Cellulose ether and carbopol 971 based gastroretentive controlled release formulation design, optimization and physiologically based pharmacokinetic modeling of ondansetron hydrochloride minitablets.

This study aims to design and optimize ondansetron (OND) gastro-retentive floating minitablets for better and prolonged control of postoperative nausea and vomiting (PONV) with improved patient compliance. Minitablets were directly compressed and encapsulated in a size 2 capsule shell with an overall dose of 24 mg. Central composite design (CCD) was applied keeping one cellulose ether derivative HPMC K15M and Carbopol 971 as variable and used as swelling and rate retarding agents. The other cellulose derivative i.e. sodium carboxymethyl cellulose, along with mannitol, sodium bicarbonate, and talc, were used in fixed quantities. The floating lag time, total floating time, swelling index, in-vitro drug release, and zero-order (RSQ value), were critical quality parameters. The optimized formulation (Fpred) was evaluated for all critical parameters, along with surface morphology, thermal stability, chemical interaction, and accelerated stability. The in silico PBPK modeling was applied to compare the bioavailability of Fpred with reference OND immediate-release tablets. The numerical optimization model predicted >90 % drug release with zero-order at 12 h. In silico PBPK modeling revealed comparable relative bioavailability of Fpred with the reference formulation. The gastroretentive floating minitablets of OND were successfully designed for prolonged emesis control in patients receiving chemotherapeutic agents.

Evaluation of the effect of carrier material on modification of release characteristics of poor water soluble drug from liquisolid compacts.

Liquisolid compact is a novel dosage form in which a liquid medication (liquid drug, drug solution/dispersion in non-volatile solvent/solvent system) is converted to a dry, free flowing powder and compressed. Objective of the study was to elucidate the effect of carrier material on release characteristics of clopidogrel from liquisolid compacts. Different formulations of liquisolid compacts were developed using microcrystalline cellulose, starch maize, polyvinyl pyrollidone and hydroxypropyl methylcellulose as carrier material in three concentrations (40, 30 and 20%, w/w). Liquid vehicle was selected on the basis of solubility of clopidogrel. Colloidal silicondioxide was used as coating material and ratio of carrier to coating material was kept 10. A control formulation comprised of microcrystalline cellulose (diluents), tabletose-80 (diluents), primojel (disintegrant) and magnesium stearate (lubricant) was prepared by direct compression technique and was used for comparison. All the formulations were evaluated at pre and post compression level. Acid solubility profile showed higher solubility in HCl buffer pH2 (296.89±3.49 µg/mL). Mixture of propylene glycol and water (2:1, v/v) was selected as liquid vehicle. Drug content was in the range of 99-101% of the claimed quantity. All the formulations showed better mechanical strength and their friability was within the official limits (<1%). Microcrystalline cellulose and starch maize resulted in faster drug release while polyvinyl pyrollidone and HPMC resulted in sustaining drug release by gel formation. It is concluded from results that both fast release and sustained release of clopidogrel can be achieved by proper selection of carrier material.

Exploring Charged Polymeric Cyclodextrins for Biomedical Applications.

Over the years, cyclodextrin uses have been widely reviewed and their proprieties provide a very attractive approach in different biomedical applications. Cyclodextrins, due to their characteristics, are used to transport drugs and have also been studied as molecular chaperones with potential application in protein misfolding diseases. In this study, we designed cyclodextrin polymers containing different contents of ß- or γ-cyclodextrin, and a different number of guanidinium positive charges. This allowed exploration of the influence of the charge in delivering a drug and the effect in the protein anti-aggregant ability. The polymers inhibit Amiloid ß peptide aggregation; such an ability is modulated by both the type of CyD cavity and the number of charges. We also explored the effect of the new polymers as drug carriers. We tested the Doxorubicin toxicity in different cell lines, A2780, A549, MDA-MB-231 in the presence of the polymers. Data show that the polymers based on γ-cyclodextrin modified the cytotoxicity of doxorubicin in the A2780 cell line.

Bacterial nanocellulose as novel carrier for intestinal epithelial cells in drug delivery studies.

