Small interfering RNA (siRNA) has been expected to be a unique pharmaceutic for the treatment of broad-spectrum intractable diseases. However, its unfavorable properties such as easy degradation in the blood and negative-charge density are still a formidable barrier for clinical use. For disruption of this barrier, siRNA delivery technology has been significantly advanced in the past two decades. The approval of Patisiran (ONPATTRO™) for the treatment of transthyretin-mediated amyloidosis, the first approved siRNA drug, is a most important milestone. Since lipid-based nanoparticles (LNPs) are used in Patisiran, LNP-based siRNA delivery is now of significant interest for the development of the next siRNA formulation. In this review, we describe the design of LNPs for the improvement of siRNA properties, bioavailability, and pharmacokinetics. Recently, a number of siRNA-encapsulated LNPs were reported for the treatment of intractable diseases such as cancer, viral infection, inflammatory neurological disorder, and genetic diseases. We believe that these contributions address and will promote the development of an effective LNP-based siRNA delivery system and siRNA formulation.

For the improvement of therapeutic efficacy in photodynamic therapy (PDT) by using a photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA), we previously prepared polyethylene glycol (PEG)-modified liposomes encapsulating BPD-MA (PEG-Lip BPD-MA). PEGylation of liposomes enhanced the accumulation of BPD-MA in tumor tissue at 3 h after injection of it into Meth-A-sarcoma-bearing mice, but, unexpectedly, decreased the suitability of the drug for PDT when laser irradiation was performed at 3 h after the injection of the liposomal photosensitizer. To improve the bioavailability of PEG-Lip BPD-MA, we endowed the liposomes with active-targeting characteristics by using Ala-Pro-Arg-Pro-Gly (APRPG) pentapeptide, which had earlier been isolated as a peptide specific to angiogenic endothelial cells. APRPG-PEG-modified liposomal BPD-MA (APRPG-PEG-Lip BPD-MA) accumulated in tumor tissue similarly as PEG-Lip BPD-MA and to an approx. 4-fold higher degree than BPD-MA delivered with non-modified liposomes at 3 h after the injection of the drugs into tumor-bearing mice. On the contrary, unlike the treatment with PEG-Lip BPD-MA, APRPG-PEG-Lip BPD-MA treatment strongly suppressed tumor growth after laser irradiation at 3 h after injection. Finally, we observed vasculature damage in the dorsal air sac angiogenesis model by APRPG-PEG-Lip BPD-MA-mediated PDT. The present results suggest that antiangiogenic PDT is an efficient modality for tumor treatment and that tumor neovessel-targeted, long-circulating liposomes are a useful carrier for delivering photosensitizer to angiogenic endothelial cells.

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Rhinacanthus nasutus KURZ. (family Acanthaceae), has been used in Thai traditional medicine for the treatment of various diseases such as eczema, pulmonary tuberculosis, herpes, hepatitis, diabetes, hypertension and various skin diseases, and its active components were widely investigated. 1-7)R. nasutus KURZ. has also been used for cancer treatment. [8][9][10] The main bioactive compounds were revealed to be naphthoquinone; rhinacanthins (A-D, G-Q), rhinacanthone and lignan groups. [1][2][3][4][5][6][7][8]10,11) Antitumor activity of R. nasutus KURZ. extracts,8) and that of rhinacanthone in the in vivo study were reported. 11) We previously reported that rhinacanthins-M, -N and -Q and related naphthoquinone esters as well as synthetic compounds, 1,2-naphthoquinones and 1,4-naphthoquinones, selectively suppressed the growth of KB, HeLa and HepG2 human cancer cells, and normal Vero cells. 12,13) We also performed mechanistic study and observed that synthetic rhinacanthins-N and -Q inhibited DNA topoisomerase II.13) A naphthoquinone compound b-lapachone, that was also derived from natural products and has a similar structure to rhinacanthone, was reported to be a potent inhibitor of DNA topoisomerase I and II, [14][15][16] and to induce apoptosis of various cancer cells. [17][18][19][20][21] Recently, we observed that rhinacanthins-C, -N and -Q suppressed human cervical carcinoma HeLaS3 cells through induction of apoptosis. 22)Therefore, in the present study, we attempted to determine actual antitumor activity of rhinacanthins in tumor-bearing mice.Since rhinacanthins-C, -N and -Q are hydrophobic compounds, they are not able to inject into bloodstream without solubilization. For in vivo use of the drugs, we attempted to solubilize them in liposomes. By the way, liposomes have been widely used in the field of drugs delivery systems (DDS): Liposomalization reduces side effects and toxicities of drugs encapsulated, and improves their bioavailability. Therefore, liposomes tended to be used for cancer treatment, since most of anticancer drugs accompany severe side effects. [23][24][25] Furthermore, liposomes with long circulating characteristics are known to accumulate in interstitial spaces of tumor tissues of which blood vessels are highly permeable. 26,27) For the purpose of DDS, liposomes having rather rigid lipid bilayer are favorable, and they are usually composed of phospholipids with saturated fatty acyl chains and cholesterol. On the other hand, liposomes have been used for the injection of hydrophobic drugs, since hydrophobic materials can be encapsulated into the lipid bilayer of the liposomes. For example, Visudyne, a liposomal formulation of benzoporphyrin derivative monoacid ring A (BPD-MA), is being used clinically in photodynamic therapy for age-related macular degeneration. In Visudyne, liposomes are used as a "solvent" of BPD-MA for the purpose of injection of the drug into bloodstream.28) In such case, liposomes having rather fluid lipid bilayer are used, and the injected drug in the bloodstream is t...