabelled with Auger-emitting ¹²⁵I and encapsulated in liposomes (DSPC:Chol:DSPE-PEG) using pH-gradient loading. Single-chain fragment F5 was anchored to the liposomes as targeting device for HER2. Uptake and specificity of ¹²⁵I-Comp1 delivered via targeting and non-targeting liposomes were analysed in cultured HER2-overexpressing cells. Cell-killing efficacy was evaluated in SKOV3 cells and biodistribution for up to 48?h was studied after intraperitoneal injection in tumor-bearing female BALB/c nu/nu mice.

Results: ¹²⁵I-Comp1 was specifically taken up by the cultured cells when administered by means of HER2-targeted liposomes and a clear dose-effect correlation in survival of cells was seen with increasing specific activity. The biodistribution studies revealed that ¹²⁵I-Comp1 accumulated in tumors when distributed using HER2-targeted liposomes and that this effect was absent when using non-targeting liposomes.

Conclusion: The HER2-targeted liposomes possess the properties needed to bring about tumor-specific delivery and therapeutic effect of ¹²⁵I-Comp1.     

Human Pancreatic Polypeptide in a Phospholipid-Based Micellar Formulation

Purpose

Pancreatic polypeptide (PP) has important glucoregulatory functions and thereby holds significance in the treatment of diabetes and obesity. However, short plasma half-life and aggregation propensity of PP in aqueous solution, limits its therapeutic application. To address these issues, we prepared and characterized a formulation of PP in sterically stabilized micelles (SSM) that protects and stabilizes PP in its active conformation.

Methods

PP-SSM was prepared by incubating PP with SSM dispersion in buffer. Peptide-micelle association and freeze-drying efficacy of the formulation was characterized in phosphate buffers with or without sodium chloride using dynamic light scattering, fluorescence spectroscopy and circular dichroism. The degradation kinetics of PP-SSM in presence of proteolytic enzyme was determined using HPLC and bioactivity of the formulation was evaluated by in vitro cAMP inhibition study.

Results

PP self-associated with SSM and this interaction was influenced by presence/absence of sodium chloride in the buffer. The formulation was effectively lyophilized, demonstrating feasibility for its long-term storage. The stability of peptide against proteolytic degradation was significantly improved and PP in SSM retained its bioactivity in vitro.

Conclusions

Self-association of PP with phospholipid micelles addressed the delivery issues of the peptide. This nanomedicine should be further developed for the treatment of diabetes.