(36e) Sequential Nanoprecipitation (SNaP) Allows Uniform Co-Encapsulation of Small Molecules and Colloidal Nanocrystals within Polymeric Nanospheres

Flash Nanoprecipitation (FNP) is used in drug delivery for the tunable, scalable, single-step synthesis of polymeric core-shell nanoparticles (NP) encapsulating small molecule active pharmaceutical ingredients (APIs). Recent interest in colloidal nanocrystals as APIs, or in co-administration with APIs, has yielded a high volume of research aimed at synthesizing hybrid, multifunctional nanoparticles that can be used as diagnostic bioimaging probes and deliver therapeutic payloads. Nanocrystals such as quantum dots, gold NP, and magnetic NP have distinct optical, electronic, and paramagnetic properties based on their size, motivating the need to be able to robustly synthesize composite NP that coencapsulate many sizes of nanocrystals and small molecules. While FNP has been previously used to encapsulate hydrophobic colloidal gold and magnetic nanocrystals, the process is limited by the size of the nanocrystals and polymer co-excipient. Additionally, characterization and workup of these composite NP reveal nonuniform loading of nanocrystals and small molecules, and a low “yield” of NP that contain significant loadings of nanocrystals.

Smoluchowski growth kinetics, which have been predicted as governing principles of FNP, predict orders of a magnitude differences in assembly timescales for dense, low diffusivity crystals versus small molecules. Thus, in this work, we aim to circumvent the problem of mismatch by delaying the co-excipient growth and stabilization phases to overcome different assembly timescales.

Herein we utilize 3D printed prototypical multistage mixers to synthesize nanocrystal-loaded polymeric nanospheres using sequential nanoprecipitation (SNaP). By separating the core components into separate inlet stages and tuning resident lengths between stages, we uncover dominating parameters of diffusion-limited growth kinetics. We demonstrate ability to synthesize uniform composite PLA-based nanospheres 200nm in diameter encapsulating quantum dots, iron oxide, and gold nanoparticles from 2nm to 20nm in size. Ultimately, we show 2+ fold increases in nanocrystal loading yields compared to FNP, and we show nanosphere formation can be decoupled from nanocrystal size.