Synthetic cell carriers (A) represent common scaffold structures for the development of cell-based in vitro models of the human intestine but due to their low porosity or unwanted molecular adhesion effects, synthetic carriers can negatively affect cell function. Alternative scaffolds such as natural extracellular matrices (ECMs) (B) were shown to overcome some of the common drawbacks. However, their fabrication is time-consuming, less well standardized and not entirely conform to the 3R principle (replacement, reduction, refinement). Nowadays, biopolymers such as bacterial nanocellulose (BNC) (C) represent interesting scaffold materials for innovative tissue engineering concepts, as they can be generated in a faster and more standardized process workflow without the need for animal material. In this study, we demonstrate the BNC as suitable carrier for the development of Caco-2-based in vitro models of the human intestine. The BNC-based models exhibit organ-specific properties comprising typical cellular morphologies, characteristic protein expression profiles, representative ultrastructural features and the formation of a tight epithelial barrier. The proof of in vivo-like transport activities further validates the high quality of the BNC-based Caco-2 models. In summary, this illustrates the BNC as alternative bioscaffold of non-animal origin to develop functional organ models in vitro.

Pickering stabilized nanocellulose-alginate: A diosgenin-mediated delivery of quinalizarin as a potent cyto-inhibitor in human lung/breast cancer cell lines.

The current study explores the facile fabrication of multilayer self-assembled electrostatic oil-in-water Pickering emulsions (PEs) using quaternized nanocellulose (Q-NC) and diosgenin-conjugate alginate (DGN-ALG) particles as stabilizers to form hydrocolloid nanocarriers. The conditions of formulation such as storage time, pH, temperature and salt effect on the emulsion stability were evaluated. The results deduced showed good emulsion droplet stability over a period of 30 days. Morphological analysis revealed the hydrodynamic sizes of the PE droplets to be spherically shaped with an average diameter of 150 ± 3.51 nm. Creaming index, wettability and critical aggregation concentrations (CAC) as well as chemical characterization of the PEs were examined. In vitro release kinetics of encapsulated quinalizarin as a model drug was investigated with a determined cumulative drug release (CDR) of 89 ± 1.21% in simulated pH blood medium of pH 7.4. In addition, cellular internalization of the PEs was studied via confocal microscopy imaging and showed high cellular uptake. Also, evaluated in vitro cytotoxicity by MTT assay demonstrated excellent anticancer activity in human lung (A549) and breast (MCF-7) cancer cell lines.

Water-dispersible, biocompatible and fluorescent poly(ethylene glycol)-grafted cellulose nanocrystals.

Fluorescent nanoprobe with good water dispersibility was synthesized by the coupling of fluorescent 1,8-naphthalimide dye (NANI) as well as biocompatible poly (ethylene glycol) (PEG) to cellulose nanocrystals (CNC). FTIR, TGA and XPS analysis confirmed the successful covalent conjugation of NANI and PEG. The rod-like morphology of CNC was generally retained after two-step successive grafting of NANI and PEG. The contact angle and transmittance measurements showed that the grafted PEG brushes improve the hydrophilicity of fluorescent CNC probes and their dispersibility in high-concentration NaCl solutions. The fluorescent CNC probe had good biocompatibility and was successfully used for the bioimaging of Hela cells in physiological environment at high salt concentration. Laser confocal microscopy showed that the fluorescent CNC probe can penetrate the cell membrane and disperse uniformly in the cell with good biocompatibility. The fluorescent CNC probe with nanometer size, strong fluorescence emission and high salt-tolerance possess potential application in biomedical field.

Multimodality labeling strategies for the investigation of nanocrystalline cellulose biodistribution in a mouse model of breast cancer.

