15This work is a proof of concept study establishing the potential of electrosprayed Janus particles for 16 combined photodynamic therapy-chemotherapy. Sub-micron sized particles of polyvinylpyrrolidone 17 containing either an anti-cancer drug (carmofur) or a photosensitiser (rose bengal; RB), and Janus 18 particles containing both in separate compartments were prepared. The functional components were 19 present in the amorphous form in all the particles, and infrared spectroscopy indicated that 20 intermolecular interactions formed between the different species. In vitro drug release studies 21showed that both carmofur and RB were released at approximately the same rate, with dissolution 22 complete after around 250 min. Cytotoxicity studies were undertaken on model human dermal 23 fibroblasts (HDF) and lung cancer (A549) cells, and the influence of light on cell death explored. 24Formulations containing carmofur as the sole active ingredient were highly toxic to both cell lines, 25 with or without a light treatment. The RB formulations were non-toxic to HDF when no light was 26 applied, and with photo-treatment caused large amounts of cell death for both A549 and HDF cells. 27The Janus formulation containing both RB and carmofur was non-toxic to HDF without light, and only 28 slightly toxic with the photo-treatment. In contrast it was hugely toxic to A549 cells when light was 29 applied. The Janus particles are thus highly selective for cancer cells, and it is hence proposed that 30 such electrosprayed particles containing both a chemotherapeutic agent and photosensitiser have 31 great potential in combined chemotherapy/photodynamic therapy. 32

In this work, we report new formulations for the combined photo-chemotherapy of colon cancer. Fibers were fabricated via coaxial-electrospinning with the intent of targeting delivery of the anti-cancer drug carmofur (CAR) and the photosensitizer rose bengal (RB) selectively to the colon site. The fibers comprised a hydroxypropyl methylcellulose (HPMC) core loaded with the active ingredients, and a pH-sensitive Eudragit L100-55 shell. The fibers were found to be homogeneous and cylindrical and have visible core-shell structures. X-ray diffraction and differential scanning calorimetry demonstrated that both CAR and RB were present in the fibers in the amorphous physical form. In vitro drug release studies showed that the fibers have the potential to selectively deliver drugs to the colon, with only 10-15 % release noted in the acidic conditions of the stomach but sustained release at pH 7.4. Cytotoxicity studies were undertaken on human dermal fibroblast (HDF) and colon cancer (Caco-2) cells, and the influence of light on cell death was also explored. The fibers loaded with CAR alone showed obvious toxicity to both cell lines, with and without the application of light. The RB-loaded fibers led to high viability (ca. 80 % for both cell types) in the absence of light, but much greater toxicity was noted (30-60 %) with light. The same trends were observed with the formulation containing both CAR and RB, but with lower viabilities. The RB and RB/CAR loaded systems show clear selectivity for cancerous over non-cancerous cells. Finally, mucoadhesion studies revealed there were strong adhesive forces between the rat colonic mucosa and the fibers after they had passed through an acidic environment. Such electrospun fibers thus could have potential in the development of oral therapies for colon 2 cancer.

We report the self-assembly of anti-cancer drug-loaded solid lipid nanoparticles (SLNs) from spray dried microparticles comprising poly(vinylpyrrolidone) (PVP) loaded with glyceryl tristearate (GTS) and either indomethacin (IMC) or 5-fluorouracil (5-FU). When the spray dried microparticles are added to water, the PVP matrix dissolves and the GTS and drug self-assemble into SLNs. The SLNs provide a non-toxic delivery platform for both hydrophobic (indomethacin) and hydrophilic (5-fluorouracil) drugs. They show extended release profiles over more than 24 h, and in permeation studies the drug cargo is seen to accumulate inside cancer cells. This overcomes major issues with achieving local intestinal delivery of these active ingredients, in that IMC permeates well and thus will enter the systemic circulation and potentially lead to side effects, while 5-FU remains in the lumen of the small intestine and will be secreted without having any therapeutic benefit. The SLN formulations are as effective as the pure drugs in terms of their ability to induce cell death. Our approach represents a new and simple route to the fabrication of SLNs: by assembling these from spraydried microparticles on demand, we can circumvent the low storage stability which plagues SLN formulations.