Co-delivery of lapatinib and 5-fluorouracil transfersomes using transpapillary iontophoresis for breast cancer therapy.

Combination chemotherapy, involving the intervention of two or more anti-neoplastic agents has been the cornerstone in breast cancer treatment, owing to the applications it holds in contrast to the mono-therapy approach. This research predominantly focussed on proving the synergy between Lapatinib (LPT) and 5-Fluorouracil (5-FU) and further enhancing its localized permeation via transfersome-loaded delivery and iontophoresis to treat breast tumors. The IC50 values for LPT and 5-FU were found to be 19.38 µg/ml and 5.7 µg/ml respectively and their synergistic effect was proven by the Chou-Talalay assay using CompuSyn software. Furthermore, LPT and 5-FU were encapsulated within transfersomes and administered via the transpapillary route. The drug-loaded carriers were characterized for their particle size, polydispersity index, zeta potential, and entrapment efficiency. The ex vivo rat skin permeation studies indicated that when compared to LPT dispersion and 5-FU solution, drug-loaded transfersomes exhibited better permeability and their transpapillary permeation was enhanced on using iontophoresis. Moreover, both LPT and 5-FU transfersomes were found to be stable for 3 months when stored at a temperature of 5 ± 3 °C. The results indicated that this treatment strategy could be an effective approach in contrast to some of the conventional treatments employed to date.

Design, development and evaluation of Resveratrol transdermal patches for breast cancer therapy.

Resveratrol (RVT) is a polyphenolic phytoestrogen which has shown antiproliferative activity in breast cancer. However, its low bioavailability and short half-life have restricted its use. The current study aimed to develop transdermal patches of RVT and evaluate its site-specific delivery for breast cancer therapy. Different penetration enhancers were screened using a computational tool, quantitative structure propery relationship (QSPR). The best permeation of RVT was observed in a patch comprising hydroxypropyl methylcellulose (HPMC) E15LV: HPMC-K4M: polyvinyl pyrrolidone (PVP) K30 in the ratio of 3:1:2 as release controlling polymers with Glycerol:Capryol 90 (4:1) as penetration enhancer and plasticizer. To assess the localized delivery of RVT, the patch was applied to the breast of female rats. Higher breast tissue disposition with lower systemic concentration was observed compared to oral administration, demonstrated by increased AUC and MRT. Further, the optimized RVT patches were tested in 7,12-Dimethylbenz[a]anthracene (DMBA) induced rat mammary cancer. Compared to oral RVT, the application of RVT tansdermal patches significantly reduced the tumor volume and serum CA 15-3, a cancer biomarker. Thus, the RVT transdermal patch may be a viable approach for ensuring high local concentration of drug for site-specific delivery in breast cancer therapy.

Drug Release and Cytotoxicity of Hyaluronic Acid and Zinc Oxide Gels, An In-Vitro Study.

Hyaluronic acid (HA) is a naturally occurring biopolymer, with a remarkable wound healing property. Zinc-oxide non-eugenol is a material widely used for periodontal dressing in dentistry. However, it has been reported that zinc oxide non-eugenol is toxic to osteoblasts and fibroblasts. Hence, the present study aimed to evaluate the drug release and cytotoxicity of HA and zinc-oxide gels. Hydrogels of HA and zinc oxide were formulated with carbopol as a carrier. In vitro drug release was performed by UV spectrophotometry, dialysis, and vial bag methods. Cytotoxicity assessment of HA and zinc-oxide gels was performed in human periodontal ligament fibroblasts (HPdLF) and human gingival fibroblasts (hGFs). An inverted phase-contrast microscope was used to assess the morphological changes. At 24 and 48 hr, HPdLF cells showed the highest viability in 0.1% low molecular weight-HA (LMW-HA) with a median value of 131.9, and hGFs showed the highest viability in 5% LMW-HA with a median of 129.56. The highest viability of HPdLF cells was observed in 5% high molecular weight-HA (HMW-HA), with a median value of 127.11. hGFs showed the highest viability in 1% HMW-HA with a median value of 97.99. Within the limitations of the present study, we concluded that LMW-HA is more efficient than HMW-HA. Both HPdLF and hGF cells showed complete cell morbidity with zinc-oxide hydrogels. Therefore, zinc oxide-based gels in concentrations as low as 9% could be toxic intraorally to soft tissues that harbor gingival and periodontal ligament fibroblasts.

