Polymeric micelles: Basic research to clinical practice.

Rapidly developing polymeric micelles as potential targeting carriers has intensified the need for better understanding of the underlying principles related to the selection of suitable delivery materials for designing, characterizing, drug loading, improving stability, targetability, biosafety and efficacy. The emergence of advanced analytical tools such as fluorescence resonance energy transfer and dissipative particle dynamics has identified new dimensions of these nanostructures and their behavior in much greater details. This review summarizes recent efforts in the development of polymeric micelles with respect to their architecture, formulation strategy and targeting possibilities along with their preclinical and clinical aspects. Literature of the past decade is discussed critically with special reference to the chemistry involved in the formation and clinical applications of these versatile materials. Thus, our main objective is to provide a timely update on the current status of polymeric micelles highlighting their applications and the important parameters that have led to successful delivery of drugs to the site of action.

In vitro cytotoxicity and in vivo efficacy of 5-fluorouracil-loaded enteric-coated PEG-cross-linked chitosan microspheres in colorectal cancer therapy in rats.

PURPOSE: Microspheres of chitosan (CS) cross-linked with polyethylene glycol (PEG) were prepared by emulsion-cross-linking followed by the solvent evaporation technique. The formulations were characterized and subjected to in vitro and in vivo tests to assess cell growth, changes in cell morphology, and activities by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on human HT-29 colon cancer cell-lines. METHODS: In vivo activity was evaluated for dimethyl hydrazine-induced colorectal cancer in albino male Wistar rats. Biochemical and histological parameters were evaluated to understand their effectiveness for colon cancer therapy. RESULTS: The 5-FU immediate release (IR) formulations suspended in SCMC produced an immediate cytotoxic effect, whereas microspheres inhibited proliferation of tumor cells to induce apoptosis over an extended time. Minimum inhibitory concentration (IC50) values for both standard plain 5-FU and 5-FU-loaded microspheres were respectively 5.00 ± 0.004 µg/mL and 165 ± 1.9 µg/mL which showed the improved safety profile of the microsphere formulation. Tissue distribution showed high concentration of 5-FU in colon that was higher than IC50 value required to stop the growth or death of colon cancer cells from the colonic dysplasia in Duke's stage A. Significant reduction in tumor volume and multiplicity was observed with increased levels of liver enzymes in animals when treated with standard 5-FU formulation compared with 5-FU loaded microspheres. Elevated levels of serum albumin, creatinine, leukocytopenia, and thrombocytopenia were observed in animals for the standard 5-FU formulation. CONCLUSION: The PEG cross-linked CS microspheres of this study slowly released 5-FU up to 24 h to colonic region and enhanced the antitumor activity.

In vitro cytotoxicity and in vivo efficacy of 5-fluorouracil-loaded enteric-coated PEG-crosslinked chitosan microspheres in colorectal cancer therapy in rats.

PURPOSE: Microspheres of chitosan (CS) crosslinked with polyethylene glycol (PEG) were prepared by emulsion crosslinking followed by solvent evaporation technique. The formulations were characterized and subjected to in vitro and in vivo tests to assess cell growth, changes in cell morphology and activities by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on human HT-29 colon cancer cell lines. METHODS: In vivo activity was evaluated for dimethyl hydrazine-induced colorectal cancer in albino male Wistar rats. Biochemical and histological parameters were evaluated to understand their effectiveness for colon cancer therapy. RESULTS: The 5-FU immediate release (IR) formulations suspended in sodium carboxymethyl cellulose (SCMC) produced an immediate cytotoxic effect, whereas microspheres inhibited the proliferation of tumor cells to induce apoptosis over an extended time. Minimum inhibitory concentration (IC50) values for both standard plain 5-FU and 5-FU-loaded microspheres were, respectively, 5.00 ± 0.004 µg/mL and 165 ± 1.9 µg/mL which showed the improved safety profile of the microsphere formulation. Tissue distribution showed high concentration of 5-FU in colon that was higher than IC50 required to stop the growth or death of colon cancer cells from the colonic dysplasia in Duke's Stage A. Significant reduction in tumor volume and multiplicity was observed with increased levels of liver enzymes in animals when treated with standard 5-FU formulation compared to 5-FU-loaded microspheres. Elevated levels of serum albumin, creatinine, leukocytopenia and thrombocytopenia were observed in animals for the standard 5-FU formulation. CONCLUSION: The PEG-crosslinked CS microspheres of this study slowly released 5-FU up to 24 h to colonic region and enhanced the antitumor activity.

