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Polymeric nanoparticles containing multiple amines and carboxylates have been frequently used in drug delivery research. Reproducible and controlled conjugation among these multifunctional biomaterials is necessary to achieve efficient drug delivery platforms. However, multiple functional groups increase the risk of unintended intramolecular/intermolecular reactions during conjugation. Herein, conjugation approaches and possible undesired reactions between multi-amine functionalized peptides, multi-carboxylate functionalized polymers, and anhydride-containing polymers [Poly(styrene-alt-maleic anhydride)-b-poly(styrene)] were investigated under different conjugation strategies (carbodiimide chemistry, anhydride ring-opening via nucleophilic addition elimination). Muti-amine peptides led to extensive crosslinking between polymers regardless of the conjugation chemistry. Results also indicate that conventional peptide quantification methods (i.e., o-phthalaldehyde assay, bicinchoninic acid assay) are unreliable. Gel permeation chromatography (GPC) provided more accurate qualitative and quantitative evidence for intermolecular crosslinking. Crosslinking densities were correlated with higher feed ratios of multifunctional peptides and carbodiimide coupling reagents. Selectively protected peptides (Lys-Alloc) exhibited no crosslinking and yielded peptide-polymer conjugates with controlled dispersity and molecular weight. Furthermore, anhydride ring-opening (ARO) nucleophilic addition elimination was successfully introduced as a facile yet robust peptide conjugation approach for cyclic anhydride-containing polymers. 

The burden of cancer continues to increase in society and negatively impacts the lives of numerous patients. Due to the high cost of current treatment strategies, there is a crucial unmet need to develop inexpensive preclinical platforms to accelerate the process of anti-cancer drug discovery to improve outcomes in cancer patients, most especially in female patients. Many current methods employ expensive animal models which not only present ethical concerns but also do not often accurately predict human physiology and the outcomes of anti-cancer drug responsiveness. Conventional treatment approaches for cancer generally include systemic therapy after a surgical procedure. Although this treatment technique is effective, the outcome is not always positive due to various complex factors such as intratumor heterogeneity and confounding factors within the tumor microenvironment (TME). Patients who develop metastatic disease still have poor prognosis. To that end, recent efforts have attempted to use 3D microengineered platforms to enhance the predictive power and efficacy of anti-cancer drug screening, ultimately to develop personalized therapies. Fascinating features of microengineered assays, such as microfluidics, have led to the advancement in the development of the tumor-on-chip technology platforms, which have shown tremendous potential for meaningful and physiologically relevant anti-cancer drug discovery and screening. Three dimensional microscale models provide unprecedented ability to unveil the biological complexities of cancer and shed light into the mechanism of anti-cancer drug resistance in a timely and resource efficient manner. In this review, we discuss recent advances in the development of microengineered tumor models for anti-cancer drug discovery and screening in female-related cancers. We specifically focus on female-related cancers to draw attention to the various approaches being taken to improve the survival rate of women diagnosed with cancers caused by sex disparities. We also briefly discuss other cancer types like colon adenocarcinomas and glioblastoma due to their high rate of occurrence in females, as well as the high likelihood of sex-biased mutations which complicate current treatment strategies for women. We highlight recent advances in the development of 3D microscale platforms including 3D tumor spheroids, microfluidic platforms as well as bioprinted models, and discuss how they have been utilized to address major challenges in the process of drug discovery, such as chemoresistance, intratumor heterogeneity, drug toxicity, etc. We also present the potential of these platform technologies for use in high-throughput drug screening approaches as a replacements of conventional assays. Within each section, we will provide our perspectives on advantages of the discussed platform technologies. 

Abstract Despite decades of progress, developing minimally invasive bone‐specific drug delivery systems (DDS) to improve fracture healing remains a significant clinical challenge. To address this critical therapeutic need, nanoparticle (NP) DDS comprised of poly(styrene‐alt‐maleic anhydride)‐b‐poly(styrene) (PSMA‐b‐PS) functionalized with a peptide that targets tartrate‐resistant acid phosphatase (TRAP) and achieves preferential fracture accumulation has been developed. The delivery of AR28, a glycogen synthase kinase‐3 beta (GSK3β) inhibitor, via the TRAP binding peptide‐NP (TBP‐NP) expedites fracture healing. Interestingly, however, NPs are predominantly taken up by fracture‐associated macrophages rather than cells typically associated with fracture healing. Therefore, the underlying mechanism of healing via TBP‐NP is comprehensively investigated herein. TBP‐NP_AR28promotes M2 macrophage polarization and enhances osteogenesis in preosteoblast‐macrophage co‐cultures in vitro. Longitudinal analysis of TBP‐NP_AR28‐mediated fracture healing reveals distinct spatial distributions of M2 macrophages, an increased M2/M1 ratio, and upregulation of anti‐inflammatory and downregulated pro‐inflammatory genes compared to controls. This work demonstrates the underlying therapeutic mechanism of bone‐targeted NP DDS, which leverages macrophages as druggable targets and modulates M2 macrophage polarization to enhance fracture healing, highlighting the therapeutic benefit of this approach for fractures and bone‐associated diseases.