β-Cyclodextrin-poly (β-Amino Ester) Nanoparticles Are a Generalizable Strategy for High Loading and Sustained Release of HDAC Inhibitors

Abstract

Therapeutic development of histone deacetylase inhibitors (HDACi) has been hampered by a number of barriers to drug delivery, including poor solubility and inadequate tissue penetration. Nanoparticle encapsulation could be one approach to improve the delivery of HDACi to target tissues; however, effective and generalizable loading of HDACi within nanoparticle systems remains a long-term challenge. We hypothesized that the common terminally ionizable moiety on many HDACi molecules could be capitalized upon for loading in polymeric nanoparticles. Here, we describe the simple, efficient formulation of a novel library of β-cyclodextrin-poly (β-amino ester) networks (CDN) to achieve this goal. We observed that network architecture was a critical determinant of CDN encapsulation of candidate molecules, with a more hydrophobic core enabling effective self-assembly and a PEGylated surface enabling high loading (up to ∼30% w/w), effective self-assembly of the nanoparticle, and slow release of drug into aqueous media (up to 24 days) for the model HDACi panobinostat. We next constructed a library of CDNs to encapsulate various small, hydrophobic, terminally ionizable molecules (panobinostat, quisinostat, dacinostat, givinostat, bortezomib, camptothecin, nile red, and cytarabine), which yielded important insights into the structural requirements for effective drug loading and CDN self-assembly. Optimized CDN nanoparticles were taken up by GL261 cells in culture and a released panobinostat was confirmed to be bioactive. Panobinostat-loaded CDNs were next administered by convection-enhanced delivery (CED) to mice bearing intracranial GL261 tumors. These studies confirm that CDN encapsulation enables a higher deliverable dose of drug to effectively slow tumor growth. Matrix-assisted laser desorption/ionization (MALDI) analysis on tissue sections confirms higher exposure of tumor to drug, which likely accounts for the therapeutic effects. Taken in sum, these studies present a novel nanocarrier platform for encapsulation of HDACi via both ionic and hydrophobic interactions, which is an important step toward better treatment of disease via HDACi therapy.

Microemulsion for Prolonged Release of Fenretinide in the Mammary Tissue and Prevention of Breast Cancer Development

“…A similar effect was observed by our group with alginate nanocarriers, which increased the MIC of miltefosine . Other authors reported comparable effects of prolonged/controlled release systems, such as polymeric and calcium phosphate nanoparticles and liposomes, attributing increases of IC 50 value to the reduced availability of the encapsulated drug. − Based on the in vitro release results, we estimate that free drug levels at 72 h should be approximately 15% of the total drug amount. Thus, if we consider that it is the free portion of the drug that will be available to exert cell effects, IC 50 values would be lower.…”

Nano-Assembly of Quisinostat and Biodegradable Macromolecular Carrier Results in Supramolecular Complexes with Slow-Release Capabilities

“…To date most of the research activity in the field has been focused on efforts of encapsulating quisinostat into various drug carriers. To that end, various macromolecular systems have been explored, such as nanoparticles on the basis of poly(lactide)-blockpoly(ethylene glycol) [15], poly (lactide-co-glycolide)-lecithin-poly(ethylene glycol) [6], and polysaccharide [16], as well as matrices composed of β-cyclodextrin-poly (β-amino ester) networks [17] and bioerodible radiopaque hydrogels [14]. Despite offering multiple distinct advantages, all of these methods usually involve sophisticated chemical and formulation approaches and require multi-step production processes.…”

Emerging Epigenetic‐Based Nanotechnology for Cancer Therapy: Modulating the Tumor Microenvironment

“…Epigenetic agents are plagued by poor water solubility, rapid clearance, and poor tissue distribution. [91] Given that the greater permeability of tumor vessels than normal vessels and the impaired lymphatic flow, nanomedicines accumulate preferentially in tumor tissue and remain for a long time, which is called the enhanced permeability and retention (EPR) effect. [92] Nanomedicine delivery strategies can utilize EPR effectmediated passive targeting or ligand-mediated active targeting to deliver nanomedicines to tumor tissue after systemic delivery.…”