Rational Formulation of targeted ABT-737 nanoparticles by self-assembled polypeptides and designed peptides.

Here we present the development of nanoparticles (NPs) formulations specifically designed for targeting the antiapoptotic Bcl-2 proteins on the outer membrane of mitochondria with the drug agent ABT-737. The NPs which are self-assembled by the natural polypeptide poly gamma glutamic acid (ϒPGA) and a designed cationic and amphiphilic peptide (PFK) have been shown to target drugs toward mitochondria. In this study we systematically developed the formulation of such NPs loaded with the ABT-737 and demonstrated the cytotoxic effect of the best identified formulation on MDA-MB-231 cells. Our findings emphasize the critical role of solutions pH and the charged state of the components throughout the formulation process as well as the concentrations of the co-components and their mixing sequence, in achieving the most stable and effective cytotoxic formulation. Our study highlights the potential versatility of designed peptides in combination with biopolymers for improving drug delivery formulations and enhance their targeting abilities.

Review old bone, new tricks.

Despite the significant progress made over the past decade with combination of molecular profiling data and the development of new clinical strategies, our understanding of metastasis remains elusive. Bone metastasis is a complex process and a major cause of mortality in breast and prostate cancer patients, for which there is no effective treatment to-date. The current review summarizes the routes taken by the metastatic cells and the interactions between them and the bone microenvironment. We emphasize the role of the specified niches and cues that promote cellular adhesion, colonization, prolonged dormancy, and reactivation. Understanding these mechanisms will provide better insights for future studies and treatment strategies for bone metastatic conditions.

Aggressiveness of 4T1 breast cancer cells hampered by Wnt production-2 inhibitor nanoparticles: An in vitro study.

Polymeric nanoparticles may enable delivery of drugs with lower systemic toxicity to solid tumors. Wnt signaling are evolutionary conserved pathways, involved in proliferation and fate decisions. Alterations in Wnt signaling play a pivotal role in various cancer types that promote cancer initiation, growth, metastasis and drug resistance. We designed a new strategy to allow an efficient targeting of both the canonical and the non-canonical Wnt pathways using nanoparticles loaded with inhibitor of Wnt productions-2 (IWP-2). This hydrophobic drug was successfully co-assembled into NPs composed of poly gamma-glutamic acid and a cationic and amphiphilic b-sheet peptide. Aggressive 4T1 breast cancer cells that were treated with IWP-2 loaded NPs gained a significant decrease in tumorigenic capacities attributed to improved IWP solubility, cellular uptake and efficacy.

Mitochondrial responses to organelle-specific drug delivering nanoparticles composed of polypeptide and peptide complexes.

Aims: The mechanistic study of the drug carrier-target interactions of mitochondria-unique nanoparticles composed of polypeptide-peptide complexes (mPoP-NPs). Materials & methods: The isolated organelles were employed to address the direct effects of mPoP-NPs on dynamic structure and functional wellbeing of mitochondria. Mitochondria morphology, respiration, membrane potential, reactive oxygen species generation, were examined by confocal microscopy, flow cytometry and oxygraphy. Lonidamine-encapsulated formulation was assessed to evaluate the drug delivery capacity of the naive nanoparticles. Results: The mPoP-NPs do not alter mitochondria structure and performance upon docking to organelles, while successfully delivering drug that causes organelle dysfunction. Conclusion: The study gives insight into interactions of mPoP-NPs with mitochondria and provides substantial support for consideration of designed nanoparticles as biocompatible and efficient mitochondria-targeted platforms.

Antitumor Effect of Lonidamine-Polypeptide-Peptide Nanoparticles in Breast Cancer Models.

Biomaterials folded into nanoparticles (NPs) can be utilized as targeted drug delivery systems for cancer therapy. NPs may provide a vehicle for the anticancer drug lonidamine (LND), which inhibits glycolysis but was suspended from use at the clinical trial stage because of its hepatotoxicity due to poor solubility and pharmacokinetic properties. The NPs prepared by coassembly of the anionic polypeptide poly gamma glutamic acid (γ-PGA) and a designed amphiphilic and positively charged peptide (designated as mPoP-NPs) delivered LND to the mitochondria in cell cultures. In this study, we demonstrate that LND-mPoP-NP effective drug concentrations can be increased to reach therapeutically relevant concentrations. The self-assembled NP solution was subjected to snap-freezing and lyophilization and the resultant powder was redissolved in a tenth of the original volume. The NP size and their ability to target the proximity of the mitochondria of breast cancer cells were both maintained in this new formulation, C-LND-mPoP-NPs. Furthermore, these NPs exhibited 40% better cytotoxicity, relative to the nonlyophilized LND-mPoP-NPs and led to tumor growth inhibition with no adverse side effects upon intravenous administration in a xenograft breast cancer murine model.

Negatively charged polypeptide-peptide nanoparticles showing efficient drug delivery to the mitochondria.

Polymeric nanoparticles (NPs) represent an effective platform for drug delivery systems, albeit with various limitations including low drug loading capacity, cytotoxicity and specificity. NPs composed of the negatively charged Polypeptide, poly gamma glutamic acid (γ-PGA) and a designed amphiphilic and cationic ß-sheet Peptide (denoted PoP-NPs) loaded with the drug lonidamine (LND), denoted LND-PoP-NPs were previously used in our lab to successfully target the mitochondria when coated with the peptide (LND-mPoP-NPs). In this study, we improved the drug capacity of the LND-mPoP-NPs in addition to lowering non-specific toxicity associated with the drug deficient mPoP-NPs. LND concentrations in LND-mPoP-NPs were increased (h-LND-mPoP-NPs) and the peptide coating concentration was decreased. The new h-LND-mPoP-NPs formulation shows the ability to carry the drug to the proximity of the mitochondria despite the NP's negative zeta potential.

Coassemblies of the Anionic Polypeptide γ-PGA and Cationic ß-Sheet Peptides for Drug Delivery to Mitochondria.

The effectiveness of a drug may be highly dependent on its delivery to its target organ and even to specific intracellular organelles. In this study we developed nanoparticles (NPs) composed of the anionic polypeptide poly-γ-glutamic acid (γ-PGA), and a designed amphiphilic and cationic ß-sheet peptide (PFK), which tends to form fibril bilayer assemblies. These peptide assemblies generate hydrophobic niches within the NPs, which enhance the NPs' capacity to deliver amphiphilic drugs. NPs created by coassembly of γ-PGA and PFK, and further coated with PFK, had a positive zeta-potential and were attracted to mitochondria. When applied to the human osteosarcoma cell line Saos2, the NP-encapsulated lonidamin drug proved to be 300 times more cytotoxic than the free drug.