Modification of α-Tocopherol Succinate with a Tumor-targeting Peptide Conjugate Enhances the Antitumor Efficacy of a Paclitaxel-loaded Lipid Aggregate.

Paclitaxel (PTX) is a widely used chemotherapeutic agent in the clinic. However, its clinical benefit is limited due to its low water solubility, off-target toxicity, and for being a multidrug-resistant (MDR) substrate. To overcome these limitations in this study, a tumor-targeting peptide (CRGDK peptide, a ligand for NRP-1 receptor) conjugate of α-tocopheryl succinate (α-TOS) was synthesized and modified on PTX-loaded lipid aggregate (TL-PTX) to leverage the benefits of α-TOS, which include a) anti-cancer activity, b) increased PTX loading, and c) inhibition of MDR activity. Use of peptide conjugate of α-TOS (α-TOS-CRGDK) in lipid aggregate increased PTX entrapment efficiency by 20%, helped in NRP-1 specific cellular uptake and significantly enhanced apoptotic and cell killing activity (p <0.01) of PTX compared to control formulation (CL-PTX) by inhibiting MDR-activity in melanoma resulting in ∼70% increment in overall survival of melanoma tumor-bearing mice. In conclusion, CRGDK- α-TOS conjugate in association with PTX-loaded liposome provided a unique NRP-1 targeted, drug-resistant reversing anticancer regimen for treating aggressive melanoma.

Amphetamine decorated cationic lipid nanoparticles cross the blood-brain barrier: therapeutic promise for combating glioblastoma.

Combating brain tumors (glioblastoma multiforme or GBM) is a formidable challenge because of the existence of blood-brain barrier (BBB), a tight cellular junction that separates the central nervous system (CNS) and systemic circulation. Such a selectively permeable barrier prevents the entry of therapeutic molecules from blood circulation to brain parenchyma. Towards enhancing the efficacy of brain tumor-selective drug delivery without perturbing the BBB integrity, nanometric drug carriers are increasingly becoming an efficient therapeutic modality in preclinical studies. Psychostimulant drugs such as amphetamine and methylated amphetamine (METH) are known to penetrate the BBB. Still, little effort has been made to exploit them in nano-drug delivery, largely due to their toxicities. Herein, for the first time, we design, synthesize, and formulate three different ß-amphetaminylated cationic lipid nanoparticles. We show that the ß-amphetaminylated cationic lipid nanoparticles are nontoxic and can cross the BBB presumably through active transcytosis. The BBB penetrating ability also depends on the hydrophilic-hydrophobic balance of the lipids, with hexadecyl lipid (16-BACL) nanoparticle showing maximum accumulation in the brain. The lipid nanoparticle of 16-BACL can simultaneously encapsulate paclitaxel and PDL1-siRNA. The dual drug-loaded lipid nanoparticles showed apoptosis driven cellular cytotoxicity against GL261 cells and improved the overall survivability of orthotopic glioblastoma bearing mice compared to their non-targeting counterpart. The present work describes a new class of BBB-crossing lipid nanoparticles and delineates their therapeutic promise against glioblastoma.

Identification and characterization of stress degradation products of sumatriptan succinate by using LC/Q-TOF-ESI-MS/MS and NMR: Toxicity evaluation of degradation products.

Sumatriptan succinate, a selective 5-HT1B receptor agonist, was subjected to forced degradation studies as per to International Conference on Harmonization-specified conditions. The drug exclusively showed its degradation under basic, photolytic, and oxidative stress conditions, whereas it was found to be stable under acidic, thermal, and neutral conditions. Eight (DP-1 to DP-8) degradation products were identified and characterized by UPLC-ESI/MS/MS experiments combined with accurate mass measurements. The effective chromatographic separation was achieved on Hibar Purospher STAR, C18 (250 × 4.6 mm, 5 µm) column using mobile phase consisting of 0.1% formic acid and methanol at a flow rate of 0.6 mL/minute in gradient elution method. It is noteworthy that 2 major degradation products DP-3 and DP-7 were isolated using preparative HPLC and characterized by advanced NMR experiments. The degradation pathway of the sumatriptan was established, which was duly justified by mechanistic explanation. In vitro cytotoxicity of isolated DPs was tested on normal human cells such as HEK 293 (embryonic kidney cells) and RWPE-1 (normal prostate epithelial cells). This study revealed that they were nontoxic up to 100 µm concentration. Further, in silico toxicity of the drug and its degradation products was determined using ProTox-II prediction tool. This study revealed that DP-4 and DP-8 are predicted for immune toxicity. Amine oxidase A and prostaglandin G/H synthase 1 are predicted as toxicity targets for DP-3, DP-4, and DP-6 whereas DP-1 and DP-2 are predicted for amine oxidase A target.