Michelson Challenge Application Process Grant Proposal 2012

TITLE Acid sensitive copolymer micelle with liposome for controlled drug delivery of indazole-3-carboxylic acid and an immunocontraceptive agent, porcine zona pellucida (PZP)       Applicant: Rahim Jindani, Department of Textile Engineering, Chemistry & Science, College of Textiles, Room 3320 North Carolina State of University, Raleigh, NC 27695-8301, USA E-mail: rjindan@ncsu.edu, Mobile: 248-821-0923

Student Advisor / Principal Investigator: Martin W. King, Professor of Biotextiles Department of Textile Engineering, Chemistry & Science, College of Textiles, Room 3305 North Carolina State of University, Raleigh, NC 27695-8301, USA E-mail: martin_king@ncsu.edu, Office: 919-515-2563 Mobile: 919-291-2563

which stimulates the formation of sperm and ova. 6. The study will also ensure that the desired effectiveness is achieved with minimal drug dosage. This mechanism needs to have the capacity to deliver the drug in a controlled way at a predictable concentration over an extended period. An effective way of controlling this drug release is by utilizing polymer systems that can respond to different pH and temperature ranges within male and female cats and dogs. We plan to use the properties of pH responsive polymers accordingly to ensure that contraception in both sexes takes place effectively at a range of different pHʼs and temperatures.Project (Abstract): Gonadotropes. These polymers can also be used with elastin like polymers [(VPGVG) 2-VPGEG-(VPGVG) which can convert thermal into mechanical energy if required to trigger the reaction.[2] Stimuli responsive polymers are required which can be cross-linked with liposomes and polysaccharides that can be triggered at specific pH ranges of the male and female reproductive systems. biological system. Introduction: There is need for a single dose drug delivery mechanism to sterilize male/female cats and dogs. Problems & Objectives: The reproductive systems of males and females vary significantly in their function and physiology. [4.5 to 8 for the sperm to survive. thermal responsive polymers will ensure the controlled drug release with liposomes & polysaccharides to ensure a minimum immunological response in vivo.2] Derivatives of indazole-3-carboxylic acid are used to inhibit aerobic glycolysis in cancer cells. whereas female ova require a pH of 3 to 6 for sustenance of the ovaries. and can cause controlled release of indazole-3-carboxylic acid and porcine zona Ppllucida as required in both sexes. A glycoprotein called porcine zona pellucida (PZP) which is extracted from the ovaries of pigs can surround the plasma membrane of a female oocyte. Anionic liposomes are used to work in a narrow pH range. The temperature range within which sperm can survive is between 33 to 36 degrees centigrade while the temperature range for ova is between 12 to 32 degrees centigrade. follicle stimulating hormone (FSH) and luteinizing hormone (LH) are generated from the hypothalamus. eating habits as well as the duration and period of puberty and menstrual cycle. and they can also be used as an antispermatogenic drug in both males and females. . These responsive polymers will be able to solublize lipophilic drugs. 14] Statement of Research: This proposal addresses the need to provide a single dose sterilization technique for both sexes of cats and dogs by targeting the testes and ova in specific pH ranges. Usually male testicies require a pH of 6. [5.11] By introducing a combination of drugs that can be triggered using specific pH and temperature ranges. and is directly involved in preventing the binding of spermatozoa. There are various considerations relevant to all breeds of dogs and cats including their size. [10.

