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Title: Micro/Nano-Structured implants for controlled Drug/protein delivery in chemo/anti-angiogenic therapy of malignant glioma
Keywords: Drug delivery, paclitaxel, glioma, chemotherapy, pharmacokinetics, PLGA
Issue Date: 25-Nov-2009
Citation: SUDHIR HULIKAL RANGANATH (2009-11-25). Micro/Nano-Structured implants for controlled Drug/protein delivery in chemo/anti-angiogenic therapy of malignant glioma. ScholarBank@NUS Repository.
Abstract: Sustained drug administration at high therapeutic levels and deeper penetration of the drug into the tumor are paramount to ensuring substantial improvements in clinical outcomes. The polymeric local drug delivery systems developed over the years have partially addressed this therapeutic challenge, but sufficient drug penetration and sustainability issues still remain as they are controlled by transport properties of the drug, type of polymeric carrier and geometry of the implant. In this study, the chemotherapeutic drug paclitaxel possessing favorable transport properties in the brain/tumor tissue was encapsulated in two types of poly(D,L-lactic-co-glycolic) acid (PLGA) based implants. First, paclitaxel-loaded PLGA was micro/nano-structured into fibers diameters ranging from micron to nanometer using electrospinning technique. Second, paclitaxel-loaded PLGA microspheres were entrapped in calcium cross-linked alginate matrix (beads) using electrospray technique and ionotropic gelation. Enhanced, therapeutic paclitaxel penetration (~1 ?M) in the mouse brain up to 5 mm from the implant site even after 42 days post-implantation from these implants was confirmed and deduced to be diffusion/elimination controlled. The implants demonstrated significant (~30 fold) tumor inhibition and significantly low tumor proliferation index after 41 days of treatment in comparison to sham and placebo controls. In another study, microcapsules with calcium cross-linked alginate core and genipin-chitosan membrane shell (GCA) were fabricated and the effects of the membrane characteristics and microcapsule size on bio-molecular mass transport across these microcapsules using mathematical models based on the balance of bio-molecular chemical potential were analyzed. Compared to other microcapsules, the GCA microcapsules possess greater perm-selectivity for they allow diffusion of small molecules and proteins but completely exclude large antibodies. In summary, the micro/nano-structuring of polymeric implants could enhance the paclitaxel availability at the implant surface resulting in deeper drug penetration in the tumor tissue and hence these implants could be potential drug delivery devices for local chemotherapy to treat malignant brain tumors. Additionally, the GCA microcapsules possessing greater perm-selectivity and capsular integrity could be used to encapsulate terminally differentiated cells to express and release proteins with anti-angiogenic and anti-tumoral properties to treat brain tumors.
Appears in Collections:Ph.D Theses (Open)

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