This work examines the release of a model water-soluble compound from electrospun polymer nanofiber assemblies. Such release attracts attention in relation to biomedical applications, such as controlled drug delivery. It is also important for stem cell attachment and differentiation on biocompatible electrospun nanofiber scaffolds containing growth factors, which have been encapsulated by means of electrospinning. Typically, the release mechanism has been attributed to solid-state diffusion of the encapsulated compound from the fibers into the surrounding aqueous bath. Under this assumption, a 100% release of the encapsulated compound is expected in a certain (long) time. The present work focuses on certain cases where complete release does not happen, which suggests that solid-state diffusion may not be the primary mechanism at play. We show that in such cases the release rate can be explained by desorption of the embedded compound from nanopores in the fibers or from the outer surface of the fibers in contact with the water bath. After release, the water-soluble compound rapidly diffuses in water, whereas the release rate is determined by the limiting desorption stage. A model system of Rhodamine 610 chloride fluorescent dye embedded in electrospun monolithic poly(methylmethacrylate) (PMMA) or poly(caprolactone) (PCL) nanofibers, in nanofibers electrospun from PMMA/PCL blends, or in core-shell PMMA/PCL nanofibers is studied. Both the experimental results and theory point at the above mentioned desorption-related mechanism, and the predicted characteristic time, release rate, and effective diffusion coefficient agree fairly well with the experimental data. A practically important outcome of this surface release mechanism is that only the compound on the fiber and pore surfaces can be released, whereas the material encapsulated in the bulk cannot be freed within the time scales characteristic of the present experiments (days to months). Consequently, in such cases, complete release is impossible. We also demonstrate how the release rate can be manipulated by the polymer content and molecular weight affecting nanoporosity and the desorption enthalpy, as well as by the nanofiber structure (monolithic fibers, fibers from polymer blends, and core-shell fibers). In particular, it is shown that, by manipulating the above parameters, release times from tens of hours to months can be attained.
Therapeutic proteins have emerged as a significant class of pharmaceutical agents over the past several decades. The potency, rapid elimination, and systemic side-effects have prompted the need of spatiotemporally controlled release for proteins maybe more than any other active therapeutic molecules. This work examines the release of two model protein compounds, bovine serum albumin (BSA) and an anti-integrin antibody (AI), from electrospun polycaprolactone (PCL) nanofiber mats. The anti-integrin antibody was chosen as a model of antibody therapy; in particular, anti-integrin antibodies are a promising class of therapeutic molecules for cancer and angiogenic diseases. The release kinetics were studied experimentally and interpreted in the framework of a recently published theory of desorption-limited drug release from non-degrading—or very slowly degrading—fibers. The results are consistent with a protein release mechanism dominated by desorption from the polymer surface, while the polycaprolactone nanofibers are not degrading at an appreciable rate.
Conventional imaging technologies (X-ray computed tomography, magnetic resonance, and optical) depend on contrast agents to visualize a target site or organ of interest. The imaging agents currently used in clinics for diagnosis suffer from disadvantages including poor target specificity and in vivo instability. Consequently, delivery of low concentrations of contrast agents to region of interest affects image quality. Therefore, it is important to selectively deliver high payload of contrast agent to obtain clinically useful images. Nanoparticles offer multifunctional capabilities to transport high concentrations of imaging probes selectively to diseased site inside the body. Polymeric nanoparticles, incorporated with contrast agents, have shown significant benefits in molecular imaging applications. These materials possess the ability to encapsulate different contrast agents within a single matrix enabling multimodal imaging possibilities. The materials can be surface conjugated to target-specific biomolecules for controlling the navigation under in vivo conditions. The versatility of this class of nanomaterials makes them an attractive platform for developing highly sensitive molecular imaging agents. The research community's progress in the area of synthesis of polymeric nanomaterials and their in vivo imaging applications has been noteworthy, but it is still in the pioneer stage of development. The challenges ahead should focus on the design and fabrication of these materials including burst release of contrasts agents, solubility, and stability issues of polymeric nanomaterials.
A tri-block nanoparticle (TBN) comprising of an enzymatically cleavable porous gelatin nanocore encapsulated with gefitinib (tyrosine kinase inhibitor (TKI)) and surface functionalized with cetuximab-siRNA conjugate has been synthesized. Targeted delivery of siRNA to undruggable KRAS mutated non-small cell lung cancer cells would sensitize the cells to TKI drugs and offers an efficient therapy for treating cancer; however, efficient delivery of siRNA and releasing it in cytoplasm remains a major challenge. We have shown TBN can efficiently deliver siRNA to cytoplasm of KRAS mutant H23 Non-Small Cell Lung Cancer (NSCLC) cells for oncogene knockdown; subsequently, sensitizing it to TKI. In the absence of TKI, the nanoparticle showed minimal toxicity suggesting that the cells adapt a parallel GAB1 mediated survival pathway. In H23 cells, activated ERK results in phosphorylation of GAB1 on serine and threonine residues to form GAB1-p85 PI3K complex. In the absence of TKI, knocking down the oncogene dephosphorylated ERK, and negated the complex formation. This event led to tyrosine phosphorylation at Tyr627 domain of GAB1 that regulated EGFR signaling by recruiting SHP2. In the presence of TKI, GAB1-SHP2 dissociation occurs, leading to cell death. The outcome of this study provides a promising platform for treating NSCLC patients harboring KRAS mutation.
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