Exploring paclitaxel-loaded adenosine-conjugated PEGylated PLGA nanoparticles for targeting triple-negative breast cancer.

In present investigation, we developed paclitaxel (PTX)-loaded adenosine (ADN)-conjugated PLGA nanoparticles for combating triple-negative breast cancer (TNBC), where ADN acts as a substrate for adenosine receptors (AR) that are overexpressed in TNBC. Using synthesized PLGA-PEG-ADN, PTX-loaded nanoparticles (PTX ADN-PEG-PLGA NPs) were prepared via emulsion diffusion evaporation process that rendered particles of size 135 ± 12 nm, PDI of 0.119 ± 0.03, and entrapment-efficiency of 79.26 ± 2.52%. The NPs showed higher %cumulative release at pH 5.5 over 7.4 with Higuchi release kinetics. The PTX ADN-PEG-PLGA NPs showed ~ 4.87- and 5.22-fold decrease in %hemolysis in comparison to free PTX and Intaxel®, indicating their hemocompatible nature. The ADN modification assisted cytoplasmic internalization of particles via AR-mediated endocytosis that resulted in ~ 3.77- and 3.51-fold reduction in IC50 and showed apoptosis index of 0.93 and 1.18 in MDA-MB-231 and 4T1 cells respectively. The pharmacokinetic profile of ADN-PEG-PLGA NPs revealed higher AUC and t1/2 than Intaxel® and Nanoxel® pharmacodynamic activity showed ~ 18.90-fold lower %tumor burden than control. The kidney and liver function biomarkers showed insignificant change in the levels, when treated with PTX ADN-PEG-PLGA NPs and exhibited no histological alterations in the liver, spleen, and kidney. Overall, the optimized particles were found to be biocompatible with improved anti-TNBC activity.

Self-nanoemulsifying formulation for oral delivery of sildenafil: effect on physicochemical attributes and in vivo pharmacokinetics.

Sildenafil (SLD) is employed for the management of erectile dysfunction and pulmonary arterial hypertension. It exhibits meagre water solubility and is available in the form of citrate salt hydrate to improve the solubility. However, it still exhibits moderate solubility, high first-pass metabolism, resulting in very less oral bioavailability. The present study demonstrates the preparation of self-nanoemulsifying drug delivery system for augmenting the oral bioavailability of SLD. Oleic acid and Capmul MCM C8 blend (oil phase), Cremophor® RH40 (surfactant), and Labrafil® M1944 CS (cosurfactant) were selected as main constituents for making liquid preconcentrate based on the solubility and emulsification study. The preconcentrate upon dilution and emulsification showed droplet size 52.03 ± 13.03 nm, PDI 0.143 ± 0.028, and % transmittance was 99.77 ± 1.86% with SLD load of 40 mg/g of formulation. The prepared formulation was further assessed for stability, in vitro release, Caco-2 cell uptake, and in vivo pharmacokinetic performance. SLD-SNEDDS formulation was found to be robust in terms of stability against several folds dilution in the gastrointestinal tract (GIT), freeze-thaw cycles, and had a storage stability of 3 months at 4 °C and 25 °C. SLD-SNEDDS showed ~4.7-fold and ~5-fold increase in time- and concentration-dependent cellular uptake as against SLD cultured with Caco-2 cells. In vivo pharmacokinetic study revealed ~5.8- and ~2.5-fold increase in AUC0-∞ values in case of SLD-SNEDDS as against SLD suspension and SLD citrate solution, respectively.

Unfolding the Potency of Adenosine in Targeting Triple Negative Breast Cancer via Paclitaxel-Incorporated pH-Responsive Stealth Liposomes.

Triple-negative breast cancer (TNBC) belongs to the category of the most destructive forms of breast cancer. Being a highly potent chemotherapeutic agent, paclitaxel (PTX) is extensively utilized in the management of various cancers. Commercially available PTX formulations contain non-targeted drug carriers that result in low antitumor activity because of non-specific tissue distribution. Thus, to resolve this issue, we designed PTX-loaded pH-sensitive liposomes (pH Lipos) in the present investigation and used adenosine (ADN) as a targeting ligand. Further, d-α-tocopheryl polyethylene glycol succinate (TPGS) was incorporated into the liposomes to impart a stealth effect to the system. For the development of these pH Lipos, different conjugates were synthesized (ADN-CHEMS and TPGS-ADN) and further utilized for the preparation of ADN-PEG-pH Lipo and ADN-pH Lipo by a thin-film hydration method. DOPE:HSPC:CHEMS:cholesterol at a molar ratio of 3:3:2:2 was selected for the preparation of pH-Lipo possessing 7.5% w/w drug loading. They showed a particle size below 140 nm, a PDI below 0.205, and a % EE greater than 60%. All of the pH Lipos displayed a biphasic pattern of PTX release at pH 7.4 and 5.5. However, the percent drug release at pH 5.5 was substantially greater because of the pH-sensitive nature of the liposomes. The MDA MB 231 and 4T1 cell lines depicted improvement in the qualitative as well as quantitative cellular uptake of PTX ADN-PEG-pH Lipo with a substantial decrease in the IC50 value. Moreover, a higher apoptotic index was observed with pH Lipo compared to free PTX. PTX ADN-PEG-pH Lipo revealed a 3.98- and 3.41-fold rise in the AUC and t1/2 values of PTX compared to Intaxel, respectively. Overall, characteristic decreases in tumor volume and serum toxicity marker levels were observed, which confirmed the development of an efficient and safe formulation.

