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Drug Delivery

Drug Delivery - Poster Session B

Poster J9 - Evaluating the Effect of PEG Concentration on Doxorubicin Loading PLGA Nanoparticles

Thursday, October 24, 2024
2:45 PM - 3:45 PM EST
Location: Exhibit Hall E, F & G

Introduction:  Triple-negative breast cancer (TNBC), is an aggressive breast cancer subtype, which accounts for approximately 20% of all breast cancer cases and leads to poor outcomes for patients. Unlike other subtypes of breast cancer, TNBC lacks the breast cancer-associated receptors that current therapies target, which makes TNBC difficult to treat. To improve the treatment of TNBC, therapeutic cargo can be encapsulated in nanoparticles (NPs), which exhibit improved tumor accumulation compared to freely administered drugs. Such NPs can be designed to either passively accumulate in tumors or they may be coated with antibodies or cell-derived biological membranes to enhance tumor delivery. Regardless of the specific surface functionalization, the underlying core NP must have the desired drug encapsulation and release kinetics. Here, we investigate the influence of polymer NP composition on the encapsulation and release of the chemotherapeutic doxorubicin (DOX). Specifically, we prepared NPs with different ratios of methoxy-poly(ethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA) and PLGA to determine the ideal composition for further development as a targeted drug delivery system for TNBC.

Materials and

Methods:  mPEG-PLGA/PLGA NPs were synthesized via single oil in water emulsion method, in which DOX dissolved in dichloromethane was added dropwise to polyvinyl alcohol in water while stirring. The DOX was then added to a vial containing different ratios of mPEG-PLGA to PLGA including 75/25, 50/50, or 25/75. After synthesis, the DOX-loaded NPs were purified via centrifugation, washing with water. Dynamic light scattering was utilized to determine NP size and zeta potential. DOX loading was measured by dissolving NPs in dimethylsulfoxide and reading DOX fluorescence against a standard curve of known DOX concentration in a plate reader.
Drug release kinetics were determine by shaking NPs at 100 rpm at 37 Cº in either pH 5.5 PBS, pH 7.4 PBS, or 10% FBS in pH 7.4 PBS. At each time point, the NPs were centrifuged and the DOX concentration of NPs were measured against a standard curve as previously described.

Results, Conclusions, and Discussions: We evaluated the stability of NP size, charge, and drug loading over time to determine the best formulation to move forward with for developing a targeted delivery system (Figure 1A-D). The 25% mPEG-PLGA/75% PLGA NPs (25/75) were observed to have the best stability in storage conditions retaining 95% of the initial encapsulated drug over a 72 hour period (Figure 1B). This formulation also showed minimal change in size and charge over 72 hours remaining the same in size compared to the 25 nm decrease of the 50% mPEG-PLGA/50% PLGA (50/50) NPs and 25 nm size increase of the 75% mPEG-PLGA/25% PLGA (75/25) NPs (Figure 1C/D). While the total drug encapsulation was less than the 50/50 NP and 75/25 NP formulations (Figure 1A) the drug encapsulation over time was more stable making this particle the most favorable composition to move forward with in future investigations.

We also investigated drug release under different physiologic conditions. In a tumor mimetic solution (pH 5.5 PBS), the 75/25 NPs showed nearly 40% release of total encapsulated drug after 4 hours, and over 70% after 24 hours (Figure 2). By comparison, they released 30% of their encapsulated DOX after 4 hours in 10% FBS (Figure 2). This demonstrates the NPs exhibit faster drug release in the more acidic tumor-like environment, a desirable trait for TNBC therapy.

Acknowledgements (Optional):