Transpapillary iontophoretic delivery of resveratrol loaded transfersomes for localized delivery to breast cancer.

Localized drug delivery to the breast tissues is an area of interest as a potential route to ensure site-specific drug delivery. Transpapillary delivery via the mammary papilla has advantages as most breast tumors arise from the milk ducts. The present study explored the plausibility of transpapillary delivery of a phytochemical, resveratrol (RVT), for breast cancer treatment. RVT was encapsulated within the transfersomes (RVT-TRF) to enable a sustained release of the drug using the biomaterial soya phosphatidylcholine (SPC). Iontophoresis was applied to further accelerate the penetration of the RVT-TRF across the mammary papilla to the breast tissue. The RVT-TRF development was optimized by the Design of Experiments (DoE) approach. The in vitro transpapillary iontophoresis study on porcine mammary papilla showed an enhanced penetration of RVT-TRF when compared to passive diffusion. The transpapillary delivery was further confirmed from the in vitro fluorescent microscopy study using FITC conjugated RVT-TRF. The optimized RVT-TRF delivered via transpapillary route showed a higher Cmax and AUC when compared to pure RVT given orally. A significant reduction in the tumor volume and the serum biomarker CA 15-3, when evaluated in a chemically induced breast cancer rat model, provided evidence of the effectiveness of the developed formulation when delivered locally via transpapillary route compared to the oral route. Thus the developed RVT-TRF administered via transpapillary iontophoresis technique is a promising strategy enabling a localized delivery for effective breast cancer therapy.

Probing nonenzymatic glycation of proteins by deep ultraviolet light emitting diode induced autofluorescence.

The suitability of deep-UV-LED (285 nm) as an excitation source to induce autofluorescence in nonenzymatically glycated proteins has been reported for the first time in this study. Non-enzymatically glycated proteins show high autofluorescence when excited with deep-UV light, i.e., deep-UV-induced autofluorescence (deep-UV-IAF). Multiple autofluorescence peaks of nonenzymatically glycated proteins between 300 and 600 nm when excited using the deep-UV-LED revealed structural and biochemical modifications. The partial unfolding of proteins in which Tryptophan (Trp) is either absent (e.g., RibonucleaseA) or the emission maxima of Trp is insensitive to nonenzymatic glycation (e.g., Human Serum Albumin and Bovine Serum Albumin) were elucidated using their Tyrosine (Tyr) emission (λem = ~320 nm). Also, the deep-UV-LED-induced autofluorescence (deep-UV-LED-IAF) is shown to detect and track a wide range of clinically relevant advanced glycation end-products (AGEs) such as Pentosidine (λem = ~380 nm), Argpyrimidine (λem = ~395 nm), Vesperlysine C (λem = ~405 nm), Vesperlysine A/B (λem = ~440 nm), Crossline (λem = ~480 nm), and Arginine derived AGEs (λem = ~525 nm) which is also supported by the chemometric analysis (PCA). The relevance of Trp/Tyr makeup of proteins in tracking AGEs using deep-UV-IAF has been carefully examined with proteins such as RibonucleaseA (RNaseA:zero Trp and six Tyr), Human Serum Albumin (HSA: one Trp and eighteen Tyr), Bovine Serum Albumin (BSA: two Trp and twenty Tyr) and Hemoglobin (Hb: four Trp and twelve Tyr). The Molecular Dynamic (MD) simulation revealed a high root-mean-square deviation (RMSD: 4.6 Å) and an increased average distance between Tyr residues and Trp214 (23.2 Å) in methylglyoxal (MG) treated HSA. This confirms the MG-induced protein unfolding and decreased fluorescence resonance energy transfer (FRET) from Tyr to Trp (Tyr â†’ Trp). The study also used systematic steady-state and time-resolved fluorescence (TRF) to explain the sudden decrease in AGEs specific fluorescence intensity and lifetime at higher concentrations of MG due to inter-AGEs FRET.