METHODS: We have developed a nuclear and fluorescence labeling strategy for nanocrystalline cellulose (CNC), an emerging biomaterial with versatile chemistry and facile preparation from renewable sources. We modified CNC through 1,1'-carbonyldiimidazole (CDI) activation with radiometal chelators desferrioxamine B and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), allowing for the labeling with zirconium-89 (t½â€¯= 78.41 h) and copper-64 (t½â€¯= 12.70 h), respectively, for non-invasive positron emission tomography (PET) imaging. The far-red fluorescent dye Cy5 was added for ex vivo optical imaging, microscopy and flow cytometry. The multimodal CNC were evaluated in the syngeneic orthotopic 4T1 tumor model of human stage IV breast cancer. RESULTS: Modified CNC exhibited low cytotoxicity in RAW 264.7 macrophages over 96 h, and high radiolabel stability in vitro. After systemic administration, radiolabeled CNC were rapidly sequestered to the organs of the reticulo-endothelial system (RES), indicating immune recognition and no passive tumor targeting by the enhanced permeability and retention (EPR) effect. Modification with NOTA was a more favorable strategy in terms of radiolabeling yield, specific radioactivity, and both the radiolabel and dispersion stability in physiological conditions. Flow cytometry analysis of Cy5-positive immune cells from the spleen and tumor corroborated the uptake of CNC to phagocytic cells. CONCLUSIONS: Future studies on the in vivo behavior of CNC should be concentrated on improving the nanomaterial stability and circulation half-life under physiological conditions and optimizing further the labeling yields for the multimodality imaging strategy presented. ADVANCES IN KNOWLEDGE: Our studies constitute one of the first accounts of a multimodality nuclear and fluorescent probe for the evaluation of CNC biodistribution in vivo and outline the pitfalls in radiometal labeling strategies for future evaluation of targeted CNC-based drug delivery systems. IMPLICATIONS FOR PATIENT CARE: Quantitative and sensitive molecular imaging methods provide information on the structure-activity relationships of the nanomaterial and guide the translation from in vitro models to clinically relevant animal models.

Systematic in vitro biocompatibility studies of multimodal cellulose nanocrystal and lignin nanoparticles.

Natural biopolymer nanoparticles (NPs), including nanocrystalline cellulose (CNC) and lignin, have shown potential as scaffolds for targeted drug delivery systems due to their wide availability, cost-efficient preparation, and anticipated biocompatibility. As both CNC and lignin can potentially cause complications in cell viability assays because of their ability to scatter the emitted light and absorb the assay reagents, we investigated the response of bioluminescent (CellTiter-Glo®), colorimetric (MTT® and AlamarBlue®), and fluorometric (LIVE/DEAD®) assays for the determination of the biocompatibility of the multimodal CNC and lignin constructs in murine RAW 264.7 macrophages and 4T1 breast adenocarcinoma cell lines. Here, we have developed multimodal CNC and lignin NPs harboring the radiometal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid and the fluorescent dye cyanine 5 for the investigation of nanomaterial biodistribution in vivo with nuclear and optical imaging, which were then used as the model CNC and lignin nanosystems in the cell viability assay comparison. CellTiter-Glo® based on the detection of ATP-dependent luminescence in viable cells revealed to be the best assay for both nanoconstructs for its robust linear response to increasing NP concentration and lack of interference from either of the NP types. Both multimodal CNC and lignin NPs displayed low cytotoxicity and favorable interactions with the cell lines, suggesting that they are good candidates for nanosystem development for targeted drug delivery in breast cancer and for theranostic applications. Our results provide useful guidance for cell viability assay compatibility for CNC and lignin NPs and facilitate the future translation of the materials for in vivo applications.

The role of viscosity on skin penetration from cellulose ether-based hydrogels.

BACKGROUND: The rheological properties of dermal drug delivery systems are of importance when designing new formulations. Viscosity not only affects features such as spreadability and skin feel, but may also affect the skin penetration of incorporated actives. Data on the latter aspect are controversial. Our objective was to elucidate the relation between viscosity and drug delivery performance of different model hydrogels assuming that enhanced microviscosity might delay drug release and penetration. MATERIALS AND METHODS: Hydrogels covering a broad viscosity range were prepared by adding either HPMC or HEC as gelling agents in different concentrations. To investigate the ability of the gels to deliver a model drug into the skin, sulphadiazine sodium was incorporated and its in vitro skin penetration was monitored using tape stripping/HPLC analysis and non-invasive confocal Raman spectroscopy. RESULTS: The trends observed with the two different experimental setups were comparable. Drug penetration depths decreased slightly with increasing viscosity, suggesting slower drug release due to the increasingly dense gel networks. However, the total penetrated drug amounts were independent of the exact formulation viscosity. CONCLUSION: Drug penetration was largely unaffected by hydrogel viscosity. Moderately enhanced viscosity is advisable when designing cellulose ether hydrogels to allow for convenient application.

