(T1130-09-60) Tailoring Polyester Topologies for Efficient Oral Drug Delivery Systems

Purpose: Polymeric nanosystems holds a great promise for oral drug delivery; however, two key challenges remain: (a) the lack of versatile polymer scaffolds with multiple functional groups that can be tailored for a variety of therapeutic agents and receptor-mediated transport, and (b) the limited availability of ligands that do not compete with endogenous counterparts but enable scalable, targeted delivery systems. While conventional polymers such as PLA and PLGA provide flexibility in drug loading and release kinetics, particularly for hydrophobic compounds, they lack the functionality required for precise ligand-receptor stoichiometry. To address these challenges, a novel Periodic Polyesters (P2s), featuring a backbone densely decorated with carboxylic acid groups, was developed (1). These functional groups facilitate efficient ligand conjugation, allowing for precise modulation of material properties such as degradation rate, hydrophilicity, mechanical strength, ligand-receptor binding, and receptor-mediated transcytosis. The objective of this study is to further develop these P2s polymers with controlled topologies, enabling the loading of a broad spectrum of drugs with diverse physicochemical properties. By utilizing polyethylene glycol (PEG) macroinitiators with varying molecular weights, we modulated the hydrophilic-lipophilic balance of the polymers, allowing for fine-tuning of drug loading capacity, release kinetics, and biological interactions. Ultimately, this work aims to establish a versatile and scalable platform for oral drug delivery, with customizable performance to meet the specific needs of different therapeutic agents.

Methods: A ligand with high affinity for the transferrin receptor was employed to facilitate receptor-mediated uptake. PEG macroinitiators of different molecular weights (400, 1000, and 2000 Da) were used to synthesize PLA-PEG-PLA prepolymers via ring-opening polymerization with L-lactide Figure 1a (1). These were reacted with HCDA to form P2s, a multivalent polyester bearing 5–8 carboxylic acid groups for ligand attachment. Gambogic acid (GA) was conjugated to P2s via EDC coupling using ethylene diamine as a linker, to yield P2s-GA. A library of P2s polymer variants and their ligand-conjugated forms (Figure 1b) were used to formulate nanoparticles encapsulating three model compounds: an anti-inflammatory agent Urolithin A (UA), an immunosuppressant Cyclosporin A (CsA), and a positive allosteric modulator GAT211. Nanoformulations were prepared using an emulsion-diffusion-evaporation method (2,3). Stability of all formulations was assessed in simulated gastric fluid (SGF) for 2 hours and simulated intestinal fluid (SIF) for 6 hours. Particle size, zeta potential, and drug entrapment efficiency were evaluated to determine the structural integrity of the nanoparticles across different polymeric backbones. An accelerated stability study was conducted on P2s-A and P2s-A-GA formulations encapsulating UA. Samples were stored for six months in an environmental test chamber under two conditions: room temperature (RT) (40 ± 2°C, 75 ± 5% RH) and refrigerated (RF) (25 ± 2°C, 60 ± 5% RH). Each month, triplicate vials (n = 3) were withdrawn and analyzed for physical appearance, particle size, morphology, zeta potential, and drug content.

Results: The polymers and ligand-conjugated variants synthesized with varying lactide feed ratios were characterized by NMR and GPC, with molecular weight and dispersity values reported. Particle size, drug entrapment, and zeta potential for all nanoparticle variants encapsulating the model compounds were summarized. Nanoparticles remained stable in SGF for 2 hours; however, exposure to SIF for 6 hours led to increased particle size and reduced zeta potential, indicating partial degradation and decreased stability. The accelerated stability study, ongoing at the time of reporting, showed that particle size, morphology, and drug content remained largely unchanged up to 3 months under both room temperature and refrigerated conditions (Figure 3).

Conclusion: This study successfully synthesized a series of tunable polymeric nanoparticles, both ligand-functionalized and non-functionalized, encapsulating various drugs and drug-like molecules. The formulations remained stable in simulated gastric fluid and exhibited partial degradation in simulated intestinal fluid, aligning with the strategy to enhance gut absorption through receptor-mediated delivery. The nanoparticles also demonstrated stability over three months under accelerated conditions, supporting their translational potential. These findings lay the groundwork for future in vitro, in vivo, and in silico studies, which can be integrated into a novel bottom-up systems PBPK model to quantitatively predict the clinical performance of orally administered nanoparticle-based therapies.

References: 1. Ganugula R, Arora M, Saini P, Guada M, Kumar MNVR. Next Generation Precision-Polyesters Enabling Optimization of Ligand–Receptor Stoichiometry for Modular Drug Delivery. Journal of the American Chemical Society. 2017;139(21):7203-16.
2. González-Barrio R, Truchado P, García-Villalba R, Hervás G, Frutos P, Espín JC, Tomás-Barberán FA. Metabolism of oak leaf ellagitannins and urolithin production in beef cattle. Journal of agricultural and food chemistry. 2012;60(12):3068-77.
3. Azzi J, Tang L, Moore R, Tong R, El Haddad N, Akiyoshi T, et al. Polylactide-cyclosporin A nanoparticles for targeted immunosuppression. Faseb j. 2010;24(10):3927-38.

Acknowledgements: This work is supported by R01GM146097-01A1.

Figure 1. a) Reaction scheme for the synthesis of polymers P2s and P2s-GA using different macroinitiators b) Tabulated feed stock ratios, % hydrophilic fractions, Mn, and PDI values for respective polymer

Figure 2. Heat maps representing the values of particle size, drug entrapment, and zeta potential of respective formulations under simulated transit conditions.

Figure 3. SEM pictographs of the P2Ns-A-UA and P2Ns-GA-A-UA under accelerated stability conditions in accordance with ICH guidelines [Room temperature (RT) conditions: 40ºC ± 2ºC & 75% ± 5% relative humidity (RH), Refrigerated (RF) conditions: 25ºC ± 2ºC & 60% ± 5% RH] along with the drug content.