Marimuthu, P; (2017) Oral delivery of therapeutic peptides using GCPQ nanoparticles. Doctoral thesis , UCL (University College London).

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Abstract

Oral delivery of therapeutic peptides poses serious challenges in the field of drug delivery. The main concerns in developing an oral formulation of therapeutic peptide is that the peptide can be susceptible to enzymes in the gastrointestinal tract, poor solubility, short circulation time in plasma and fast renal clearance. This study focuses on improving the oral availability of therapeutic peptide by its encapsulation in a biodegradable polymer called GCPQ. GCPQ has been reported previously to solubilize small molecular weight hydrophobic drugs and peptides. GCPQ also demonstrated to improve their oral bioavailability. In the present study, two therapeutic peptides, Methionine enkephalin (anticancer peptide) and Labyrinthopeptin (anti-noiciceptive peptide) was characterized and formulated with GCPQ nanoparticles. Labyrinthopeptin, a hydrophobic peptide having poor solubility was solubilized using GCPQ nanoparticles and their oral uptake was evaluated in vivo. Anti-noiciceptive activity of Laby GCPQ B2 formulation was evaluated in rat CFA model and compared against Laby glycofurol formulation. Therapeutic effect of Laby GCPQ B2 oral and nasal formulation was found to be significantly higher to control at time points 240 min and 40 min respectively as demonstrated in rat CFA model. Laby glycofurol formulation also showed significant therapeutic effect (40 and 60 min) after nasal administration as a result of permeation enhancing property of glycofurol itself. Concentrations of Laby in plasma were observed to be higher for Laby GCPQ B3 oral and nasal formulation compared to Laby glycofural formulation, suggesting that GCPQ improves oral uptake of Laby peptide. However, concentrations of Laby in plasma for Laby GCPQ B1 formulation were lower than that it was observed for Laby GCPQ B3 and Laby glycofural formulation, suggesting that the characteristics of GCPQ can be modified to control the uptake of Laby peptide. Similarly, Methionine enkephalin, a peptide having poor stability in the gut was formulated with GCPQ B1 & B2 and characterized in vitro and in vivo. Their therapeutic effect was evaluated in nude mice tumor xenograft model. Significant reduction in tumor volume for mice treated with MENK-GCPQ B2 oral formulation was observed compared to MENK formulation and control. The concentration of MENK following oral administration of MENK GCPQ B2 formulation (100 mg/kg) were variable and at nanogram levels. However, this concentration could be sufficient to cause therapeutic effect in mice xenograft model. The concentrations of MENK in plasma were observed to be at nanogram levels (298 ng/mL), 180 min after administration of MENK-GCPQ B1 IV formulation. Following administration of MENK IV formulation, the concentrations of MENK in mice plasma were not detectable after 5 min. This result also suggests that only a fraction of MENK was encapsulated in MENK GCPQ B1 formulation. Although, there were significant differences in pharmacokinetic effect between MENK and MENK GCPQ B1 IV formulations, the therapeutic effect of MENKGCPQ B1 IV formulation in tumor xenograft model was only significant to that of control but insignificant to that of MENK IV formulation. Excess MENK concentration resulting from MENK-GCPQ B1 IV formulation may not have improved the therapeutic effect due to saturation of OGFr receptor and clearance from the system. An alternative mode of MENK-GCPQ administration such as subcutaneous or intra-peritoneal could delay MENK release in the systemic circulation and thereby enhancing the therapeutic effect compared to MENK only formulation.

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