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Lypo-Spheric Studies and Resources

Bansal SS, Goel M, Aqil F, Vadhanam MV, Gupta RC, (2011), "Advanced Drug-Delivery Systems of Curcumin for Cancer Chemoprevention," Cancer Prev Res (Phila). May 5.

Liposomes used to improve delivery of curcumin
Liposomal delivery greatly improves bioavailability of orally administered curcumin. The authors conclude that liposome encapsulation can provide an effective means to bypass the bioavailability problems that restrict or prevent the oral use of many therapeutic agents.


Since ancient times, chemopreventive agents have been used to treat/prevent several diseases including cancer. They are found to elicit a spectrum of potent responses including anti-inflammatory, antioxidant, antiproliferative, anticarcinogenic, and antiangiogenic activity in various cell cultures and some animal studies. Research over the past 4 decades has shown that chemopreventives affect a number of proteins involved in various molecular pathways that regulate inflammatory and carcinogenic responses in a cell. Various enzymes, transcription factors, receptors, and adhesion proteins are also affected by chemopreventives. Although, these natural compounds have shown significant efficacy in cell culture studies, they elicited limited efficacy in various clinical studies. Their introduction into the clinical setting is hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Therefore, to circumvent these limitations and to ease their transition to clinics, alternate strategies should be explored. Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been shown to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation. In this review article, we have attempted to provide a comprehensive outlook for these delivery approaches, using curcumin as a model agent, and discussed future strategies to enable the introduction of these highly potent chemopreventives into a physician's armamentarium. Cancer Prev Res; 4(8); 1158-71. ©2011 AACR.

Gropper SS, Smith JL, Groff JL, (2009), Advanced Nutrition and Human Metabolism, West Publishing Co. p 313.

Vitamin C [non-liposomal] bioavailability decreases with dose size
As dose size increases, bioavailabiity decreases dramatically. The authors express this finding by stating that 98% of a 20 mg oral dose of [non-liposome-encapsulated] vitamin C is bioavailable (enters the bloodstream) whereas only 16% of a 12,000 mg dose does so.

Gerster H, (1987), Human vitamin C requirements, Z Ernahrungswiss. Jun;26(2):125-37.

Bioavailability of [non-liposome-encapsulated] vitamin C
Based on previous recommended daily allowance (RDA) studies by the National Institutes of Health, author suggests that a 200 mg daily intake of vitamin C is sufficient to provide tissue saturation. By implication, any additional vitamin C would not be used or bioavailable. He does also suggest that smokers and those in disease states may have a higher requirement for vitamin C. [NOTE: Hickey & Roberts (2004) debunk the flawed nature of these NIH studies]


The importance of vitamin C is reflected in its multifunctional roles which include participation in collagen and carnitine syntheses, promotion of iron absorption and the more recently discovered participation in noradrenaline synthesis, inactivation of free radical chain reactions, prevention of N-nitroso compound formation and more. Given the many extra-antiscorbutic functions of the vitamin, the Recommended Dietary Allowances (RDA) should not just prevent deficiency disease but should aim at providing sufficient amounts for all vitamin C-dependent functions to operate at full capacity. The concept of vitamin C tissue saturation is best able to meet this demand. The use of kinetic models has shown that the body pool is saturated with a daily intake of 100 mg vitamin C in non-smokers and 140 mg in smokers, amounts that may be regarded as optimal RDA values. Certain disease states may be accompanied by still higher vitamin C requirements but the exact amounts are not yet known.


Hickey S., Roberts H, Miller N, (2008), "Pharmacokinetics of oral vitamin C" Journal of Nutritional & Environmental Medicine July 31.

Liposome-encapsulated vitamin C dramatically increases blood levels
Authors found that a liposome-encapsulated vitamin C nearly doubled bioavailability over that thought possible from studies published by the National Institutes of Health. 


