Abstract
Polymeric micelles are extensively investigated as drug delivery systems for hydrophobic drugs including photosensitizers (PSs). In order to benefit from micelles as targeted delivery systems for PS, rather than only solubilizers, the stability and cargo retention of the (PS-loaded) micelles should be properly assessed in biologically relevant media to get insight into the essential parameters predicting their in vivo performance (i.e., pharmacokinetics). In the present study, asymmetric flow field-flow fractionation (AF4) was used to investigate the in vitro stability in human plasma of empty and meta-tetra(hydroxyphenyl)chlorin (mTHPC)-loaded dithiolane-crosslinked micelles based on poly(ɛ-caprolactone)-co-poly(1,2-dithiolane‑carbonate)-b-poly(ethylene glycol) (p(CL-co-DTC)-PEG) and non (covalently)-crosslinked micelles composed of poly(ε-caprolactone)-b-poly(ethylene glycol) (pCL-PEG). AF4 allows separation of the micelles from plasma proteins, which showed that small non (covalently)-crosslinked pCL9-PEG (17 nm) and pCL15-PEG (22 nm) micelles had lower stability in plasma than pCL23-PEG micelles with larger size (43 nm) and higher degree of crystallinity of pCL, and had also lower stability than covalently crosslinked p(CL9-DTC3.9)-PEG and p(CL18-DTC7.5)-PEG micelles with similar small sizes (~20 nm). In addition, PS (re)distribution to specific plasma proteins was observed by AF4, giving strong indications for the (in)stability of PS-loaded micelles in plasma. Nevertheless, fluorescence spectroscopy in human plasma showed that the retention of mTHPC in non (covalently)-crosslinked but semi-crystalline pCL23-PEG micelles (>8 h) was much longer than that in covalently crosslinked p(CL18-DTC7.5)-PEG micelles (~4 h). In line with this, in vivo circulation kinetics showed that pCL23-PEG micelles loaded with mTHPC had significantly longer half-life values (t½-β of micelles and mTHPC was 14 and 18 h, respectively) than covalently crosslinked p(CL18-DTC7.5)-PEG micelles (t½-β of both micelles and mTHPC was ~2 h). As a consequence, long circulating pCL23-PEG micelles resulted in significantly higher tumor accumulation of both the micelles and loaded mTHPC as compared to short circulating p(CL18-DTC7.5)-PEG micelles. These in vivo data were in good agreement with the in vitro stability studies.In conclusion, the present study points out that AF4 and fluorescence spectroscopy are excellent tools to evaluate the (in)stability of nanoparticles in biological media and thus predict the (in)stability of drug loaded nanoparticles after i.v. administration, which is favorable to screen promising delivery systems with reduced experimental time and costs and without excessive use of animals.
Highlights
Photosensitizers (PSs) are compounds that are activated by absorbed light to the excited state, following by release of its energy to dissolved oxygen to yield singlet oxygen species, which in turn cause cell death [1,2]
Non-crosslinked micelles consisting of 10 mg/mL poly(ε-caprolactone)-bpoly(ethylene glycol) (pCL-PEG) were prepared by a film hydration method [16,17]
Different block co polymers were chosen for the preparation of crosslinked micelles, which differed in the sequence of CL and DTC and/or molecular weight of the hydrophobic block (Table S1, supporting in formation)
Summary
Photosensitizers (PSs) are compounds that are activated by absorbed light to the excited state, following by release of its energy to dissolved oxygen to yield singlet oxygen species, which in turn cause cell death [1,2] This process is exploited in so-called photodynamic therapy (PDT), a modality that has been clinically approved for treatment of different types of cancer [3,4]. There are currently some research methods available to explore the stability of drug-loaded polymeric micelles in well-defined and simple media, for example, dialysis [30,31] and par ticle size analysis [32,33]. Hardly exploited for this purpose, is asymmetrical flow field-flow fractionation (AF4), which al lows high resolution separation of particles and plasma proteins based on size differences under physiologically relevant conditions [34]
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