At pH < 4. Mc Master University. Vol. Characterization and Application Françoise M. 2) To determine if drug release occurs in a controlled manner in both sexes of dogs and cats. Department of Chemistry. Visualization of the drug movement will use green fluorescent protein (GFP) for tagging.1295-1307.5. N-isopropyl acrylamide will release cationic liposomes attached to indazole-3-carboxylic acid causing sperm counts to drop to zero ideally within 12 hours of injection.2. Nos. that can be activated at specific pH levels and temperatures. Billing. b. J. Chem. [53] Contraception using PZP has been evaluated on various animals. At pH > 7. At this time a number of species have been studied. Lyda and Kimberly M. Robin O. Responsive Polymer/Liposome Complexes: Design. Literature Review: pH-Sensitive Polymer--Liposome Systems Elizabeth R. 2004. USA Vaccines for contraception of wildlife animals have been tested and tried in various parts of the world. namely the testes and the ova.. To observe liposomes and the subsequent drug reaction on the interaction with ova and testes by studying GFP tags. 76. The Science and Conservation Center. carboxylic acid is able to release anionic liposomes attached to PZP as they become responsive. including 76 exotic species in various countries. at specific pH and temperature ranges. Pure Appl. The only drawback of using multilamellar liposomes is that during preparation they cause the drug to have a high viscosity. Winnik and Tania Principi. Frank.Keeping these factors in mind the objective of the study is to have controlled drug release on targeted areas. Zoo Montana. Hamilton. Ontario Canada L8S 4M1. Kirkpatrick. pp. c. Gillies and Jean M. MT. Liposomes are known to reduce the immunological response of the body to foreign interactions. 1280 Main St W. and can be triggered to achieve sterility with a minimum inflammatory and immune response in both male and female cats and dogs. A better approach would be to use . Testable Objectives for Hypotheses: a. “Contraceptive vaccines for wildlife: a review”. and their use with multilamellar liposomes has caused effective contraception for 3 years in horses and deer. 7-8. Contraceptive Vaccines for Wildlife Jay F. Hypotheses: 1) To test if the polymer carrier N-isopropylacrylamide (NIPAM) and carboxylic acid with liposomes are able to respond within the specified pH ranges. “Development of acid sensitive co-polymer micelles for drug delivery”. Frechet.

Picture source: http://www. which ensures the survival of both sperm and ovaries. The image of the proposed drug molecule will be similar to drug molecule presented in the following diagram with liposomes attached to it. Liposomes containing polysaccharides are used to ensure a low immunogenic response.[52. Liposomes can be cross-linked with other polymer systems to create membranes that will hold the drug molecules prior to being released at specific pH values. It can also be used as a contraceptive drug since it is considered an anti-spermatozoa drug.aspx?ArticleID=1538 The reproductive systems for males and females have different pH ranges and temperatures. GFPʼs will be attached to these liposomes so as to visualize how anionic and cationic liposomes assist in the drug release profile of both sexes and promote drug interactions in both reproductive systems.com/article. especially in the male reproductive system. The other useful part of using indazole-3carboxylic acid is that a minimum concentration is required to achieve an effective performance.small chains of liposomes with polymeric biomaterials that could help reduce the viscosity of the drug. Joseph Tash and Dr. have shown significant effectiveness in clinical trials in both sexes. 53] Indazole-3-carboxylic acid has been used as a drug to kill cancer cells by inhibiting aerobic glycolysis. which kills sertoli cells. its structure and release properties can be switched according to the specific pH. Kathy Roby. Indazole-3carboxylic acid if used with liposomes can cause effective contraception in both sexes. By developing acid sensitive copolymer micelles for the controlled release of drugs at different specific pHʼs it will be easy to establish contraception in both sexes with delivery of a single dose. with different charges and effective pH ranges will be used as required to interact with ova and testes. The drug has already shown successful results in clinical trials on rats. and thus a 10 year release profile can be constructed easily and injected easily in the reproductive systems of both sexes. [12] . Various liposome concentrations.azonano. Given that the drug is encapsulated in between two layers of polymeric biomaterials. derivatives of indazole-3-carboxylic acid. It is a commercial product named Lonidamine. such as KU-AS-272 developed by Dr. For example.

