(M1130-07-44) Melt-Extruded Paclitaxel Nanocrystal-Loaded Fibers for Local Chemotherapy with Sustained Antitumor Activity

Purpose: Localized chemotherapy offers a promising approach to minimizing systemic toxicity while enhancing treatment efficacy. This study focuses on the development of biodegradable sutures loaded with paclitaxel nanocrystals using melt extrusion technology to enable sustained drug delivery following tumor resection. Given the significant risk of local recurrence post-surgery, incorporating paclitaxel as nanocrystals aims to mitigate this challenge [1]. These drug-loaded sutures serve a dual function: they provide structural integrity for wound closure while simultaneously delivering targeted chemotherapy at the surgical site. By promoting healing and reducing tumor recurrence, this approach optimizes post-resection outcomes. Paclitaxel was chosen for its broad-spectrum efficacy across multiple cancer types, and its nanocrystal formulation enhances cellular uptake, improving therapeutic impact. Melt extrusion, a solvent-free and continuous process, ensures efficient and reproducible suture fabrication, making this strategy a viable and safer alternative to conventional cancer treatments such as radiotherapy.

Methods: Paclitaxel nanocrystals were prepared using a wet milling technique with Kolliphor P 407 as a stabilizer at a drug-to-stabilizer weight ratio of 4:1. Zirconium beads (0.5 mm) served as milling media, and the nanosuspension was processed in a roller mill at 155 rpm for 48 hours. Particle size during the milling process was monitored using Dynamic Light Scattering. Ultracentrifugation was performed at 15,000 rpm for 1 hour to precipitate paclitaxel nanocrystals. The supernatant containing unbound surfactant was discarded, and the remaining suspension was freeze-dried to yield solid paclitaxel nanocrystals. Wide-angle X-ray Scattering was used to evaluate the crystallinity of paclitaxel nanoparticles.A two-step extrusion approach was employed to ensure homogeneous drug distribution using the HAAKE minilab extruder. First, Paclitaxel nanocrystals were extruded into a Resomer 504H polymer matrix. The blend was densified, producing free-flowing granules. Second, these granules were extruded at 10 rpm and 110°C, followed by processing through a heated 0.48 mm die to form cylindrical rods. The extruded rods were then drawn on a heated guide plate using a dual-wheel puller to achieve the target suture diameter (130-150 µm). Multiple suture formulations (Figure 2) were developed and analyzed for their mechanical properties and drug release profiles. To compare these formulations, an accelerated in vitro release study was conducted at 50°C in 1% w/v Tween 80 normal saline solution. During the study, fiber shrinkage was observed upon contact with the release media. This shrinkage prompted further investigation into its causes and effects. To address the issue, an annealing step was introduced to stabilize the fibers

Results: Milled Paclitaxel nanoparticles had an average size of 318 nm with a polydispersity index (PDI) of 0.192, indicating uniform size distribution. Following ultracentrifugation, the drug content in the nanocrystals was determined to be 87.3%, with the remaining percentage attributed to adsorbed surfactant particles. Wide-angle X-ray Scattering verified the crystalline nature of Paclitaxel after media milling and within the suture, also revealing orientation of the crystals due to the drawing process (Figure 1).The fiber drawing process also led to the orientation of polymer chains in Resomer 504H, an amorphous polymer, where molecular chains were aligned due to applied stress [2]. This alignment enhanced mechanical strength, as tensile testing showed that stretched suture (F1) exhibited superior strength (82.1±11.9 MPa) compared to unstretched fiber (59.6 ±2.5 MPa). Paclitaxel release studies conducted at 50°C showed a notable increase in drug release following the incorporation of PEG 8000 (Figure 2). While 15% PEG 8000 yielded the highest drug release, phase separation with Resomer 504H led to weakened mechanical integrity, causing suture breakage. A lower concentration (8% PEG 8000) improved drug release while preserving fiber strength. During the release study, fiber shrinkage was observed, likely due to a preference for a more random configuration driven by increased entropy [3]. F1 exhibited a shrinkage rate of 62% within one day, whereas F3 showed a reduced shrinkage rate of 24% within the same period. To address this issue, an annealing step was introduced. While F1 fractured during annealing, F3 remained structurally stable, demonstrating enhanced integrity. Post-annealing, no shrinkage was observed in F3, confirming that thermal stabilization effectively preserved fiber morphology.

Conclusion: This study demonstrates the feasibility of paclitaxel-loaded biodegradable sutures as a system for localized chemotherapy. By employing melt extrusion technology, a solvent-free and scalable process, we successfully dispersed paclitaxel nanocrystals within a polymer matrix, enhancing drug dispersion and cellular uptake. By optimizing the content of PEG 8000, we achieved controlled drug release with mechanical integrity. Annealing was also proven effective in eliminating fiber shrinkage, ensuring long-term structural integrity. This two-in-one suture system not only closes tissue but also releases sustained chemotherapy to the site of surgery, reducing the risk of local tumor recurrence. The findings refer to the potential of melt-extruded drug-loaded sutures for enhancing targeted cancer therapy strategies. Further polymer-drug combinations may be explored in future studies to continue optimizing therapeutic activity and maximizing clinical utility.

References: 1. Cahlon O, Brennan MF, Jia X, Qin LX, Singer S, Alektiar KM. A postoperative nomogram for local recurrence risk in extremity soft tissue sarcomas after limb-sparing surgery without adjuvant radiation. Annals of surgery. 2012 Feb 1;255(2):343-7.
2. Xu S, Zhou J, Pan P. Structural evolutions of initially amorphous polymers during near‐tg stretching: a minireview of recent progresses. Macromolecular Chemistry and Physics. 2022 Jan;223(2):2100427.
3. Shadman S, Nguyen‐Dang T, Das Gupta T, Page AG, Richard I, Leber A, Ruza J, Krishnamani G, Sorin F. Microstructured biodegradable fibers for advanced control delivery. Advanced Functional Materials. 2020 Mar;30(13):1910283.


Figure 1. Wide-angle X-ray Scattering of Paclitaxel raw material, Paclitaxel nanocrystals, and Paclitaxel loaded suture (20% Paclitaxel nanocrystals dispersed in Resomer504H).
(a) WAXS pattern of paclitaxel-loaded suture, showing crystal orientation behavior.
(b) WAXS pattern of plain (unloaded) suture, included as a control for comparison.



Figure 2. Accelerated in vitro release of paclitaxel from sutures at 50 °C in 1% w/v Tween 80 normal saline solution, comparing formulations with and without PEG 8000.