Spasmolytic effect of traditional herbal formulation on guinea pig ileum.

BACKGROUND: The herbal formulation consisting of Andrographis paniculata Nees., Cassia fistula L., Foeniculum vulgare Mill. and Cuminum cyminum L. is widely used by the local traditional practitioners in rural Northern Karnataka for spasmodic abdominal pain. OBJECTIVE: The present study was undertaken to evaluate safety and spasmolytic effect of poly-herbal formulation. MATERIALS AND METHODS: Acute toxicity studies were carried out in Swiss mice, as per the Organization for Economic Co-operation and Development (OECD) guidelines. The spasmolytic activity of the formulation was studied in isolated guinea pig ileum model using histamine and acetylcholine as agonists. The data were analyzed by one-way ANOVA, followed by Dunnetts post-hoc test and P ≤ 0.05 was considered as significant. RESULTS: The formulation did not show any adverse toxic effects and found to be safe. It also showed significant (P < 0.05) relaxation in different agonist like histamine and acetylcholine-induced contractions in guinea pig ileum. CONCLUSION: Antispasmodic activity of the herbal formulation can be attributed to its atropine-like activity. The present findings, therefore, support its utility in spasmodic abdominal pain.

Oral insulin delivery using deoxycholic acid conjugated PEGylated polyhydroxybutyrate co-polymeric nanoparticles.

AIM: To develop insulin loaded deoxycholic acid conjugated PEGylated polyhydroxybutyrate co-polymeric nanoparticles and carry out in vitro and in vivo testing of enteric coated granules comprising these nanoparticles. MATERIALS & METHODS: Insulin loaded nanoparticles were prepared and characterized in vitro. Cellular uptake was studied using hyperspectral and live cell confocal microscopy. Enteric coated granules of nanoparticles were fed orally to diabetic rats and the pharmacokinetic and pharmacodynamic parameters were evaluated. RESULTS: Ultra small (˜10 nm) nanoparticles with polydispersity index of 0.299 were obtained. The enteric coated granules showed a negligible insulin release in acidic pH, but released insulin in alkaline environment. High cellular uptake was observed and nanoparticles were able to maintain the blood glucose levels up to 24 h. CONCLUSION: These enteric-coated nanoparticle granules sustained the release of insulin and showed enhanced insulin bioavailability. Hence, these may serve as a platform device for oral insulin delivery with extended release.

Activity of Plumbago zeylanica Linn. root and Holoptelea integrifolia Roxb. bark pastes in acute and chronic paw inflammation in Wistar rat.

BACKGROUND: The pastes prepared from roots of Plumbago zeylanica Linn. and barks of Holoptelea integrifolia Roxb. are widely used by traditional healers for the treatment of arthritis in rural northern Karnataka. OBJECTIVE: The present study was undertaken to scientifically evaluate the safety and efficacy of traditionally used formulations in experimental animals. MATERIALS AND METHODS: The study, approved by IAEC was carried out in male Wistar rats and dermal toxicity in rabbits. Carrageenan model was used to assess effect on acute inflammation. Paw volume were measured at 1, 2, 4, and 6(th) hour postchallenge. Chronic inflammation was developed by using Complete Freund's Adjuvant (CFA). Paw volume, ankle joint circumference, and body weight were assessed on 1(st), 4(th), 8(th), 14(th), 17(th), and 21(st) day. Paste was applied once every day to the inflamed area of the paw of respective groups of animals, continuously for 14 days. STATISTICS: The data were analyzed by one way analysis of variance followed by Dunnett's post hoc test. P ≤ 0.05 was considered as significant. RESULTS: The formulations did not show any dermal toxicity and found to be safe. Both the pastes significantly (P < 0.05) suppressed, carrageenan-induced paw edema at 6(th) hour and Holoptelea integrifolia appears to be more effective than Plumbago zeylanica. Significant reduction was observed in paw volume, ankle joint circumference and animal body weight gained. CONCLUSIONS: The tested formulations (P. zeylanica root and H. integrifolia bark pastes) showed significant antiinflammatory activity. The present findings therefore support its utility in arthritic pain, inflammation and the claim of traditional practitioners.