At pH values less than 7. given that it will vary depending upon the size to weight ratio of the animal under investigation. it will be necessary to crosslink the cationic liposome (pH 3 – 5) with carboxylic acid (pH 4 . ovaries need to be exposed to a pH range of 3. On the other hand. Kathy Roby [3. When indazole-3-carboxylic acid is at a pH range of 6. This needs to be explored further so that the respective levels of toxicity and their responses need to be identified precisely. it will start killing cells.5. It is only by further experimentation that we will be able to find how these polymers will behave.7.5. FSH and LH levels play important roles in the production of sperm and ovaries.5. 46] have been undertaken on the derivatives of the ionidamine cancer treatment drug. Since these polymers act in a more dynamic way. which acts as an antiseptic and protects it from bacterial vaginosis and other diseases.The mechanism of sperm and ovary production is controlled by the release of FSH and LH hormones. [43] In order to develop a pH responsive polymer that can be activated at pH values less than 4. is toxic to sertoli cells and affects normal spermatogenesis. and in the proposed study elasticity is being explored to achieve its intended purpose. 7. Recent studies by Dr Joseph Tash and Dr. The percentage concentration of the delivered drug also needs to be defined.6. Nature has provided the female reproductive system with a more acid pH range of 3. It should be noted that the controlled release of the same drug in both male and female reproductive systems has not until now been found effective. Biopolymers as discussed elsewhere [5] are an innovative way of interacting elastomeric protein chains with polymers to achieve elastomeric-like properties.2. 9. Sperm remain alive in a temperature range of 2 to 7 degrees centigrade and in a pH range of 7. 9].0 .8 to 4. During menstruation the FSH level is high.0. Further studies are being conducted to see their effectiveness in pre-pubertal and post-pubertal rats. there are real possibilities for converting the surrounding energy to mechanical energy so as to enhance the reaction rate.4.8 . 12. 13]. Surface modification and surface treatments will ensure that for every menstrual cycle or whenever the pH sensitive polymer is in contact with sperm. However. [3] It is important to understand that drug release for the female reproductive system needs to be at high concentrations over an extended period of time since the length of the menstrual cycle in various breeds of female cats and dogs is comparatively short but cyclic. then the pH level will drop from the normal value which will cause the pH sensitive polymer to release PZP.5 and a temperature range of 4 to 38 degree centigrade for survival and maturation [1. Alterations to the indazole-3-carboxylic acid structure have provided them with KU-AS-272 a filed patented product that has shown success in mature pubertal rats. Carboxylic acid and cationic liposomes can act as the core for micelles. In a similar manner drug delivery systems can be developed using surface activation by corona discharge of N-isopropyl acrylamide and anionic liposomes to achieve activation in the pH range of 6. .2 the entrapped indazole-3-carboxylic acid is an anti spermatozoa agent. As long as the pH is high enough.7. dogs and cats. The drug KU-AS-272 targets cells in the ovaries and testes.6) at various concentrations which can then entrap any neutral charged porcine zona pellucida (PZP) antigens.2 to 8. First it will start apoptosis of granulose cells in the female reproductive system at normal pH levels which will effect the female reproductive system. and same agents are currently being utilized to kill cancer cells. and it falls with the release of blood.0 . [1. it will only work over a specific pH range for the male reproductive system. PZP will not induce cytotoxicity nor interactions with other systems under these conditions.

such as cats. these early studies show that PZP contraception is reversible [20]. studied by Dr. Preliminary Data: The results of rat animal trials for KU-AS-272.ppt   .[3.Another study of a similar product on the market called Adjuvin uses a lonidamine derivative of indazole-3carboxylic acid.e. Studies on using PZP with resorbable PLA/PLGA carrier materials have been attempted. blocks the production and flow of semen. dogs.[20] A new reversible contraceptive drug for humans that is already in Stage III of clinical trials in India and has been successful for almost 7 years now on experimental in vivo animal assays.51] This synthetic polymer has already been successfully used to induce reversible contraception in Indian males. 49]   Figure 1: Source: Tash-Roby KU-AS-272 final. It uses styrene maleic anhydride (SMA) monomer which. as early as the 1980ʼs. A study at Duke University [45]. when dissolved and polymerized in dimethyl sulphoxide. which has been grafted with FSH hormone. a derivative of indazole-3-carbohydrazide. In the event that contraception needs to be reversed. The effectiveness and reversibility of such RISUG polymers can be studied in terms of sperm blockage and subsequent growth in dogs and cats. While PZP has been utilized for female contraception of wildlife animals. evaluated temperature and pH sensitive hydrogels for the prevention of sexually transmitted diseases through use of a microbiocidal vehicle which investigated the options using such biomaterial polymers which has served as one of the sources of inspiration behind this approach. is the drug RISUG. but there is no product on the market that utilizes responsive polymers to deliver the same drug to both reproductive systems. Kathy Roby. both pH responsive and temperature responsive polymers. Additional in vivo data for indazole-3-carbohyrazide shows considerable sperm reduction in Figure 2. and has been utilized to provide reversible contraception in the male reproductive system [39].[40. There was no specific mechanism found that utilized a combination of PZP and indazole-3-carboxylic acid derivatives to deliver drugs in a controlled manner for the male and female reproductive systems at the same time using pH responsive polymers. can be observed in Figure 1. i. to induce controlled drug delivery in both males and females. elephants and fishes. a reversal injection of sodium bicarbonate solution is delivered to dissolve the polymer. That is why the novel approach of this submission is to propose the use of dual responsive polymers. Joseph Tash and Dr. Note how the sperm count has decreased significantly by Week 4. to induce a false attraction. This causes a decrease in total sperm count for the male reproductive system over time.

