Nanocarriers for photodynamic therapy—rational formulation design and medium-scale manufacture

Abstract

The development and manufacture of novel nanocarriers for drug delivery has proved challenging with regards to scale-up and pharmaceutical quality. Polymeric nanocarriers composed of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-PEG) were prepared and the photosensitizer meso-tetrakis(3-hydroxyphenyl) chlorin (mTHPC) was effectively encapsulated. Furthermore, the interplay of various process and formulation parameters and their impact on the most important product specifications were investigated by using a factorial design and a central composite design in a microfluidic manufacturing process. These nanoparticles for intravenous administration with a size of 97 ± 0.13 nm, narrow size distribution, and an encapsulation efficiency of more than 80% were produced at high throughput. In vitro stability and in vitro drug release testing were applied for quality control purposes. Finally, the toxicity of the photosensitizer was tested in vitro. The cytotoxicity was successfully reduced while the efficacy of the formulation was maintained. First observations using in vivo imaging suggest effective distribution of the nanocarrier system after injection into rodents. Thus, further in vivo testing of the beneficial effects of nanoencapsulation into the matrix system and its formulation will be considered for the delivery of mTHPC to tumor tissues during photodynamic therapy.

Theranostic polymeric nanocarriers modified by enhanced gadolinium conjugation techniques

“…As a first technique, nanoprecipitation with Triton X-100 and Pluronic F127 as stabilizing agents resulted in a pronounced aggregation of the nanoparticles for all polymers. Similar observations have been made in medium-scale suggesting also a poor 'scalability' during later stages of process translation [8].…”

“…On the contrary, block copolymers comprising polylactic-co-glycolic acid (PLGA) and PEG were processed to nanoparticles at medium-scale using microfluidic technology [8] and emulsion techniques [9]. Recently, formulations manufactured by BIND Therapeutics successfully passed phase 1 clinical trials [10].…”

Photoinduced effects of m-tetrahydroxyphenylchlorin loaded lipid nanoemulsions on multicellular tumor spheroids

“…liposomal mTHPC formulations [28, 29] or the encapsulation of mTHPC into nanoparticles composed of poly(lactic-co-glycolic acid) [30], poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) [31], poly(ethylene glycol) methacrylate-co-2-(diisopropylamino)ethyl methacrylate copolymers [32], human serum albumin [33], organic-modified silica [34] or calcium phosphate. [35] These studies describe promising carriers for mTHPC by improving solubility and reducing dark toxicity however it is not possible to directly compare them as very different model systems were used in each case.…”

Preparation of Model Protein-Loaded PLGA Microparticles Using Lutensol XL 80 Emulsifier

“…HSA release of the model drug-loaded composites was studied for 5 days (Figure 4). The initial burst of HSA from particles formed using Lutensol XL 80 and with its combination with poloxamer 188 was found to be 18.3 ± 4.7% and 13.7 ± 2.3%, respectively, that can be the result of poorly entrapped drug, or drug adsorbed on the surface of the particles [17]. Till the end of the release test, the particles prepared by exclusively Lutensol XL 80 emulsifier released significantly higher amount of protein (30.5 ± 3.4%) compared to that of the composites prepared by the emulsifiers combination (17.8 ± 0.2%).…”