Purpose. To test whether plasma vitamin C levels, following oral doses in supplemented volunteers,
are tightly controlled and subject to a maximum in the region of 220 mM L
, as suggested by previous
researchers for depleted subjects. To determine plasma levels following single, variable-sized doses of
standard and liposomal formulations of vitamin C and compare the effects of the different
formulations. To determine whether plasma levels above ,280 mM L
, which have selectively killed
cancer, bacteria or viruses (in laboratory experiments), can be achieved using oral doses of vitamin C.
Design. This was a single blind study, measuring plasma levels in two subjects, in samples taken halfhourly or hourly for 6 hours, following ingestion of vitamin C. Data were compared with published
results and with data from 10 years of laboratory plasma determinations.
Materials and methods. Standard 1 gram tablets of vitamin C; liposomal vitamin C. Plasma levels were
analysed using the method of Butts and Mulvihill.
Results. Preliminary investigations of the effects of liposomal and standard formulation ascorbate
showed that blood plasma levels in excess of the previously assumed maximum of 220 mM L
possible. Large oral doses of liposomal ascorbate resulted in plasma levels above 400 mM L
Conclusions. Since a single oral dose can produce plasma levels in excess of 400 mM L
pharmacokinetic theory suggests that repeated doses could sustain levels well above the formerly
assumed maximum. These results have implications for the use of ascorbate, as a nutrient and as a
drug. For example, a short in vitro treatment of human Burkitt’s lymphoma cells with ascorbate, at
400 mM L
, has been shown to result in ,50% cancer cell death. Using frequent oral doses, an
equivalent plasma level could be sustained indefinitely. Thus, oral vitamin C has potential for use as a
non-toxic, sustainable, therapeutic agent. Further research into the experimental and therapeutic
aspects of high, frequent, oral doses of ascorbic acid either alone or (for cancer therapy) in

Hickey S, Roberts H, (2004), Ascorbate: The Science of Vitamin C, 2004.

Ascorbate: The Science of Vitamin C
This book presents a new model, describing the action of vitamin C in health. It demonstrates conclusively that the establishment has misinterpreted the evidence. The dynamic flow model explains the current results and points the way for future experiments. This book is a must for people who want to understand the scientific evidence and support for high-dose vitamin C.


The relationship between vitamin C and health is controversial. Double Nobel Prize winner, Linus Pauling, argued that ascorbate could prevent or cure heart disease, stroke, cancer and infections. Conventional experts disagreed, disparaging supplements in favour of fruits and vegetables. This book presents a new model, describing the action of vitamin C in health and disease. It demonstrates conclusively that the establishment has misinterpreted the evidence, potentially resulting in epidemic levels of avoidable disease. The dynamic flow model explains the current results and points the way for future experiments. Vitamin C supplementation could eradicate many diseases. In pharmacological doses, it could cure the major killers of the industrialised world. Failure to test these ideas may condemn countless people to chronic illness and premature death. 

Kelly C, Jefferies C, Cryan SA, (2011), "Targeted liposomal drug delivery to monocytes and macrophages," J Drug Deliv.

Liposomes used to deliver drugs to specifically targeted cells
Liposomes can be used to effectively deliver therapeutic agents particular cell types (mononuclear phagocytic system, particularly macrophages). These cells are of particular importance in the immune system. 


As the role of monocytes and macrophages in a range of diseases is better understood, strategies to target these cell types are of growing importance both scientifically and therapeutically. As particulate carriers, liposomes naturally target cells of the mononuclear phagocytic system (MPS), particularly macrophages. Loading drugs into liposomes can therefore offer an efficient means of drug targeting to MPS cells. Physicochemical properties including size, charge and lipid composition can have a very significant effect on the efficiency with which liposomes target MPS cells. MPS cells express a range of receptors including scavenger receptors, integrins, mannose receptors and Fc-receptors that can be targeted by the addition of ligands to liposome surfaces. These ligands include peptides, antibodies and lectins and have the advantages of increasing target specificity and avoiding the need for cationic lipids to trigger intracellular delivery. The goal for targeting monocytes/macrophages using liposomes includes not only drug delivery but also potentially a role in cell ablation and cell activation for the treatment of conditions including cancer, atherosclerosis, HIV, and chronic inflammation.

Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, Park JB, Lazarev A, Graumlich JF, King J, Cantilena LR. (1996), "Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance," Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3704-9..

Bioavailability of (non-liposomal) vitamin C decreases rapidly with dose size
Authors report very rapid decline in bioavailability [of non-liposome-encapsulated vitamin C] with dose size. The "steep portion of the curve" starts between 30 mg and 100 mg of daily dose. Based on their findings, they suggest that "vitamin C daily doses above 400 mg have no evident value." This conclusion is based on the faulty presupposition that the appearance of vitamin C in the urine indicates all bodily tissues are saturated and the body requires no additional vitamin C. This assumption is clearly refuted by Hickey, et al. in his book Ascorbate: The Science of Vitamin C referenced above.