Understanding the Effect of Functionalization on Loading Capacity and Release of Drug from Mesoporous Silica Nanoparticles: A Computationally Driven Study.

MCM-41, a type of mesoporous silica nanoparticle, has garnered widespread interests as a useful carrier for drug delivery wherein the drug gets adsorbed into the pores of the carrier. To understand the adsorption mechanism and release of the drug at the molecular level, in the current study, it was attempted to generate a computational model for the loading of 5-fluorouracil (5-FU), a chemotherapeutic agent into surface-modified MCM-41. The molecular surface models of the mesoporous silica (MCM-41) nanoparticle with different surface substitutions were created. In the first stage, molecular mechanics (MM) simulations were carried out to obtain the optimized surface structures. Subsequently, a 5-FU drug molecule in its different forms was docked on top of different MCM-41 surfaces to understand the adsorption orientation and energetics. To further validate the results, more accurate quantum mechanical (QM) calculations were also carried out, and the energetics between the QM and MM calculations are found to be similar. All the substitutions (-NH2, -CN, -COOH) except the methyl substitution exhibited favorable interactions compared to the unsubstituted MCM-41 surface which was in accordance with the experimental observations. The release rate of 5-FU from MCM-41 and aminopropyl-substituted MCM-41 (MCM-NH2) was studied using molecular dynamics simulations which revealed that the release rate of 5-FU from the MCM-NH2 surface was slower compared to that of plain MCM-41. The detailed surface characteristics and the adsorption energies from the molecular simulations correlating the loading capacity and release are reported in here.

The Beginning of a New Era: Artificial Intelligence in Healthcare.

The healthcare sector is considered to be one of the largest and fast-growing industries in the world. Innovations and novel approaches have always remained the prime aims in order to bring massive development. Before the emergence of technology, the healthcare sector was dependent on manpower, which was time-consuming and less accurate with lack of efficiency. With the recent advancements in machine learning, the condition has been steadily revolutionizing. Artificial intelligence (AI) lies in the computer science department, which stresses on the intelligent machines' creation, that work and react just like human beings. Currently, the applications of AI have been expanding into those fields, which was once thought to be the only domain of human expertise such as healthcare sector. In this review, we have shed light on the present usage of AI in the healthcare sector, such as its working, and the way this system is being implemented in different domains, such as drug discovery, diagnosis of diseases, clinical trials, remote patient monitoring, and nanotechnology. We have also briefly touched upon its applications in other sectors as well. The public opinions have also been analyzed and discussed along with the future prospects. We have discussed the merits, and the other side of AI, i.e. the disadvantages in the last part of the manuscript.

Development and preclinical evaluation of microneedle-assisted resveratrol loaded nanostructured lipid carriers for localized delivery to breast cancer therapy.

Resveratrol (RVT) is one of the potent anticancer phytochemicals which has shown promising potential for breast cancer therapy. However, its short half-life and low bioavailability is a major hurdle in its effective use. In this study, we have developed nanostructured lipid carriers (NLCs) of RVT to enable localized delivery of the drug to the breast tissues using microneedle arrays to improve effectiveness. The NLCs were optimized using the Design of Experiments approach and characterized for their particle size, polydispersity index, zeta potential and entrapment efficiency. The RVT-NLCs delivered using microneedle array 1200 showed a higher permeation of RVT across the skin with lower skin retention compared to pure RVT. Further, RVT-NLCs showed higher anticancer activity on MDA-MB-231 breast cancer cell lines and enhanced internalization compared to pure RVT. Moreover, the RVT-NLCs were found to inhibit the migration of MDA-MB-231 breast cancer cell lines. Preclinical studies in rats showed that RVT-NLCs delivered via microneedles demonstrated a remarkable increase in the Cmax, Tmax and AUC0-inf, and a higher localization in breast tissue compared to pure RVT administered orally. These results suggests that the RVT-NLCs administered by microneedle array system is an effective strategy for the local delivery of RVT for breast cancer therapy.