Formulation of Ethyl Cellulose Microparticles Incorporated Pheophytin A Isolated from Suaeda vermiculata for Antioxidant and Cytotoxic Activities.

BACKGROUND: This study is designed to discover a method for delivering an efficient potent pheophytin a (pheo-a) into more absorbed and small polymeric ethyl cellulose (EC) microparticles. METHODS: Silica gel and Sephadex LH-20 columns were used to isolate pheo-a from the chloroform extract of the edible plant, Suaeda vermiculata. Pheo-a was incorporated into EC microparticles using emulsion-solvent techniques. The antioxidant activity of pheo-a microparticles was confirmed by the level of superoxide radical (SOD), nitric oxide (NO), and reducing power (RP) methods. Meanwhile, the cytotoxic effect of the product was investigated on MCF-7 cells using MTT assay. RESULTS: Pheo-a was isolated from S. vermiculata in a 12% concentration of the total chloroform extract. The structures were confirmed by NMR and IR spectroscopic analysis. The formulated microparticles were uniform, completely dispersed in the aqueous media, compatible as ingredients, and had a mean diameter of 139 ± 1.56 µm as measured by a particle size analyzer. Pheo-a demonstrated a valuable antioxidant activity when compared with ascorbic acid. The IC50 values of pheo-a microparticles were 200.5 and 137.7 µg/mL for SOD, and NO respectively. The reducing power of pheo-a microparticles was more potent than ascorbic acid and had a 4.2 µg/mL for IC50 value. Pheo-a microparticles did not show notable cytotoxicity on the MCF-7 cell line (IC50 = 35.9 µg/mL) compared with doxorubicin (IC50 = 3.2 µg/mL). CONCLUSIONS: the results showed that water-soluble pheo-a microparticles were prepared with a valuable antioxidant activity in a wide range of concentrations with a noteworthy cytotoxic effect.

Preparation and Characterization of Cellulose Ether Liposomes for the Inhibition of Prion Formation in Prion-Infected Cells.

Prion accumulation in the brain and lymphoreticular system causes fatal neurodegenerative diseases. Our previous study revealed that cellulose ethers (CE) have anti-prion activities in vivo and in prion-infected cells when administered at high doses. This study aims to improve the bioavailability of a representative CE using a liposomal formulation and characterized CE-loaded liposomes in cultured cells. The liposomal formulation reduced the EC50 dose of CE by <1/200-fold in prion-infected cells. Compared to empty liposomes, CE-loaded liposomes were taken up much more highly by prion-infected cells and less by macrophage-like cells. Phosphatidylserine modification reduced the uptake of CE-loaded liposomes in prion-infected cells and did not change the anti-prion activity, whereas increased the uptake in macrophage-like cells. Polyethylene glycol modification reduced the uptake of CE-loaded liposomes in both types of cells and reduced the anti-prion activity in prion-infected cells. These results suggest that a liposomal formulation of CE is more practical than unformulated CE and showed that the CE-loaded liposome uptake levels in prion-infected cells were not associated with anti-prion activity. Although further improvement of the stealth function against phagocytic cells is needed, the liposomal formulation is useful to improve CE efficacy and elucidate the mechanism of CE action.

Selectively Oxidized Cellulose with Adjustable Molecular Weight for Controlled Release of Platinum Anticancer Drugs.

The synthesis of selectively oxidized cellulose, 2,3-dicarboxycellulose (DCC), is optimized for preparation of highly oxidized material for biological applications, which includes control over the molecular weight of the product during its synthesis. Conjugates of DCC and cisplatin simultaneously offer a very high drug binding efficiency (>90%) and drug loading capacity (up to 50 wt %), while retaining good aqueous solubility. The adjustable molecular weight of the DCC together with variances in drug feeding ratio allows to optimize cisplatin release profiles from delayed (<2% of cisplatin released during 6 h) to classical burst release with more than 60% of cisplatin released after 24 h. The release rates are also pH-dependent (up to 2 times faster release at pH 5.5 than at pH 7.4), which allows to exploit the acidic nature of tumor microenvironment. Extensive in vitro studies were performed on eight different cell lines for two cisplatin-DCC conjugates with different release profiles. In comparison with free cisplatin, both cisplatin-DCC conjugates demonstrated considerably lower cytotoxicity toward healthy cells. Conjugates with burst release profiles were found more effective against prostate cell lines, while DCC conjugates with slower release were more cytotoxic against ovarian and lung carcinoma cell lines. In vivo studies indicated a significantly longer survival rate, a reduction in tumor volume, and a higher accumulation of platinum in tumors of mice treated with the cisplatin-DCC conjugate in comparison to those treated by free cisplatin.

