Biodegradable Hydrogels
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Biodegradable Hydrogels for Brachytherapy in Breast Cancer, presented by Nick Potter at St. Louis College of Pharmacy
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Biodegradable Hydrogels
- 1. Nick Potter Pharm D. Candidate 2017 St. Louis College of Pharmacy Washington University Department of Radiation Oncology Azab Laboratory 4th Annual Student Research Symposium 04/06/2013 Biodegradable Hydrogels for Brachytherapy in Breast Cancer
- 2. 2nd leading cause of cancer death in women ~ 1/8 U.S. women will be affected by invasive breast cancer in lifetime ~232,340 cases of invasive breast cancer ~29,620 cases of death as a result
- 5. Neoadjuvant Therapy Adjuvant Therapy Targeted – Tratuzumab Chemotherapy – Methotrexate, 5-Fluoroucil Hormone – Anastrozole, Letrozole http://www.encognitive.com/files/images/chemo-chemotherapy-side-effects-baldness.jpg
- 6. 3-6 Weeks of daily treatment Not Localized Serious Side Effects http://www.cancers.biz/wp-content/uploads/2012/11/How-is-the-use-of-radiation-therapy-in-the-treatment-of-medical.jpg http://www.fashion-era.com/images/Photosfam/rt11blkexudate.jpg
- 7. Catheters inserted into breast are filled with radioactive pellets. Requires two Surgeries Results in Scarring May induce Infection 5 Days Outpatient, 2 Times/Day http://radonc.ucsd.edu/patient-info/treatment-options/procedures/PublishingImages/PBI_Technique.jpg http://0.tqn.com/d/breastcancer/1/G/4/9/-/-/Mammosite-art.jpg
- 8. Biodegradable hydrogels loaded with radioactive isotopes implanted in the cavity formed after tumor removal will allow localized radiotherapy.
- 9. Inserted into breast following a Lumpectomy No need for additional surgery to implant it Directly implanted where tumor was removed Increase efficacy of treatment Less side effects to adjacent tissues and distant organs Less Expensive One Time Treatment No Risk for Infection Biodegradable in Body No need for surgery remove it http://www.mountainside-medical.com/product_images/uploaded_images/hydrogel-wound-care-filler.jpg
- 10. Alpha Radiation Gamma Radiation Beta Radiation Iodine -131 http://www.bbc.co.uk/schools/gcsebitesize/science/images/116_radiation_penetration.gif
- 11. Chitosan Natural Poly-Sugar Glutaraldehyde http://vintageprintable.com/wordpress/wp-content/uploads/2010/08/Animal-Crustacean-Lobster1.jpg
- 14. Increased amounts of glutaraldehyde produce more cross-linked hydrogels. http://www.rsc.org/ej/GC/2008/b800584b/b800584b-f1.gif Glutaraldehyde (%)
- 15. 0 0.25 0.5 0.75 1 0 50 100 150 200 FractionofHydrogelinSyringe Time (sec) Control 0.2 % GA 0.4 % GA 0.6 % GA 0.8 % GA 1 % GA Chitosan cross-linked with moderate concentrations (0.6%) of glutaraldehyde demonstrates desirable linear shear- stress properties.
- 16. Chitosan cross-linked with moderate concentrations of glutaraldehyde (0.6%) are semi-solid hydrogels that display linear shear-stress properties. These hydrogels will serve as a potential platform for loading of radioactive isotopes, as a novel biodegradable radioactive implant in brachytherapy of breast cancer.
- 17. Iodine-131 with Hydrogel In Vivo
- 18. American Cancer Society. Breast Cancer Facts & Figures 2011-2012. Atlanta: American Cancer Society, Inc. 2012. Azab K, et al. Crosslinked chitosan implants as potential degradable devices for brachytherapy: In vitro and in vivo analysis. Journal of Controlled Release 111 (2006) 281–289. Azab K, et al. Biocompatibility evaluation of crosslinked chitosan hydrogels after subcutaneous and intraperitoneal implantation in the rat. Journal of BiomedicalMaterials Research Part A DOI: 10.1002/jbm.a.31256. 2007. Azab K, et al. Prevention of tumor recurrence and distant metastasis formation in a breast cancer mouse model by biodegradable implant of 131 I-norcholesterol. Journal of Controlled Release 123 (2007) 116–122.