Chitosan-glucuronic acid conjugate coated mesoporous silica nanoparticles: A smart pH-responsive and receptor-targeted system for colorectal cancer therapy.

Glycosylated pH-sensitive mesoporous silica nanoparticles (MSNs) of capecitabine (CAP) were developed for targeting colorectal cancer. The MSNs possessed an average pore diameter of 8.12 ± 0.43 nm, pore volume of 0.73 ± 0.21 cm3/g, and particle size of 245.24 ± 5.75 nm. A high loading of 180.51 ± 5.23 mg/g attributed to the larger pore volume was observed. The surface of the drug-loaded MSNs were capped with chitosan-glucuronic acid (CHS-GCA) conjugate to combine two strategies viz. pH-sensitive, and lectin receptor mediated uptake. In vitro studies demonstrated a pH-sensitive and controlled release of CAP which was further enhanced in the presence of rat caecal content. Higher uptake of the (CAP-MSN)CHS-GCA was observed in HCT 116 cell lines. The glycosylated nanoparticles revealed reduction in the tumors, aberrant crypt foci, dysplasia and inflammation, and alleviation in the toxic features. This illustrated that the nanoparticles showed promising antitumor efficacy with reduced toxicity and may be used as a effective carrier against cancer.

Asphaltene Aggregation in Aqueous Solution Using Different Water Models: A Classical Molecular Dynamics Study.

The aggregation behavior of asphaltene in aqueous solution is systematically investigated based on a classical molecular dynamics study. In this work, a novel approach is adopted in order to investigate the structural and dynamical properties of the asphaltene nanoaggregates using different water models. The end-to-end distance of the asphaltene molecule is probed in order to understand the aggregation behavior in aqueous solution. The accuracy of different water models, that is, simple point charge, TIP4P-D, and TIP5P, is thoroughly investigated. In order to probe the dynamical properties of the asphaltene nanoaggregates, the transport coefficients, namely, diffusion coefficient and shear viscosity, are computed. The obtained results highlight the importance of using the appropriate water model in order to accurately study the aggregation behavior of asphaltene in aqueous solution.

Combination Therapy and Nanoparticulate Systems: Smart Approaches for the Effective Treatment of Breast Cancer.

Breast cancer has become one of the biggest concerns for oncologists in the past few decades because of its unpredictable etiopathology and nonavailability of personalized translational medicine. The number of women getting affected by breast cancer has increased dramatically, owing to lifestyle and environmental changes. Besides, the development of multidrug resistance has become a challenge in the therapeutic management of breast cancer. Studies reveal that the use of monotherapy is not effective in the management of breast cancer due to high toxicity and the development of resistance. Combination therapies, such as radiation therapy with adjuvant therapy, endocrine therapy with chemotherapy, and targeted therapy with immunotherapy, are found to be effective. Thus, multimodal and combination treatments, along with nanomedicine, have emerged as a promising strategy with minimum side effects and drug resistance. In this review, we emphasize the multimodal approaches and recent advancements in breast cancer treatment modalities, giving importance to the current data on clinical trials. The novel treatment approach by targeted therapy, according to type, such as luminal, HER2 positive, and triple-negative breast cancer, are discussed. Further, passive and active targeting technologies, including nanoparticles, bioconjugate systems, stimuli-responsive, and nucleic acid delivery systems, including siRNA and aptamer, are explained. The recent research exploring the role of nanomedicine in combination therapy and the possible use of artificial intelligence in breast cancer therapy is also discussed herein. The complexity and dynamism of disease changes require the constant upgrading of knowledge, and innovation is essential for future drug development for treating breast cancer.