Magnetic cellulose nanocrystal stabilized Pickering emulsions for enhanced bioactive release and human colon cancer therapy.

Stimuli-responsive drug release and controlled delivery play crucial roles in enhancing the therapeutic efficacy and lowering over-dosage induced side effects. In this paper, we report magnetically-triggered drug release and in-vitro anti-colon cancer efficacy of Fe3O4@cellulose nanocrystal (MCNC)-stabilized Pickering emulsions containing curcumin (CUR). The loading efficiency of CUR in the micron-sized (≈7 µm) MCNC-stabilized Pickering emulsions (MCNC-PE) template was found to be 99.35%. The drug release profiles showed that the exposure of MCNC-PE to external magnetic field (EMF) (0.7 T) stimulated the release of bioactive from MCNC-PE achieving 53.30 ±â€¯5.08% of the initial loading over a 4-day period. The MTT assay demonstrated that the CUR-loaded MCNC-PE can effectively inhibits the human colon cancer cells growth down to 18% in the presence of EMF. The formulation also resulted in 2-fold reduction on the volume of the 3-D multicellular spheroids of HCT116 as compared to the control sample. The MCNC particle was found to be non-toxic to brine shrimp up to a concentration of 100 µg/mL. Our findings suggested that the palm-based MCNC-PE could be a promising yet effective colloidal drug delivery system for magnetic-triggered release of bioactive and therapeutics.

Pickering emulsions stabilized nanocellulosic-based nanoparticles for coumarin and curcumin nanoencapsulations: In vitro release, anticancer and antimicrobial activities.

Coumarin and curcumin have a wide spectrum of biological and pharmacological activities including antioxidant, anti-inflammatory, antimicrobial and anticancer but hindered therapeutic applications due to low stability and poor solubility in water. The main objective of the current study was to overcome these drawbacks via improved bioavailability by nanoencapsulated emulsions. Pickering emulsion (PE) via oil-in-water approach were stabilized by aminated nanocellulose (ANC) particles through application of a full factorial optimization design for nanoemulsions containing different composition of oil phase with medium chain triglyceride (MCT) and Tween 80. The fabricated nanoemulsions and PEs with average particle sizes (≤150 nm) were obtained. Influencing factors such as ANC concentration, storage time and pH on the stability of emulsions were examined alongside zeta potentials. Encapsulation efficiency (EE) of coumarin and curcumin were determined as >90%. Release kinetic profiles for encapsulated PEs displayed sustained release with supposed increase bioavailability. Higher release percent were detected for curcumin encapsulated PE in contrast to coumarin. In vitro cytotoxicity evaluation for coumarin and curcumin loaded PEs were further investigated for anticancer and antimicrobial activities using human cell lines (L929 and MCF-7) and different microorganisms (Gram (+), Gram (-) and fungi), respectively. The results clearly demonstrated PE coumarin and curcumin as promising candidates to inhibit microbial growth and to prevent preferential killing of cancer cells compared to normal cells.

Polyion complex hydrogels from chemically modified cellulose nanofibrils: Structure-function relationship and potential for controlled and pH-responsive release of doxorubicin.

