Photodynamic therapy (PDT) is a cancer treatment modality that requires three components, namely light, dioxygen and a photosensitizing agent. After light excitation, the photosensitizer (PS) in its excited state transfers its energy to oxygen, which leads to photooxidation reactions. In order to improve the selectivity of the treatment, research has focused on the design of PS covalently attached to a tumor-targeting moiety. In this paper, we describe the synthesis and the physico-chemical and photophysical properties of six new peptide-conjugated photosensitizers designed for targeting the neuropilin-1 (NRP-1) receptor. We chose a TPC (5-(4-carboxyphenyl)-10,15, 20-triphenyl chlorine as photosensitizer, coupled via three different spacers (aminohexanoic acid, 1-amino-3,6-dioxaoctanoic acid, and 1-amino-9-aza-3,6,12,15-tetraoxa-10-on-heptadecanoic acid) to two different peptides (DKPPR and TKPRR). The affinity towards the NRP-1 receptor of the conjugated chlorins was evaluated along with in vitro and in vivo stability levels. The tissue concentration of the TPC-conjugates in animal model shows good distribution, especially for the DKPPR conjugates. The novel peptide-PS conjugates proposed in this study were proven to have potential to be further developed as future NRP-1 targeting photodynamic therapy agent.
Vascular endothelial growth factor (VEGF) and its co-receptor neuropilin-1 (NRP-1) are important targets of many pro-angiogenic factors. In this study, nine peptides were synthesized and evaluated for their molecular interaction with NRP-1 and compared to our previous peptide ATWLPPR. Docking study showed that the investigated peptides shared the same binding region as shown by tuftsin known to bind selectively to NRP-1. Four pentapeptides (DKPPR, DKPRR, TKPPR and TKPRR) and a hexapeptide CDKPRR demonstrated good inhibitory activity against NRP-1. In contrast, peptides having arginine residue at sites other than the C-terminus exhibited low activity towards NRP-1 and this is confirmed by their inability to displace the VEGF165 binding to NRP-1. Docking study also revealed that replacement of carboxyl to amide group at the C-terminal arginine of the peptide did not affect significantly the binding interaction to NRP-1. However, the molecular affinity study showed that these peptides have marked reduction in the activity against NRP-1. Pentapeptides having C-terminal arginine showed strong interaction and good inhibitory activity with NRP thus may be a good template for anti-angiogenic targeting agent.
Folic acid is a small molecule, also known as vitamin B9. It is an essential compound involved in important biochemical processes. It is widely used as a vector for targeted treatment and diagnosis especially in cancer therapeutics. Nevertheless, not many authors address the problem of folic acid degradation. Several researchers reported their observations concerning its denaturation, but they generally only took into account one parameter (pH, temperature, light or O2etc.). In this review, we will focus on five main parameters (assessed individually or in conjunction with one or several others) that have to be taken into account to avoid the degradation of folic acid: light, temperature, concentration, oxygen and pH, which are the most cited in the literature. Scrupulous bibliographic research enabled us to determine two additional degradation factors that are the influence of singlet oxygen and electron beam on folic acid stability, which are not considered as among the prime factors. Although these two factors are not commonly present as compared to the others, singlet oxygen and electron beams intervene in new therapeutic technologies and must be taken in consideration for further applications such photodynamic or X-rays therapies.
Nanoparticles (NPs) have been shown to have good ability to improve the targeting and delivery of therapeutics. In the field of photodynamic therapy (PDT), this targeting advantage of NPs could help ensure drug delivery at specific sites. Among the commonly reported NPs for PDT applications, NPs from zinc oxide, titanium dioxide, and fullerene are commonly reported. In addition, graphene has also been reported to be used as NPs albeit being relatively new to this field. In this context, the present review is organized by these different NPs and contains numerous research works related to PDT applications. The effectiveness of these NPs for PDT is discussed in detail by collecting all essential information described in the literature. The information thus assembled could be useful in designing new NPs specific for PDT and/or PTT applications in the future.
Targeting vascular endothelial growth factor receptor (VEFGR) and its co-receptor neuropilin-1 (NRP-1) is an interesting vascular strategy. tLyp-1 is a tumor-homing and penetrating peptide of 7 amino acids (CGNKRTR). It is a truncated form of Lyp-1 (CGNKRTRGC), which is known to target NRP-1 receptor, with high affinity and specificity. It is mediated by endocytosis via C-end rule (CendR) internalization pathway. The aim of this study is to evaluate the importance of each amino acid in the tLyp-1 sequence through alanine-scanning (Ala-scan) technique, during which each of the amino acid in the sequence was systematically replaced by alanine to produce 7 different analogues. In silico approach through molecular docking and molecular dynamics are employed to understand the interaction between the peptide and its analogues with the NRP-1 receptor, followed by in vitro ligand binding assay study. The C-terminal Arg is crucial in the interaction of tLyp-1 with NRP-1 receptor. Substituting this residue dramatically reduces the affinity of this peptide which is clearly seen in this study. Lys-4 is also important in the interaction, which is confirmed via the in vitro study and the MM-PBSA analysis. The finding in this study supports the CendR, in which the presence of R/K-XX-R/K motif is essential in the binding of a ligand with NRP-1 receptor. This presented work will serve as a guide in the future work pertaining the development of active targeting agent towards NRP-1 receptor.