ATRP-grown protein-polymer conjugates containing phenylpiperazine selectively enhance transepithelial protein transport.
J Control Release. 2017 Apr 25;:
Authors: Cummings CS, Fein K, Murata H, Ball RL, Russell AJ, Whitehead KA
Despite its patient-friendliness, the oral route is not yet a viable strategy for the delivery of biomacromolecular therapeutics. This is, in part, due to the large size of proteins, which greatly limits their absorption across the intestinal epithelium. Although chemical permeation enhancers can improve macromolecular transport, their positive impact is often accompanied by toxicity. One element potentially contributing to this toxicity is the lack of co-localization of the enhancer with the protein drug, which can result in non-specific permeation of the intestine as well as enhancer overdosing in some areas due to non-uniform distribution. To circumvent these issues, this study describes a new way of increasing protein permeability via a polymer conjugation process that co-localizes permeation enhancer with the protein. Based on previous reports demonstrating the utility of 1-phenylpiperazine as an intestinal permeation enhancer, we synthesized protein-polymer conjugates with a phenylpiperazine-containing polymer using polymer-based protein engineering. A novel phenylpiperazine acrylamide monomer was synthesized and chain extended using atom transfer radical polymerization from the model protein bovine serum albumin (BSA). At non-cytotoxic doses, the protein-polymer conjugates induced a dose dependent reduction in the trans-epithelial electrical resistance of Caco-2 monolayers and an impressive ~30-fold increase in BSA permeability. Furthermore, this permeability increase was selective, as the permeability of the small molecule calcein co-incubated with the protein-polymer conjugate increased only 5-fold. Together, these data represent an important first step in the development of protein polymer conjugates that facilitate selective protein transport across membranes that are typically impermeable to macromolecules.
PMID: 28455168 [PubMed - as supplied by publisher]
Drug release studies from lipid nanoparticles in physiological media by a new DSC method.
J Control Release. 2017 Apr 24;:
Authors: Roese E, Bunjes H
Lipid nanoparticles are an interesting parenteral delivery system for poorly water-soluble drugs. In order to approach physiological conditions when conducting release studies from such systems the release media should preferentially contain lipophilic acceptor compartments such as lipoproteins or other colloid lipophilic components. In practice, drug release studies under such close to physiological conditions may be complicated by the small size of lipid nanoparticles, which is in the same range as that of the potential acceptor particles. This study describes a novel differential scanning calorimetry (DSC) method for drug release measurements which works without separation of donor and acceptor particles. The technique is based on measuring the crystallization temperature of trimyristin nanoparticles by DSC. The crystallization temperature of the nanoparticles decreases proportionally with the amount of active ingredient incorporated and thus increases as a result of drug release. Liquid trimyristin nanoparticles loaded with fenofibrate, orlistat, tocopherol acetate and ubidecarenone were studied in three different release media with increasing complexity and comparability to physiological conditions: a rapeseed oil nanoemulsion, porcine serum and porcine blood. Using the new method, a correlation between release behavior and drug lipophilicity was observed: the higher the logP value of the drug, the slower the release. The extent of drug release was influenced by partition equilibrium as indicated by increased drug release in the rapeseed oil nanoemulsion compared to porcine serum and blood.
PMID: 28450207 [PubMed - as supplied by publisher]
Development of a discriminative biphasic in vitro dissolution test and correlation with in vivo pharmacokinetic studies for differently formulated racecadotril granules.
J Control Release. 2017 Apr 24;:
Authors: Deng J, Staufenbiel S, Hao S, Wang B, Dashevskiy A, Bodmeier R
The purpose of this study was to discriminate the release behavior from three differently formulated racecadotril (BCS II) granules and to establish an in vitro-in vivo correlation. Three granule formulations of the lipophilic drug were prepared with equivalent composition but prepared with different manufacturing processes (dry granulation, wet granulation with or without binder). In vitro release of the three granules was investigated using a biphasic dissolution system (phosphate buffer pH6.8 and octanol) and compared to the conventional single phase USP II dissolution test performed under sink and non-sink conditions. In vivo studies with each granule formulation were performed in rats. Interestingly, the granule formulations exhibited pronouncedly different behavior in the different dissolution systems depending on different wetting and dissolution conditions. Single phase USP II dissolution tests lacked discrimination. In contrast, remarkable discrimination between the granule formulations was observed in the octanol phase of biphasic dissolution system with a rank order of release from granules prepared by wet granulation with binder>wet granulation without binder>dry granulation. This release order correlated well with the wettability of these granules. An excellent correlation was also established between in vitro release from the octanol phase of the biphasic test and in vivo data (R(2)=0.999). Compared to conventional dissolution methods, the biphasic method provides great potential to discriminate between only minor formulation and process changes within the same dosage form for poorly soluble drugs.
PMID: 28450206 [PubMed - as supplied by publisher]
Nucleic acid combinations: A new frontier for cancer treatment.
J Control Release. 2017 Apr 24;:
Authors: Remant Bahadur KC, Thapa B, Valencia-Serna J, Aliabadi HM, Uludağ H
The emerging molecular understanding of cancer cell behavior is leading to increasing possibilities to control unchecked cell growth and metastasis. On the other hand, development of multifunctional drug carriers at the 'nano'-scale is providing exciting new therapeutic strategies in clinical management of cancer beyond the conventional cytotoxic drugs. A new frontier in this regard is the combinational use of complementary agents based on nucleic acids to overcome the limitations of conventional therapy. The existence of tightly-integrated cross-talk through multiple signaling and effector pathways have been appreciated for some time, and the plasticity of such a network to overcome one-dimensional intervention is stimulating development of combinational therapy. The objective of this review is to underline the cutting edge technologies and opportunities employed in combination cancer therapy using nucleic acids therapeutics for successful clinical translation. Here, we provide a detailed analysis of the multifunctional carriers designed for different types of payloads, surveying the biomaterials used to construct the functional carriers. We then provide effective nucleic acid combinations employed to obtain more comprehensive outcomes, highlighting the critical factors involved in successful therapy. We conclude with an authors' perspective on the future of combinational therapy using nucleic acid therapeutics, articulating the main challenges to advance this promising approach to the clinical realm.
PMID: 28450205 [PubMed - as supplied by publisher]