Stimuli sensitive core-shell nanoparticles for targetted drug delivery

Master'sMASTER OF ENGINEERIN

A new class of polymeric amphiphile

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The molecular shape of poly(propylenimine) dendrimer amphiphiles has a profound effect on their self assembly

The shape of dendrimer amphiphiles has an unexpected effect on their self-assembly. A series of diaminobutane poly(propylenimine) generation 3 dendrimer (DAB-dendr-(NH(2))(16)) amphiphiles has been synthesized, bearing an average of five (PD5), three (PD3) and one (PD1) palmitoyl group(s) per dendrimer molecule. Additionally DAB-dendr-(NH(2))(16) was derivatized with a layer of poly(ethylene glycol) (PEG, degree of polymerization = 12) groups and conjugated to an average of 1 palmitoyl group at the PEG end (PPD1). A final amphiphile resulted from the conjugation of DAB-dendr-(NH(2))(16) with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-succinimidylpropionate (DSPE-PEG(3400)-SPA), i.e.: DPD5 (with 4 DSPE-PEG arms). The critical micellar concentration in aqueous media followed the trend: DPD5 <PD5 = PD3 <PD1 <PPD1 and amphiphiles eventually formed 10-20 nm monomolecular or multimolecular micelles and/or 200 nm spheres or tubules. Aggregation was entropy driven, as expected, for DPD5, PD5 and PD1 and enthalpy driven with the most hydrophilic compound PPD1, but was unexpectedly enthalpy driven for PD3. PD3 aggregates formed low capacity hydrophobic domains with a limited capacity for encapsulation of cyclosporine A; encapsulation levels (mole drug per mole polymer) were 0.099, 0.014, 0.099, and 0.735 for PD1, PD3, PD5, and DPD5 and, respectively. We conclude that star shaped amphiphiles such as PD3 are sterically hindered from self-assembling into high capacity hydrophobic domains in aqueous media. Amphiphile-membrane interactions were promoted by hydrophobic groups, but diminished by PEG moieties. DPD5 is the most suitable amphiphile for biomedical applications

Claw Amphiphiles with a Dendrimer Core: Nanoparticle Stability and Drug Encapsulation Are Directly Proportional to the Number of Digits

There are numerous pharmaceutical, food, and consumer product applications requiring the incorporation of hydrophobic solutes within aqueous media. Often amphiphiles and/or polymers are used to produce encapsulating nanostructures. Because the encapsulation efficiencies of these nanostructures directly impact on the process or product, it is often desirable to optimize this parameter. To produce these advanced functional materials, we hypothesized that an amphiphile with a claw shape would favor polymer aggregation into nanoparticles and hydrophobic compound encapsulation. Claw amphiphiles were prepared by attaching one end of comb-shaped chitosan amphiphile chains [<i>N</i>,<i>N</i>,<i>N</i>-trimethyl,<i> N</i>,<i>N</i>-dimethyl,<i> N</i>-monomethyl,<i> N</i>-palmitoyl,<i> N</i>-acetyl, 6-<i>O</i>-glycol chitosan (GCPQA)] to a central dendrimer core [generation 3 diaminobutane poly­(propylenimine) dendrimer (DAB)] to give DAB-GCPQA. The linear chitosan amphiphile (GCPQA) forms the digits of the claw. These claw amphiphiles were very stable and had a high encapsulating efficiency. DAB-GCPQAs (<i>M</i>_n = 30 and 70 kDa) had extremely low critical micelle concentrations [CMCs = 0.43 μg mL^–1 (13 nM) and 0.093 μg mL^–1 (0.9 nM), respectively], and their CMCs were lower than that of linear GCPQA [<i>M</i>_n = 14 kDa, CMC = 0.77 μg mL^–1 (38 nM)]. The claw amphiphile CMCs decreased linearly with the number of digits (<i>r</i>² = 0.98), and drug encapsulation (hydrophobic drug propofol) in 4 mg mL^–1 dispersions of the amphiphiles increased linearly (<i>r</i>² = 0.94) with the number of digits. DAB-GCPQA70 (4 mg mL^–1, 0.058 mM) encapsulated propofol (7.3 mg mL^–1, 40 mM). Finally, despite their stability, claw amphiphile nanoparticles are able to release the encapsulated drug <i>in vivo</i>, as shown with the claw amphiphile–propofol formulations in a murine loss of righting reflex model

Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels – A Strategy for Brain Cancer Treatments

This is an open access article. The final publication is available at Springer via http://dx.doi.org/10.1007/s11095-016-1872-x.Purpose The blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosuppression. Methods Mice were dosed with either intravenous lomustine Molecular Envelope Technology (MET) nanoparticles (13 mg kg-1) or ethanolic lomustine (6.5 mg kg-1) and tissues analysed. Efficacy was assessed in an orthotopic U-87 MG glioblastoma model, following intravenous MET lomustine (daily 13 mg kg-1) or ethanolic lomustine (daily 1.2 mg kg-1 - the highest repeated dose possible). Myelosuppression and MET particle macrophage uptake were also investigated. Results The MET formulation resulted in modest brain targeting (brain/ bone AUC0-4h ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC0-4h ratios for MET and ethanolic lomustine = 0.24 and 0.15 respectively). The MET formulation significantly increased mice (U-87 MG tumours) survival times; with MET lomustine, ethanolic lomustine and untreated mean survival times of 33.2, 22.5 and 21.3 days respectively and there were no material treatment-related differences in blood and femoral cell counts. Macrophage uptake is slower for MET nanoparticles than for liposomes. Conclusions Particulate drug formulations improved brain tumour therapy without major bone marrow toxicity.Wellcome TrustTertiary Education Trust Fund (TETFund, formerly Education Trust Fund), NigeriaObafemi Awolowo University, Ile-Ife, Nigeri