Herein, we report the fabrication of a polyion complex hydrogel from two oppositely charged derivatives of cellulose nanofibrils (CNF). CNF was produced from dissolving pulp through subsequent periodate oxidation, chemical modification, and microfluidization. Three different durations for periodate oxidation (30 min, 120 min, and 180 min) resulted in three different aldehyde contents. Further, two types of chemical modifications were introduced to react with the resulting aldehydes: chlorite oxidation to yield anionic CNF with carboxylic acid groups (DCC) and imination with Girard's reagent T to yield cationic CNF containing quaternary ammonium groups (CDAC). Functional group contents were assessed using conductometric titration and elemental analysis, while nanofibril morphologies were assessed using atomic force microscopy (AFM). Longer durations of periodate oxidation did not yield different width profile but was found to decrease fibril length. The formation of self-standing hydrogel through mixing of DCC and CDAC dispersions was investigated. Oscillatory rheology was performed to assess the relative strengths of different gels. Self-standing hydrogels were obtained from mixture of DCC180 and CDAC180 dispersions in acetate buffer at pH 4 and 5 at a low concentration of 0.5% w/w that displayed approximately 10-fold increase in storage and loss moduli compared to those of the individual dispersions. Self-standing gels containing doxorubicin (an anticancer drug) displayed pH-responsive release profiles. At physiological pH 7.4, approximately 65% of doxorubicin was retained past a burst release regime, while complete release was observed within 5 days at pH 4. Biocompatibility of DCC180, CDAC180, and their mixture were investigated through quantification of the metabolic activity of NIH3T3 cells in vitro. No significant cytotoxicity was observed at concentrations up to 900 µg/mL. In short, the nanocellulose-based polyion complex hydrogels obtained in this study are promising nature-derived materials for biomedical applications. STATEMENT OF SIGNIFICANCE: We demonstrate that polyion complex can be formed between two cellulose nanofibrils containing complementary charges. To the best of our knowledge, this is the first time that polyion complex formation between complementarily-modified cellulose nanofibrils has been reported, and the results may lead to new ideas on applications of the very promising nanocellulosic materials. The polyion complex helps form a self-standing network that is demonstrated to provide controlled and pH-responsive release of doxorubicin. Particularly, the report explores the connection between the physical properties of functionalizable nanocellulosic materials and their potential biomedical applications. Thus, the study encompasses several broad fields of materials science and engineering, chemistry, and biomedical science that we believe is in line with the readers' interests.

Conceptually Novel Black Phosphorus/Cellulose Hydrogels as Promising Photothermal Agents for Effective Cancer Therapy.

Black phosphorus (BP) has recently emerged as an intriguing photothermal agent in photothermal therapy (PTT) against cancer by virtue of its high photothermal efficiency, biocompatibility, and biodegradability. However, naked BP is intrinsically characterized by easy oxidation (or natural degradation) and sedimentation inside the tumor microenvironment, leading to a short-term therapeutic and inhomogeneous photothermal effect. Development of BP-based nanocomposites for PTT against cancer therefore remains challenging. The present work demonstrates that green and injectable composite hydrogels based on cellulose and BP nanosheets (BPNSs) are of great efficiency for PTT against cancer. The resultant cellulose/BPNS-based hydrogel possesses 3D networks with irregular micrometer-sized pores and thin, strong cellulose-formed walls and exhibits an excellent photothermal response, enhanced stability, and good flexibility. Importantly, this hydrogel nanoplatform is totally harmless and biocompatible both in vivo and in vitro. This work may facilitate the development of BP-polymer-based photothermal agents in the form of hydrogels for biomedical-related clinic applications.

Influence of polymeric carrier on the disposition and retention of 20(R)-ginsenoside-rg3-loaded swellable microparticles in the lung.

The objective of this study was to investigate the influence of differently charged biocompatible polymers, including chitosan (CS), hyaluronic acid (HA), and hydroxypropyl cellulose (HPC), on the disposition and retention of 20(R)-ginsenoside-rg3 (Rg3)-loaded swellable microparticles in the lung. A high-pressure homogenization method combined with spray drying was used to prepare Rg3-loaded microparticles. In vitro aerodynamic performance of different microparticles was characterized by the Next Generation Impactor (NGI). Retention of the swellable microparticles in the rat lung was investigated using bronchoalveolar lavage fluid method. Influence of drug loading, polymer molecular weight, and polymer charge on the properties of the swellable microparticles was investigated. It was found that drug loading had no significant influence on experimental mass median aerodynamic diameter (MMADe) and fine particle fraction (FPF). Increasing polymer molecular weight caused no remarkable change in MMADe value, but the FPF value decreased with the increase of polymer molecular weight. At the same molecular weight level, polymer structure and charge had no statistical influence on the in vitro aerodynamic properties of the microparticles and lung disposition, but it influenced the swelling and bioadhesion behavior and therefore lung retention profile. Desirable phagocytosis escapement and inhibition of A549 cell proliferation were achieved for the developed swellable microparticles. In conclusion, the lung retention of swellable microparticles can be adjusted by selecting polymeric carriers with different structure and charge.