- 19. Noha Salama, PhD. Joseph Abraham Kareem Azab, BScPharm, PhD. Pilar de la Puente, PhD. Feda Azab, BScPharm Barbara Muz, PhD Chizelle Rush, BSc Raymundo Marcelo
Editor's Notes
- Lung Cancer 1st
- Cancer starts when cells begin to divide and grow out of control Breast cancer appears in the breast, to understand better how the breast cancer works, we need to remember the anatomy of the breast. The anatomy of the breast is…. The breast is filled with fatty tissue with the areola in the center of the breast. Lymph nodes are in very close proximity to the breast tissue. The lymph nodes are responsible for draining and filtering fluid. The areola is surrounded by many lobes. Lobes connect to the areola via ducts. The lobes are filled with lobules that secrete breast milk when stimulated. Most breast cancers begin in the epithelium of the ducts of the breast, some in the lobules The classification of breast cancer is determined based upon the size of the tumor and its spread The therapeutic options of the breast cancer are limited by the size and spread of the cancer cells. Stage 1 – Very small and almost no spreading Stage 2 – intermediate size and the cancer has spread to some lymph nodes Stage 3 – large sized tumor and has spread to surrounding skin, muscles, and many lymph nodes Stage 4 – cancer has moved to other parts of the body
- The standard care of treatment of non-metastatic breast caner is surgical resection of the tumor followed by radiotherapy. The most common surgeries are lumpectomy and mastectomy and the selection of which one depends of the stage. Most effective first-line method Lumpectomy – Cancerous tissue and rim of normal tissue are removed from the breast. Typically only stage 1 and early stage 2 Mastectomy – removal of entire breast and associated lymph nodes. Later stages Lumpectomy Salvage Breast Followed by radiation – greater chance of reoccurrence\ Only for local breast cancer Solution that allows Lumpectomy, but minimizes the chance for reocurrence Both treatments are usually followed by another type of therapy to prevent reoccurence
- In more metastatic stages we required more therapies, like systemic therapies, p.e Neoadjuvant Therapy – used before surgery to shrink tumor for easier removal, but more so for Stage 3 or 4 Cancer Adjuvant therapy – given after surgery to kill any cancer cells that were undetectable or that have migrated to other parts of the body Targeted Therapy Tratuzumab – targets HER2 protein which is produced by tumor cells and promotes cell tumor cell growth – only certain tumors express excessive amounts of HER2 Approximately 15%-30% of breast cancers overproduce the growth-promoting protein HER2/neu. Chemotherapy – used for patients who do not have excessive HER2 – many side affects Often still use chemotherapy even if excessive HER2 targets unseen cancer so there is less reoccurance Hormone – anti-hormone drugs can be used to inhibit the binding of hormones to cancer (estrogen) Hormones such as estrogen and progesterone stimulate cancer cell growth in those cancer cells, but more so in cancer cells who have receptors for either progesterone, estrogen, or both – only 2/3 have a receptor for at least 1. This explains why breast cancer is much more prevelant in women than in men Aromatase inhibitors such as anastrozole and letrozole are used for post-menopausal women in inhibiting an enzyme that produces small amounts of estrogen – does not work in premenopausal Solution for premenopausal In premenopausal women, removing or shutting down the ovaries (ovarian oblation), which are the main source of estrogens, effectively makes the woman postmenopausal. This may allow some other hormone therapies to work better. Permanent ovarian ablation can be done by surgically removing the ovaries. More often, ovarian ablation is done with drugs such as Zoladex and Lupron. These drugs stop the signal that the body sends to the ovaries to make estrogens in premenopausal women. Many side effects and other issues involved in shutting down ovaries Although adjuvant therapies are necessary in later stages of breast cancer, it is still used in earlier stages. Solution that does not have these major side effects on the body?
- Pros - Targets tissue surrounding tumor – lower risk of returning cancer No invasive surgery Cons 3-6 weeks of treatment Requires trained professionals Affect other internal organs Not very localized Solution?
- Stages 1 and 2 Radioactive pellets are put into the catheters 5 days outpatient – 2 times a day Pros More localized therapy Cons Requires two surgeries Scarring Infection Better solution?
- My project focused on producing hydrogels and characterized their physiochemical properties A – tumor inside of the breast B – cavity formed after surgical removal by lumpectomy C – Catheters inserted breast as indicative by brachytherapy which can cause scarring, requires 2 surgeries, and possible infection D – implantation of the hydrogel after surgical removal of the tumor in the surgical room which is very sterile and does not require a surgery to remove the hydrogel and provide radiotherapy at a highly localized level.
