Silylated Precision Particles for Controlled Release of Proteins

Abstract

With the recent advances in the development of novel protein based therapeutics, controlled delivery of these biologics is an important area of research. Herein, we report the synthesis of microparticles from bovine serum albumin (BSA) as a model protein using Particle Replication in Non-wetting Templates (PRINT) with specific size and shape. These particles were functionalized at room temperature using multifunctional chlorosilane that cross-link the particles to render them to slowly-dissolving in aqueous media. Mass spectrometric study of the reaction products of diisopropyldichlorosilane with individual components of the particles revealed that they are capable of reacting and forming cross-links. Energy dispersive spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS) were also used to confirm the functionalization of the particles. Cross sectional analysis using focused ion beam (FIB) and EDS proved that the functionalization occurs throughout the bulk of the particles and is not just limited to the surface. Circular dichroism data confirmed that the fraction of BSA molecules released from the particles retains its secondary structure thereby indicating that the system can be used for delivering protein based formulations while controlling the dissolution kinetics.

Particles for Local Delivery of Proteins Using Intra‐Articular Route

“…Unfunctionalized dry particles that were not exposed to the reconstitution medium are also shown for comparison (Figure 2.A and 2.E). These observations are consistent with the faster dissolution rate of 12 hr silylated particles when compared to the particles silylated for 24 hr, [8] and qualitatively show the structural changes associated with the exposure of the silylated particles to the reconstitution medium. The relative size of the particles is compared with the diameter of the needle used for the i.a.…”

“…According to Mitragotri and Yoo, [7] carrier systems that release the drug in a controlled manner in the synovial area and are rationally designed based on physiochemical properties of the drug and pathophysiological characteristics of the disease are greatly needed for treating arthritis. In this work, possibility of using slowly-dissolving silylated bovine serum albumin (BSA) particles (functionalization and characterization details can be found elsewhere), [8] as a carrier for i.a. delivery is investigated.…”

“…Stability is conferred to the particles with diisopropyldichlorosilane (DIDCS) as a crosslinking agent that retains the secondary structure of the molecule while shape and size of the particles is precisely controlled with Particle Replication in Non-wetting Templates (PRINT) to prepare micro-toroids with rectangular cross-section. [8] …”

“…[8] In Figure 2.A–2.H effect of exposure of the particles to the reconstitution medium post lyophilization from freeze-drying medium (TBA+5% w/v PVP) is evaluated with SEM. The 24 hr silylated particles are highly stable in aqueous medium with very slow dissolution rate.…”

Nanodiamonds Mediate Oral Delivery of Proteins for Stem Cell Activation and Intestinal Remodeling in Drosophila

“…Aberrant protein functions are responsible for a variety of diseases, including cancers. , Whereas chemical drugs and gene delivery have been widely used to alleviate intracellular protein dysfunctions for therapeutic purposes, direct delivery of proteins is of higher specificity and safety and minimizes the risks of altering genetic information . More significantly, direct introduction of functional proteins into cells can quickly alter cellular activities and rescue cellular functions without delay, which is in contrast to the introduction of DNA or RNA constructs that rely on endogenous transcription and translation machinery to produce appropriate protein products or delete dysfunctional proteins. − Furthermore, the nonreplicable nature of protein is especially useful for transient regulation. − Hence, delivery of functional proteins into cells and organisms can provide enhanced specificity, increased safety, and fast and temporal regulation. As one elegant example, Liu and co-workers developed agents based on cationic lipid nanoparticles to deliver the CRISPR-Cas9 system to achieve efficient genome editing …”