Thermoresponsive Supramolecular Chemotherapy by "V"-Shaped Armed ß-Cyclodextrin Star Polymer to Overcome Drug Resistance.

Pump mediated drug efflux is the key reason to result in the failure of chemotherapy. Herein, a novel star polymer ß-CD-v-(PEG-ß-PNIPAAm)7 consisting of a ß-CD core, grafted with thermo-responsive poly(N-isopropylacrylamide) (PNIPAAm) and biocompatible poly(ethylene glycol) (PEG) in the multiple "V"-shaped arms is designed and further fabricated into supramolecular nanocarriers for drug resistant cancer therapy. The star polymer could encapsulate chemotherapeutics between ß-cyclodextrin and anti-cancer drug via inclusion complex (IC). Furthermore, the temperature induced chain association of PNIPAAm segments facilitated the IC to form supramolecular nanoparticles at 37 °C, whereas the presence of PEG impart great stability to the self-assemblies. When incubated with MDR-1 membrane pump regulated drug resistant tumor cells, much higher and faster cellular uptake of the supramolecular nanoparticles were detected, and the enhanced intracellular retention of drugs could lead to significant inhibition of cell growth. Further in vivo evaluation showed high therapeutic efficacy in suppressing drug resistant tumor growth without a significant impact on the normal functions of main organs. This work signifies thermo-responsive supramolecular chemotherapy is promising in combating pump mediated drug resistance in both in vitro and in vivo models, which may be encouraging for the advanced drug delivery platform design to overcome drug resistant cancer.

Development of Crystalline Cellulosic Fibres for Sustained Release of Drug.

Natural quinoline alkaloid camptothecin (CPT) is used for the treatment of colon, lung, breast and ovarian cancers still facing challenges due to low solubility in aqueous and biological fluids. Its lactone form easily converts into a toxic carboxylic form at slightly basic pH, typical in blood and tissue fluid has rapid clearance from systemic administration. We report a new approach based on micro crystalline cellulose (MCC) and nano crystalline cellulose (NCC) isolated from natural sources such as Cymbopogan flexuosus to stabilize and regulate the release kinetics of CPT in physiological solution. Langmuir and Freundlich isotherm studies approve that degree of crystallinity i.e. ratio of amorphous and crystalline cellulose regulate the adsorption of CPT. The freeze dried celluloses of Cymbopogan flexuosus origin (MCC and NCC) further were optimized for drug delivery with a mimicked physiologically relevant solution. Both carriers can significantly extend the release of drug as compared to reported values, however, NCC showed better results. Not only the crystallinity but crystal size and hydrogen bonding play critical role in drug release. Free diffusion of drug into physiological solution follows the Ritger- Peppes kinetic model. The coefficient of the model signifies the Fickian diffusion mechanism of release. The investigation indicates that NCC cellulosic matrix can act as a better carrier of CPT for its sustained release formulation.

Cellulose conjugated FITC-labelled mesoporous silica nanoparticles: intracellular accumulation and stimuli responsive doxorubicin release.

Herein, we design novel cellulose conjugated mesoporous silica nanoparticle (CLS-MSP) based nanotherapeutics for stimuli responsive intracellular doxorubicin (DOX) delivery. DOX molecules are entrapped in pores of the fabricated mesoporous silica nanoparticles (MSPs) while cellulose is used as an encapsulating material through esterification on the outlet of the pores of the MSPs to avoid premature DOX release under physiological conditions. In in vitro studies, stimuli responsive DOX release is successfully achieved from DOX loaded cellulose conjugated mesoporous silica nanoparticles (DOX/CLS-MSPs) by pH and cellulase triggers. Intracellular accumulation of DOX/CLS-MSPs in human liver cancer cells (HepG2 cells) is investigated through confocal microscope magnification. Cell viability of HepG2 cells is determined as the percentage of the cells incubated with DOX/CLS-MSPs compared with that of non-incubated cells through an MTT assay.