Determinants of the recommended dietary allowance (RDA) for vitamin C include the relationship between vitamin C dose and steady-state plasma concentration, bioavailability, urinary excretion, cell concentration, and potential adverse effects. Because current data are inadequate, an in-hospital depletion-repletion study was conducted. Seven healthy volunteers were hospitalized for 4-6 months and consumed a diet containing <5 mg of vitamin C daily. Steady-state plasma and tissue concentrations were determined at seven daily doses of vitamin C from 30 to 2500 mg. Vitamin C steady-state plasma concentrations as a function of dose displayed sigmoid kinetics. The steep portion of the curve occurred between the 30- and 100-mg daily dose, the current RDA of 60 mg daily was on the lower third of the curve, the first dose beyond the sigmoid portion of the curve was 200 mg daily, and complete plasma saturation occurred at 1000 mg daily. Neutrophils, monocytes, and lymphocytes saturated at 100 mg daily and contained concentrations at least 14-fold higher than plasma. Bioavailability was complete for 200 mg of vitamin C as a single dose. No vitamin C was excreted in urine of six of seven volunteers until the 100-mg dose. At single doses of 500 mg and higher, bioavailability declined and the absorbed amount was excreted. Oxalate and urate excretion were elevated at 1000 mg of vitamin C daily compared to lower doses. Based on these data and Institute of Medicine criteria, the current RDA of 60 mg daily should be increased to 200 mg daily, which can be obtained from fruits and vegetables. Safe doses of vitamin C are less than 1000 mg daily, and vitamin C daily doses above 400 mg have no evident value.


Mitsopoulos P, Suntres ZE, (2011), "Protective Effects of Liposomal N-Acetylcysteine against Paraquat-Induced Cytotoxicity and Gene Expression," J Toxicol.

Liposomal encapsulation improves delivery of therapeutic agent
N-acetylcysteine (NAC) was encapsulated in liposomes and administered as a trea™ent for paraquat poisoning. Pretrea™ent with this liposomal NAC was found to be more effective than conventional drugs in reducing the effects of paraquat poisoning.


Paraquat (PQ) is a herbicide that preferentially accumulates in the lung and exerts its cytotoxicity via the generation of reactive oxygen species (ROS). There is no specific treatment for paraquat poisoning. Attempts have been made to increase the antioxidant status in the lung using antioxidants (e.g., superoxide dismutase, vitamin E, N-acetylcysteine) but the outcome from such treatments is limited. Encapsulation of antioxidants in liposomes improves their therapeutic potential against oxidant-induced lung damage because liposomes facilitate intracellular delivery and prolong the retention of entrapped agents inside the cell. In the present study, we compared the effectiveness of conventional N-acetylcysteine (NAC) and liposomal-NAC (L-NAC) against PQ-induced cytotoxicity and examined the mechanism(s) by which these antioxidant formulations conferred cytoprotection. The effects of NAC or L-NAC against PQ-induced cytotoxicity in A549 cells were assessed by measuring cellular PQ uptake, intracellular glutathione content, ROS levels, mitochondrial membrane potential, cellular gene expression, inflammatory cytokine release and cell viability. Pretreatment of cells with L-NAC was significantly more effective than pretreatment with the conventional drug in reducing PQ-induced cytotoxicity, as indicated by the biomarkers used in this study. Our results suggested that the delivery of NAC as a liposomal formulation improves its effectiveness in counteracting PQ-induced cytotoxicity.

Parmentier J, Thewes B, Gropp F, Fricker G, (2011), "Oral peptide delivery by tetraether lipid liposomes," Int J Pharm. Jun 2.

Liposome encapsulation improves peptide bioavailability
Liposomes were used to deliver peptides agents which normally break down in the stomach. Bioavailability in some tests improved by 460%.


The aim of this study is to improve of oral peptide delivery by a novel type of liposomes containing tetraether lipids (TELs) derived from archaea bacteria. Liposomes were used for the oral delivery of the somatostatin analogue octreotide. TELs were extracted from Sulfolobus acidocaldarius and subsequently purified to single compounds. Liposomes were prepared by the film method followed by extrusion. Vesicles in size between 130 and 207nm were obtained as confirmed by photon correlation spectroscopy. The pharmacokinetics of radiolabeled TELs in liposomes was investigated after oral administration to rats. 1.6% of the applied radioactivity in fed and 1.5% in fasted rats was recovered in the blood and inner organs after 2h, while most of the radioactivity remained in the gastro-intestinal tract. After 24h the percentage of radioactivity in inner organs was reduced to 0.6% in fed rats, respectively 1.0% in fasted animals. Several liposomal formulations containing dipalmitoyl phosphatidylcholine (DPPC) and TELs in different ratios were loaded with octreotide and orally administered. Liposomes with 25% TEL could improve the oral bioavailability of octreotide 4.1-fold and one formulation with a cationic TEL derivative 4.6-fold. TEL-liposomes probably act by protecting the peptide in the gastro-intestinal tract.

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