- Create something that is highly localized, not highly invasive, biodegradable, and not very systemic at a lower cost In the surgical room which is very sterile and does not require a surgery to remove the hydrogel and provide radiotherapy at a highly localized level. How will we produce this radiotherapy?
- Alpha – Common, but not a lot of energy. Eject Helium atom with energy. Loses this energy quickly (5 MeV) Gamma – Very invasive and too much energy – release high energy photon Beta – Emit a positron or electron. Intermediate strength and energy Iodine 131 is used to treat thyroid cancer, so it has been shown to be biodegradable by the body, lots of people have worked with it and it is highly tested and proven effective. If it gets into systemic circulation will directly affect the thyroid, so it is crucial to make sure that I131 remains in the tumor bed until it is no longer radioactive (half-life of 8 days) We need to create something that is gel-like enough to keep the radioactive substances localized, but also liquid enough to allow the release of radiation and provide biodegradability
- Chitosan – comes from chitin, the main element of crustacean's shells. Contains an amine group which has a lone pair of electrons that will allow it to be a nucleophile Glutaraldehyde – can be used as a cross-linker
- Acetic Acid is used to make the chitosan soluble in water, and it is a catalyst for the reaction. Chitosan acts as a nucleophile 1. Acetic Acid contains a carboxylic acid group which resonates and makes it fairly acidic and willing to protonate the aldehyde group of glutaraldehyde Amine of chitosan attacks the Carbon that is now positively charge and unstable. Proton leaves amine group with the aid of the acetic acid Alcohol is protonated and forms water as it leaves Carbon group is now positively charged again, lone pair on nitrogen moves up (positive to negative) and forms double bond Acetic acid once again deprotonates the positively charged nitrogen and is reformed, making the acetic acid a true catalyst Glutaraldehyde is now combined with chitosan
- Acetic Acid is used to make the chitosan soluble in water, and it is a catalyst for the reaction. Chitosan acts as a nucleophile 1. Acetic Acid contains a carboxylic acid group which resonates and makes it fairly acidic and willing to protonate the aldehyde group of glutaraldehyde Amine of chitosan attacks the Carbon that is now positively charge and unstable. Proton leaves amine group with the aid of the acetic acid Alcohol is protonated and forms water as it leaves Carbon group is now positively charged again, lone pair on nitrogen moves up (positive to negative) and forms double bond Acetic acid once again deprotonates the positively charged nitrogen and is reformed, making the acetic acid a true catalyst Glutaraldehyde is now combined with chitosan
- Viscosity is proportional to concentration of glutaraldehyde
- Filled a syringe with the cross-linked with the newly formed cross-linked chitosan with glutaraldehyde hydrogel. Applied a constant force of 500 grams onto the syringe and timed how long it would take to be released from the syringe, while marking how long it took to reach different points remaining within the syringe 0.6% appears to be the injectable concentration of choice Control, 0.2% and 0.4% are too liquid and were released too quickly 1% was too viscous and actually became stuck in the syringe during the experiment 0.8% could work but is not linear and consistent throughout the experiment 0.6% appears to be the best concentration of glutaraldehyde
- Come from a natural polysugar Biodegradable No surgery Very localized Less expensive Does not require follow-up that would also require trained specialists The proper viscosity of the hydrogel is crucial in that it must be liquid enough to be biodegradable and effective, but also viscous enough to properly house the radioactive I131 and not allow it to enter the systemic circuit and harm other part of the body. Cross-linking of chitosan with glutaraldehyde will satisfy the requirements, but the proper ratio must be established. The results of my experiment show that 0.6% Glutaraldehyde with Chitosan is the proper ratio, and that this is the concentration of choice for further studies.
- Come from a natural polysugar Biodegradable No surgery Very localized No cosmetic issues (scarring) No burns Less expensive Does not require follow-up that would also require trained specialists The proper viscosity of the hydrogel is crucial in that it must be liquid enough to be biodegradable and effective, but also viscous enough to properly house the radioactive I131 and not allow it to enter the systemic circuit and harm other part of the body. Cross-linking of chitosan with glutaraldehyde will satisfy the requirements, but the proper ratio must be established. The results of my experiment show that 0.6% Glutaraldehyde with Chitosan is the proper ratio, and that this is the concentration of choice for further studies. Further testing of the release with the hydrogel with the radioactive material The efficacy in the body will also have to be tested.