. These data support our belief that PZP provides a tougher and more durable glycoprotein layer for sperm.Figure 2: Sperm count reduction in male rats can be observed on treatment with indazole-3-carbohydrazide Figure 3: Results showing ZP digestion time for porcine oocytes. [50] The above experimental data gives a better idea of the effectiveness of the drug on rats and other wild life species.

a.4 degrees Celsius. Male and female adult dogs (beagles) b. and the initial dosage concentrations of less than 2% by weight will be used and studied to ensure drug dosage remains within toxicological limits. . post-pubertal rats and then continue with prepubertal rats. The same number of male and female rats will be included for study with an immediate focus on acute toxicity and sensitization tests prior to assessing the long term evaluation over 6 months. the next step will involve designing a longer term in vivo animal protocol with 4 male and female cats and dogs in which the drug effectiveness will be studied on the following animals (Study 2). Male and female adult cats (short hair) d. Samples for dogs and cats will need to be assessed independently as well as in pairs since their data points will be same through out the study. Both male and female contraceptive studies will be undertaken initially over the short term (4-6 weeks). yet sterilization is maintained throughout the trial. [3] After studying drug effectiveness in these two preliminary studies and assuming that our conclusions indicate that our approach is effective and reliable in ensuring sterility over the 6 month period. which can be studied by the incidence of pregnancy and histological staining of the gonads. dogs and cats in the two trials proposed above.Proposed Experimental Methods: Initially we will prepare samples of the drug / liposome complexes so that they are stable. The in vivo rat trials (Study 1) will commence with mature. it will be time to propose a longer term in vivo study to evaluate the long-term effectiveness of the drug for at least 2 ½ years for a range of different breeds of animals. thermal and physical properties prior to planning a detailed in vivo protocol in rats. Pre-pubertal male and female cats (short hair) Variations in results with respect to “sterility” and “cytotoxicity” will occur based on the drug concentration and the animal size. The drug / liposome complex will be administered by intramuscular injection. Pre-pubertal male and female dogs (beagles) c. saline and phosphate buffered saline. Histological staining of the drug molecules will be performed to observe the acute effects on internal organs. After successfully performing all these tests and trials on rats in Study 1 in a proper controlled environment. solubility. Statistical methods will be used to compare the four populations for cats and dogs using their central values and population variances. activated and resorbable over a range of different pH values at 37. Variations assessed while sampling will be calculated in terms of p value to ensure appropriate reliability and confidence intervals. In particular we need to assess their solubility and stability in different aqueous solutions such as distilled water. drug dosage volume and concentration will be studied and compared using various methods such as multiple comparison studies using Scheffeʼs S method. It will be necessary to characterize their chemical. Statistical Analysis: Computing the data and presenting results is an important task from studying the success rate of administering sterility drugs to rats. The variables such as size of assay.

Animal Use Justification: We will be starting our study with rats.August 2012 2 3 Preparation & characterization of liposome drug complex. and later continuing with cats and dogs. Data Analysis & Conclusions August – December 2012 Justification Application process time ends June 1st. approval within 4 to 6 weeks Experimentation and data gathering January – February 2013 February 2013 – July 2013 4 5 In Vivo Trial (Study 2) Development of protocol and performing experimental work for intended 4 groups of dogs and cats Data compilation and analysis Understanding of data and results of Study 1 Experimentation and data gathering August 2013 – October 2013 Results and analysis of Study 2 Once the preliminary studies (Study 1 and 2) are completed. An initial proposal and justification on the use of laboratory animals will be submitted to the local . All the animals used in the experimental studies will be spayed and neutered once the experimentation has been performed. then we will propose conducting further studies using a number of different breeds of animals for at least 2-½ year in which the number of testable factors will be expanded. IACUC inspectors approval will be required. effectiveness study on male and female rats (Study 1). if their outcomes are successful. NC State University. The protocol used throughout the trials will include the requirements as defined by the standard National Research Councils Guide for the care and use of Laboratory Animals guideline (2008) in accordance with IACUC regulations. and a visit will be made by the inspectors to the animal holding facilities at the College of Veterinary Medicine. IACUC approvals and regulations will be required at each stage of the studies.Timeline: S No Event 1 Grant Application Submission and Approval Duration June . before the start of the project as required.

