Browsing by Author "Banskota, Samagya"
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Item Open Access Brachytherapy via a depot of biopolymer-bound 131I synergizes with nanoparticle paclitaxel in therapy-resistant pancreatic tumours.(Nature biomedical engineering, 2022-10) Schaal, Jeffrey L; Bhattacharyya, Jayanta; Brownstein, Jeremy; Strickland, Kyle C; Kelly, Garrett; Saha, Soumen; Milligan, Joshua; Banskota, Samagya; Li, Xinghai; Liu, Wenge; Kirsch, David G; Zalutsky, Michael R; Chilkoti, AshutoshLocally advanced pancreatic tumours are highly resistant to conventional radiochemotherapy. Here we show that such resistance can be surmounted by an injectable depot of thermally responsive elastin-like polypeptide (ELP) conjugated with iodine-131 radionuclides (131I-ELP) when combined with systemically delivered nanoparticle albumin-bound paclitaxel. This combination therapy induced complete tumour regressions in diverse subcutaneous and orthotopic mouse models of locoregional pancreatic tumours. 131I-ELP brachytherapy was effective independently of the paclitaxel formulation and dose, but external beam radiotherapy (EBRT) only achieved tumour-growth inhibition when co-administered with nanoparticle paclitaxel. Histological analyses revealed that 131I-ELP brachytherapy led to changes in the expression of intercellular collagen and junctional proteins within the tumour microenvironment. These changes, which differed from those of EBRT-treated tumours, correlated with the improved delivery and accumulation of paclitaxel nanoparticles within the tumour. Our findings support the further translational development of 131I-ELP depots for the synergistic treatment of localized pancreatic cancer.Item Open Access Development of Genetically Encoded Zwitterionic Polypeptides for Drug Delivery(2019) Banskota, SamagyaThe clinical utility of many peptide, protein and small molecule drugs is limited by their short in-vivo ¬half-life. To address this limitation, we report a new class of biomaterials that have a long plasma circulation time. In particular, taking inspiration and cues from natural proteins and synthetic polymers, we have worked to create polypeptide-based drug carriers that are biocompatible and biodegradable. These peptide polymers or polypeptides can be attached to therapeutics with molecular precision as they are designed from the gene level.
In the first part of this thesis (Chapter 3-4), we report on the development of a new class of biomaterials called zwitterionic polypeptides (ZIPPs) that exhibit “stealth” behavior, and when fused to therapeutics, improve their pharmacological efficacy. To identify an optimal polypeptide design, we first synthesized a library of ZIPPs by incorporating various oppositely charged amino acids within an intrinsically disordered polypeptide motif, (VPX1X2G)n, where X1 and X2 are cationic and anionic amino acids, respectively, and n is the number of repeats. The (VPX1X2G)n motif is derived from the disordered region of human tropo-elastin. By systematically varying the identity of the charged amino acids and the chain length of the polypeptide, we determined the optimal polypeptide sequence that maximizes the pharmacokinetics for intravenous and subcutaneous routes of administration. We show that a combination of lysine and glutamic acid in the ZIPP confer superior pharmacokinetics, for both intravenous and subcutaneous administration, compared to uncharged control polypeptides. We report detailed physicochemical characterization of this new class of polypeptide-based drug carriers and show its clinical utility for drug delivery by using it to deliver a peptide drug. The peptide drug used is Glucagon like peptide 1 (GLP1) – a therapeutic peptide that is approved for treatment of type 2 diabetes but has seen limited clinical utility because of its short two-minutes half-life. We find that the GLP1-ZIPP conjugate reduced blood glucose level for up to 3 days in a diet induced obesity model of type-2 diabetes in mice after a single s.c. injection. This is a 70-fold improvement over the injection of the unmodified drug and a 1.5-fold improvement over an uncharged polypeptide control.
To further demonstrate the clinical utility of ZIPPs, in the second part of this thesis (Chapter 5), we used ZIPPs to create a nanoparticle system that can package and deliver hydrophobic chemotherapeutic drugs to the tumor with higher efficacy and lower toxicity. Such nanoparticle drug carriers are attractive for systemic delivery of chemotherapeutics because they improve the half-life of the drug, protect the drug from early degradation, and increase selective accumulation of drugs in tumors via the enhanced permeation and retention effect (EPR). The EPR effect is a consequence of the leaky vasculature and poorly developed lymphatic drainage system present in the tumors. These attributes of nanoparticles are significant and desirable because drug delivery systems that can improve circulation time and tumor accumulation of chemotherapeutics have the ability to improve the patient prognosis and survival by controlling the tumors at their local sites. To that end, we conjugated paclitaxel a chemotherapy drug that is used to treat different types of cancer to ZIPPs and showed that it imparts sufficient amphiphilicity to the polypeptide chain to drive its self-assembly into sub-100 nm nanoparticles. We report that ZIPPs can increase the systemic exposure of paclitaxel by 17-fold compared to the free drug and 1.6-fold compared to uncharged recombinant control. Treatment of mice bearing highly aggressive prostate cancer or colon cancer with a single dose of ZIPP-Paclitaxel nanoparticles leads to a near complete-eradication of the tumors (5 out of 7 cures in prostate cancer) and (2 out of 7 cures in colon cancer) and it outperforms Abraxane, which is an FDA approved taxane nanoformulation and current gold standard for paclitaxel delivery.
In summary, this doctoral research is multidisciplinary, which integrates the field of protein engineering, molecular biology, bioconjugate chemistry, soft matter physics and cancer biology for rational design of biomaterials for drug delivery.