This part of the grant proposal involves the synthesis and formulation of a novel class of biodegradable polymers - polyanhydrides. Our research group will develop systems for releasing those substances desired by other research groups in the NCDDG using approaches developed in our laboratory and conduct research to create polyanhydrides that can encapsulate proteins and to release multiple drugs, and to release drugs for longer times. We will also explore new methods to create nanospheres. This work builds on earlier studies in which we proposed the first approaches for the synthesis of new biodegradable polymers that would display surface erosion (this would make the erosion process constant (for slabs) and predictable and had heretofore not been accomplished with biocompatible polymers without additives). Our proposal was that this might be achieved by synthesizing hydrophobic polyanhydrides. We developed new synthesis procedures for polyanhydrides and obtained the first high molecular weight (Mw>40,OOO) polyanhydrides; synthesized polyanhydrides, which can, by the choice of copolymer, degrade at different rates; developed microencapsulation approaches for these polymers and conducted toxicology studies on this class of polymers. All of these studies have led to the point where these are one of the very few synthetic biodegradable polymers and the only surface eroding polymer that are to be used as implants in clinical studies. In the past grant period, we successfully achieved our specific objectives. The last proposal had three specific aims: l) synthesis of polyanhydrides, 2) development of methods to incorporate substances in polyanhydride discs or pellets, and 3) development of microencapsulation approaches for polyanhydrides. Thirty-one papers were published on these topics.
The specific aims of the current proposal are to l) develop approaches for creating nanospheres, 2) develop delivery systems for proteins, 3) develop systems that can release molecules from l month to l year, and develop systems to release multiple drugs.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program--Cooperative Agreements (U19)
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Johns Hopkins University
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Gabikian, Patrik; Tyler, Betty M; Zhang, Irma et al. (2014) Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres. J Neurosurg 120:1078-85
Tyler, Betty; Wadsworth, Scott; Recinos, Violette et al. (2011) Local delivery of rapamycin: a toxicity and efficacy study in an experimental malignant glioma model in rats. Neuro Oncol 13:700-9
Slager, Joram; Tyler, Betty; Shikanov, Ariella et al. (2009) Local controlled delivery of anti-neoplastic RNAse to the brain. Pharm Res 26:1838-46
Pradilla, Gustavo; Wang, Paul P; Gabikian, Patrik et al. (2006) Local intracerebral administration of Paclitaxel with the paclimer delivery system: toxicity study in a canine model. J Neurooncol 76:131-8
Sampath, Prakash; Rhines, Laurence D; DiMeco, Francesco et al. (2006) Interstitial docetaxel (taxotere), carmustine and combined interstitial therapy: a novel treatment for experimental malignant glioma. J Neurooncol 80:9-17
Legnani, Federico G; Pradilla, Gustavo; Thai, Quoc-Anh et al. (2006) Lactacystin exhibits potent anti-tumor activity in an animal model of malignant glioma when administered via controlled-release polymers. J Neurooncol 77:225-32
Li, Yawen; Ho Duc, Hong Linh; Tyler, Betty et al. (2005) In vivo delivery of BCNU from a MEMS device to a tumor model. J Control Release 106:138-45
Sorg, Brian S; Peltz, Cathryn D; Klitzman, Bruce et al. (2005) Method for improved accuracy in endogenous urea recovery marker calibrations for microdialysis in tumors. J Pharmacol Toxicol Methods 52:341-9
Li, Yawen; Shawgo, Rebecca S; Tyler, Betty et al. (2004) In vivo release from a drug delivery MEMS device. J Control Release 100:211-9
Grossi, Peter M; Ochiai, Hidenobu; Archer, Gary E et al. (2003) Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer. Clin Cancer Res 9:5514-20

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