Polysaccharide-based micro/nanohydrogels for delivering macromolecular therapeutics.

Increased interest in developing novel micro/nanohydrogel based formulations for delivering macromolecular therapeutics has led to multiple choices of biodegradable and biocompatible natural polymers. This interest is largely due to the availability of large number of highly pure recombinant proteins and peptides with tunable properties as well as RNA interference technology that are used in treating some of the deadly diseases that were difficult to be treated by the conventional approaches. The majority of marketed drugs that are now available are in the form of injectables that pose limited patient compliance and convenience. On the other hand, micro/nanotechnology based macromolecular delivery formulations offer many alternative routes of administration and advantages with improved patient compliance and efficient or targeted delivery of intracellular therapeutics to the site of action. This review outlines and critically evaluates the research findings on micro and nano-carrier polymeric hydrogels for the delivery of macromolecular therapeutics.

Polymeric hydrogels for oral insulin delivery.

The search for an effective and reliable oral insulin delivery system has been a major challenge facing pharmaceutical scientists for over many decades. Even though innumerable carrier systems that protect insulin from degradation in the GIT with improved membrane permeability and biological activity have been developed, yet a clinically acceptable device is not available for human application. Efforts in this direction are continuing at an accelerated speed. One of the preferred systems widely explored is based on polymeric hydrogels that protect insulin from enzymatic degradation in acidic stomach and delivers effectively in the intestine. Swelling and deswelling mechanisms of the hydrogel under varying pH conditions of the body control the release of insulin. The micro and nanoparticle (NP) hydrogel devices based on biopolymers have been widely explored, but their applications in human insulin therapy are still far from satisfactory. The present review highlights the recent findings on hydrogel-based devices for oral delivery of insulin. Literature data are critically assessed and results from different laboratories are compared.

Cyclodextrin-based siRNA delivery nanocarriers: a state-of-the-art review.

INTRODUCTION: The discovery of synthetic small interfering RNA (siRNA) has led to a surge of interest in harnessing RNA interference (RNAi) technology for biomedical applications and drug development. Even though siRNA can be a powerful therapeutic drug, its delivery remains a major challenge, due to the difficulty in its cellular uptake. Naked siRNA has a biological half-life of less than an hour in human plasma. To increase the lifetime and improve its therapeutic efficacy, non-viral vectors have been developed. As a natural evolution, cyclodextrins (CDs), which are natural cyclic oligosaccharides, have recently been applied as delivery vehicles for siRNA, and this in turn, has led to a surge of interest in this area. AREAS COVERED: This review discusses the recent advances made in the design of delivery strategies for siRNA, focusing on CD-based delivery vectors, because these have demonstrated clinical success. The methods of preparation of CD-based vectors, their characterization, transfection efficiencies, cellular toxicity, preclinical and clinical trials are also addressed, as well as future therapeutic applications. EXPERT OPINION: siRNA-mediated RNAi therapeutics is beginning to transform healthcare, particularly, for the treatment of solid tumors. For example, CALAA01, a targeted, self-assembling nanoparticle system based on CD complexed with siRNA has been effective in phase I clinical trials. Although siRNA therapeutics suffers from problems related to off-target effects and non-specific gene silencing, these problems can be overcome by reducing the nanoparticle size, improving the targeting efficiency and by modifying the primary sequence of the siRNA.