Green surfactant-dendrimer aggreplexes: An ingenious way to launch dual attack on arch-enemy cancer.

Combination therapy, which combines anti-cancer drugs with different oligonucleotides, have shown potential in cancer treatment. However, delivering a hydrophobic anti-cancer drug and a hydrophilic oligonucleotide simultaneously is a herculean task. This study takes advantage of interactions between histidine-lauric acid-based green surfactant and poly(amidoamine) dendrimers to achieve this aim. The green surfactant was synthesized by carbodiimide chemistry and characterized by FTIR, 1H-NMR, and mass spectroscopy. Further, green surfactant-dendrimer aggregates encapsulating DTX and complexing SIRT 1 shRNA i.e., "aggreplexes" were developed and characterized. The term "aggreplexes" signifies complexes which are formed between green-surfactant-dendrimer aggregates and SIRT-1 shRNA via electrostatic interaction. The aggreplexes displayed particle size of 262.33 ± 3.87 nm, PDI of 0.25 and entrapment efficiency of 70.56 %. The TEM images revealed spherical shape of aggreplexes with irregular outer surface and corroborated particle size obtained from zetasizer. The in-vitro release study revealed biphasic release patterns of DTX from aggreplexes and were compatible for intravenous administration. Further, aggreplexes augmented cellular uptake in MDA-MB-231 cells by ∼1.87-fold compared to free DTX. Also, EGFP expression revealed significantly higher transfection of aggreplexes compared to naked shRNA and Superfect™ complexes. Further, aggreplexes showed higher cytotoxicity in MDA-MB-231 cells and ∼4.16-fold reduction in IC50 value compared to free DTX. Finally, apoptosis-index observed in case of aggreplexes was ∼3.57-fold higher than free DTX. These novel aggreplexes showed increased drug loading capacity and superior gene transfection potential. Thus, they open new avenues for co-delivery of hydrophobic anti-cancer drugs and hydrophilic therapeutic genes for improving current standards of cancer therapy.

Drug-Phospholipid Complex-a Go Through Strategy for Enhanced Oral Bioavailability.

Among many, the oral route of delivery is considered to be the most favorable route with the highest patient compliance. The main issue with oral delivery is the environmental vulnerability of gastro intestinal tract (G.I.T). The bioavailability could further decrease when drug has poor aqueous solubility and permeability through biological membrane. This drawback could be resolved by employing drug-phospholipid complex strategy, as they utilize mechanism which is similar to the absorption mechanism of nutritional constituents form G.I.T. The drug-phospholipid complexes are considered ideal for oral delivery as they are biodegradable and non-toxic, which enable them to be employed as solubilizer, emulsifier, and as a matrix forming excipient for dugs with poor solubility and/or permeability. The present review compiles the basic know how about the phospholipids and the mechanism through which it improves the bioavailability of drugs. Further, it also compiles the crucial formulation aspects and methods of preparations of drug-phospholipid complex along with its physical and in silico characterization techniques. The increase in number of recent reports involving the utilization of drug-phospholipid complex to improve oral bioavailability of drugs thus explains how vital the strategy is for a successful oral delivery.

Near infra red spectroscopy: a tool for solid state characterization.

Physical characterization of solid form of drug is of paramount importance as its biopharmaceutical properties and/or its processing behavior may be altered. Early identification and monitoring of solid state transformation is a critical requirement for pharmaceutical product development. In combination with chemometrics, a non destructive and non invasive technique like NIR is a powerful tool for solid state characterization. Main focus of this review is application of NIR for qualitative and quantitative analysis of solid forms of drugs and excipients. In addition, this review also sheds light on recent advancement in NIR, such as NIR chemical imaging and NIR based hyphenated techniques.