Drug Delivery: Improving Bioavailability and Overcoming Toxicity. Matthew J. Medina Biology of Toxins Spring 2012

Transcription

1 Drug Delivery: Improving Bioavailability and Overcoming Toxicity Matthew J. Medina Biology of Toxins Spring 2012

2 Introduction Utilizing nanomaterials has gained considerable interest when it comes to improving the bioavailability of drugs Bioavailability- after administration of a drug, is the rate to which the drug becomes available at a target site. Improving public heath relies on development of new drugs and sometimes new drugs need to overcome the obstacles that affect their bioavailability to pass clinical trials What makes drug delivery incredible is using nanomaterials as a tool to derive approaches of improving drugs.

3 What Factors Affect Bioavailability? Poor drug solubility in aqueous environments. Poor drug stability in vivo and/or in vitro. Ability to cross membrane barriers. Toxicity of drugs.

4 Overcoming the Factors Affecting Bioavailability Novel approaches to avoid the factors affecting bioavailability has been achieved by drug delivery, that is utilizing nanocarriers to deliver drugs to their target sites. What makes nanocarriers attractive for drug delivery are: 1. Ability to carry other compounds. 2. Surface Functionality, utilizing ligands to bind to targets. 3. Avoid adverse effects of drugs. 4. Ability to cross membranes. In context of this course, avoiding adverse effects is particularly interesting. Nanocarriers are capable of avoiding adverse effects of a given drug by avoiding contact with susceptible tissues by encapsulating the drug.

5 Biomimicry Nanocarriers: Liposomes Micelles Liquid and solid lipid carriers Liposome carriers

6 Benefits and Drawbacks of Liposome Nanocarriers Liposome carriers have increased circulation lifetimes. Functionality and easy modification of surfaces. Liposome carriers are capable of fusing with one another. Fusing carriers result in payload loss. Biocompatibility. Capable of carrying hydrophilic lipophilic drugs. Ability to cross membranes.

7 Other Types of Nanocarriers Carbon Nanotubes Cyclodextrins- Synthesized cyclic molecules capable of binding to smaller molecules.

8 Using Liposome Carriers for Antimicrobial Delivery In a 2011 study, scientists reported an approach of delivering liposome encapsulated antimicrobials to a site of bacterial infection taking advantage of toxins secreted by the bacteria for drug release.

9 Vancomycin *Models for this study include : S. aureus bacterium and vancomycin as an antibiotic. *Vancomycin generally treats infections educing colitis. Methicillin-resistant Staphycoccus aureus (MRSA)

10 Design of Vancomycin-Liposome Complex A Liposome carrier was designed to cary vancomycin, and coated with gold nanoparticles bonded to chitosan. To control for fusing among lipid carriers, the surfaces of liposomes are coated with things, e,g, metal nanoparticles or polymers such as polyethylene gylcol. In this case, the vancomycinliposome complex is coated with gold nanoparticles modified with chitosan to create a cationic surface to avoid attraction among the carriers.

11 How is Vancomycin Released? S. aureus secrets alfa hemolysin, a protein that binds to the lipid membranes. Alfa hemolysin forms holes on lipid membranes resulting in the loss of important components (ATp and ions). Cell lysis ultimately occurs due to osmotic swelling.

12 How is Vancomycin Released? In the case of vancomycin-liposome complex discussed in the study, alfa hemolysin forms a heptameric structure on the surface which contains a central pore the size of about 2 nanometers. When the vanocomycin drug delivery systems makes contact with S. aureus, and the alfa hemolysin secreted by the bacteria, the therapeutic payload is released. This mechanism involves taking advantage of toxins to release a therapeutic payload.

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14 Efficiency of Vancomycin Delivery System in Inhibiting S. aureus Growth The bacterial growth was measured by absorbance at 600 nanometers, and the optical density was observed. Positive controls include: free vancomycin and vancomycin encapsulated (not AuChi stabilized). Negative Controls include: Liposome carrier with AuChi surface and phosphate buffered saline (generally not toxic to cells). Given the results of the study, the experimental vancomycin delivery system compares to free vancomycin in inhibiting MRSA growth.

15 What s the Significance of the Vancomycin Study? The study serves as a model for utilizing this approach in other drugs which may be highly toxic or which could interact with other drugs. The study also shows that we can take advantage of toxins secreted by bacteria to release a therapeutic payload, given that the toxin in context forms pores on lipid surfaces.

16 Other Drugs That Utilize Liposome Carriers Trade name Active Drug Clinical Trial Phase Myocet Doxorubicin III Aroplatin Cisplatin II DaunoXome Daunorubicin III Marqibo Vinorelbine I Ambisome Amphotericin B III Nyotran Nystatin III

17 Doxorubicin Doxorubicin is used to treat various types of cancer: breast, Hodgkin s disease, Kaposi s sarcoma, among other cancers. The drug has been labeled as red devil because of its appearance and cardiac toxicity it possesses. Myocet doxorubicin is encapsulated in a liposome carrier which helps reduce cardiac toxicity.

18 Can Nanocarriers Pose Toxicity Risk Themselves? Possible toxic effects of drug delivery carriers lies in accumulation and degradation after releasing their therapeutic payload. Lipid derived systems show to be promising when toxicity is concerned this because of their biocompatibility. Carbon nanotubes pose toxic risks due to high reactivity and oxygen free-radical scavenger properties.

19 How to Asses Toxicity in Carriers. To asses the possible toxicity of nanocarriers a relativity new area in research known as nanoinformatics serves an approach to collecting data on toxicity of nanomaterials.

20 Conclusion Improving public health remains a priority when it comes to therapeutics. In context of toxicity of drugs, drug delivery remains a significant tool in reducing toxic effect of certain drugs. Drug delivery also improves bioavailability of drugs. Reducing toxicity by utilizing lipid nanocarriers had been demonstrated as seen in doxorubicin, and proves to be a successful tool in how we use drugs.

21 References Cattaneo A.G., Gornati R., Sabbioni E., et al Nanotechnology and human health: risks and benefits. Applied Toxicology. (wileyonlinelibrary) DOI /jat Pornpattananangkul D., Zhang L., Olson S., Aral S., et al Bacterial Toxin Triggered Drug Release from Gold Nanoparticle-stabilized Liposomes for the treatment of Bacterial Infection. J Am Chem Soc. 133(11), Hettiarachchi G., Nguyen D., Wu J., Lucus D., Ma D., et al Toxicology and Drug Delivery by Cucyrbit[n]uril Type Molecular containers. PLoS ONE 5(5):e doi: /journal.phone Leonard R.C.F., Williams S., Tulpule A., Levine A.M. and Oliveros S Improving the therapeutic index of anthracycline chemotherapy: Focus in liposomal doxorubicin (mycocet). The Breast. Vol 18 (4) Song L., Hobaugh M.R., et al Structure os staphylococcal alfa-hemolysin, a heptameric transmembrane pore. Science. vol Maurer N., Fenske D.B., Cullis P Developments in liposomal drug delivery systems. Expert Opin. Biol. Ther. 1(6). PubMed Health. (2012) Doxorubicin.