RESUMO
The development of chemoresistance is a major obstacle in post-surgical adjuvant therapy of cancer, leading to cancer cell survival, recurrence, and metastasis. This study reports a 3D-printed plasmonic implant developed for the post-surgical adjuvant therapy of cisplatin-resistant cancer cells to prevent relapse. The implant was printed using optimized biomaterial ink containing biodegradable polymers [poly(L-lactide) and hydroxypropyl methylcellulose] blended suitably with laser-responsive graphene and chemo drug (Cisplatin). The irradiation of scar-driven 3D-printed implant with a laser stimulates graphene to generate a series of hyperthermia events leading to photothermolysis of cisplatin-resistant cancer cells under the combined influence of sustained cisplatin release. The developed personalized implant offers pH-responsive sustained drug release for 28 days. The implant exhibited acceptable biophysical properties (Tensile strength: 3.99 ± 0.15 MPa; modulus: 81 ± 9.58 MPa; thickness: 110 µm). The 3D-printed implant effectively reverses the chemoresistance in cisplatin-resistant 3D spheroid tumor models. Cytotoxicity assay performed using cisplatin-resistant (CisR) cell line revealed that the cell viability was reduced to 39.80 ± 0.68 % from 61.37 ± 0.98 % in CisR tumor spheroids on combined chemo-photothermal therapy. The combination therapy reduced the IC50 value from 71.05 µM to 48.73 µM in CisR spheroids. Apoptosis assay revealed an increase in the population of apoptotic cells (35.45 ± 1.56 % â52.53 ± 2.30 %) on combination therapy. A similar trend was observed in gene expression analysis, where the expression of pro-apoptotic genes Caspase 3 (3.73 ± 0.04 fold) and Bcl-2-associated X protein (BAX) (3.35 ± 0.02 fold) was increased on combination therapy. This 3D-printed, biodegradable implant with chemo-combined thermal ablating potential may provide a promising approach for the adjuvant treatment of resistant cancer.
RESUMO
BACKGROUND: Kaempferol is a natural polyflavonol that has gained considerable attention as antidiabetic therapeutics. Recent reports emphasize the role of hyperglycemia and RhoA/Rho Kinase activity in the pathogenesis of diabetic nephropathy (DN). This study aims to evaluate the GLP-1 and insulin release along with RhoA/Rho Kinase inhibition pertaining to the anti-fibrotic and reno-protective effects of Kaempferol in DN. METHODS: The effect of Kaempferol on GLP-1 and insulin release along with underlying mechanisms (Ca2+ and cAMP levels) in GLUTag and MIN6 cells as well as in their co-culture has been evaluated. Further, the effect of Kaempferol on GLP-1 and insulin release was evaluated under in-vivo circumstances in the DN C57BL/6 mouse model. Histology and fibrosis specific staining was performed to study the renal injuries and fibrosis, while the expression of mRNA and protein of interest was evaluated by RT-PCR and western blot analysis. RESULTS: Kaempferol treatment promoted the GLP-1 and insulin release, which was accompanied by increased intracellular levels of cAMP and Ca2+ in GLUTag and MIN6 cells. In agreement with in vitro studies, Kaempferol also increased the release of GLP-1 and insulin in the DN mouse model. Notably, Kaempferol showed the potential to ameliorate the histological changes as well as renal fibrosis while decreasing the expression levels of DN markers including TGF-ß1, CTGF, fibronectin, collagen IV, IL-1ß, RhoA, ROCK2, and p-MYPT1 in DN kidney tissues. A rise in the expression of E-cadherin and nephrin was also noted in the same study. CONCLUSION: This study establishes that Kaempferol ameliorates renal injury and fibrosis by enhancing the release of GLP-1, insulin, and inhibition of RhoA/Rho Kinase. This study recommends Kaempferol for further clinical trials to be developed as novel therapeutics for improving the renal function in DN patients.
RESUMO
The search for effective and non-invasive delivery modules to transport therapeutic molecules across skin has led to the discovery of a number of nanocarriers (viz.: liposomes, ethosomes, dendrimers, etc.) in the last few decades. However, available literature suggests that these delivery modules face several issues including poor stability, low encapsulation efficiency, and scale-up hurdles. Recently, carbon nanotubes (CNTs) emerged as a versatile tool to deliver therapeutics across skin. Superior stability, high loading capacity, well-developed synthesis protocol as well as ease of scale-up are some of the reason for growing interest in CNTs. CNTs have a unique physical architecture and a large surface area with unique surface chemistry that can be tailored for vivid biomedical applications. CNTs have been thus largely engaged in the development of transdermal systems such as tuneable hydrogels, programmable nonporous membranes, electroresponsive skin modalities, protein channel mimetic platforms, reverse iontophoresis, microneedles, and dermal buckypapers. In addition, CNTs were also employed in the development of RNA interference (RNAi) based therapeutics for correcting defective dermal genes. This review expounds the state-of-art synthesis methodologies, skin penetration mechanism, drug liberation profile, loading potential, characterization techniques, and transdermal applications along with a summary on patent/regulatory status and future scope of CNT based skin therapeutics.