Equipment: All equipment purchases will be made within the policy and guidelines of NC State University. such as Dr. such as rats. Proper food. details of the proposed changes will be submitted to the local IACUC Committee for prior approval. faculty fringe benefits of 19.000. 1st Year Budget: $80. cats and dogs before the studies start.000 per year. will be the principal investigator and will lead the research. Maintenance Cost: Maintenance and calibration costs of the equipment and facilities are charged each month at 2. Professor Dr. King.000) .000 for every academic year. Martin W.000 and 3rd Year Budget: $60. Budget: Project timeline: 3 year. dogs and cats.000 to $16.5% and are taken care by NCSU administration except for purchased items.2015 Personnel: There will be only one Principal Investigator but a co-investigator will be added.000. and to undertake the in vivo animal trials and complete the statistical analysis. registration and accommodation while attending such a conference will be covered by the budget. once the project is funded and the animal studies will start. Animals and Supplies: For the purchase maintenance. diet. The grant amount may wary starting from $9. Overall Budget: $266. temperature and housing for animals will be provided at all times.000) Other Direct Costs: Materials. teaching grants and fellowship grants. (Total: $20.000) Facilities & Administrative Costs: All equipmentʼs and facilities utilized by graduate students for experimentation are charged and billed each month to the Principal Investigator. 2nd Year Budget: $60. DVM. care. (Total $40.000. As defined by NCSU regulations. exercise.000. If there is a need for any change in the study protocols. The estimated cost is proposed in a realistic manner to cover the costs of Studies 1 and 2. Travel: The graduate student and/or faculty member will be expected to travel and attending national and international conferences to present the results of this work. Professor of Surgery at the College of Veterinary Medicine. food and housing of the animals the estimated cost will be approximately $110. Kyle Mathews.000) Graduate Student tuition: All research assistantships at NCSU have their in-state tuition paid and supported by federal grant. (Total: $30. Two full-time graduate student research assistants (RAʼs) will be required to prepare and characterize the drug / liposome complex biomaterials. The costs for travel. NC State University. Justification for Proposed Budget for 2012 . (Total: $6. The annual cost of a graduate student assistantship including “out-of-state” tuition and health insurance coverage is approximately $60.IACUC Committee so that prior approval can be obtained in all matters requiring the testing of rats.1% of salary will be added to the first yearʼs budget.

    June  2010  –  Dec  2010  Management  Trainee.  Kids.   Co-curricular Activates: Headed Rotract TIP-Karsaz as Vice President Worked with UNICEF.  Quality  Management  System. currently member of TCF-USA team for awareness and promotion of TCF work internationally.K.  Resource   Management  and  Marketing  and  Planning. Worked as TCF mentor.  Pakistan   • Assisted  in  Product  Development  for  GAP. Raleigh. Apt 307 Mission Valley Apt.  Pakistan   • Worked  on  Global  Reporting  Indicators  (GRi3). 27606 (248) 821-0923 rjindan@ncsu.edu Work Address: 1267 College of Textiles Box 8301.  with  Engro  Pakistan  and  AkzoNobel  Pakistan  and  verified   their  sustainability  initiatives  taken  in  year  2010   • Certified  Lead  Auditor  for  ISO  9001:2008.S in Textile Technology GPA: 3. NC Objective: My objective is to work at NCSU in a challenging environment and utilize my skills with advisors to solve problems that are affecting the world around us by coming up with innovative solutions for highlighted problems at large in developing countries. Working with Ray of Hope in Africa on HIV Aids project proposal.  Published  by  LAP     Experience:   March  2011  –  July  2011   United  Registrar  of  Systems  (URS).  audited  various  conglomerates  in   the  capacity  of  Auditor. Education: August2011 – Dec2014 North Carolina State University M. planner in Pakistan.58/4.       • Studied  Courses  from  Chartered  Management  Institute  of  U.  (Gap  Men’s.  Artistic  Milliners  (AM).  Women)     • Counter  Development  and  Quality  Control  for  proto-­‐samplings  before  Premier  Vision  (France)  Show  Fall   2010.  Karachi   BSc  in  Textile  Sciences  GPA:  3.0   Thesis:  Enhancing  surface  properties  of  textile  materials  using  organic  solvents.02  /4.Rahim Jindani Home Address: 701 Centenial Parkway.  ISBN:  978-­‐ 3-­‐8433-­‐8615-­‐9. NC.   • Studied  Better  Cotton  (BT)  initiatives  taken  by  H&M. .  Advisor:  Faiza  Saeed.  on  financial  Control. WHO on Polio eradication Working Currently with The Citizen Foundation to ensure better education for all young students.0 Concentrations in medical textiles and nonwovens August  2006  –  May  2010   Textile  Institute  of  Pakistan  (TIP). Raleigh.

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