Intracellular targeting specificity of novel phthalocyanines assessed in a host-parasite model for developing potential photodynamic medicine.
Intracellular targeting specificity of novel phthalocyanines assessed in a host-parasite model for developing potential photodynamic medicine.
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DOI：
10.1371/journal.pone.0020786
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Chang KP
中科院分区：
文献类型：
--
作者：
Dutta S;Ongarora BG;Li H;Vicente Mda G;Kolli BK;Chang KP
光动力疗法，不太可能引起耐药性，值得关注，作为一种策略，以解决这一突出的问题，共同的所有疾病的化疗。以前，我们利用锥虫原虫利什曼原虫的不寻常特性，即它们天生能够归巢到抗原呈递细胞的吞噬溶酶体并在其中选择性光解的能力，利用内源性诱导卟啉积累的转基因突变体，扩大了这种模式在光动力疫苗接种中的适用性。在这里，我们通过探索外源提供的光敏剂，扩展了这种宿主-寄生虫模型在体外光动力治疗和疫苗接种中的效用。筛选了17种新型酞菁类化合物体外抗培养利什曼原虫的光解活性。为细胞摄取而呈现阳离子和可溶性（csPcs）的pc对寄生虫和宿主细胞（即巨噬细胞和树突状细胞）都具有光毒性。靶向线粒体的csPcs比局限于内吞室的csPcs更具有光解作用。用内吞性csPc处理感染细胞导致它们在含利什曼的吞噬溶酶体中积累，表明它们达到了光动力治疗的目标，尽管它们的寄生虫对宿主特异性仅限于csPc浓度的狭窄范围。相比之下，预先装载csPc的利什曼原虫在细胞内被选择性地光解，使宿主细胞存活。预光照这种cspc负载利什曼原虫不妨碍其传染性，但确保其胞内裂解。卵清蛋白（OVA）通过光灭活的OVA转染物传递到小鼠巨噬细胞和树突状细胞，这些抗原呈递细胞将其与MHC I类分子共同呈递，激活OVA表位特异性CD8+T细胞。本文提出的体外证据首次证明，内吞csPcs不仅具有光动力治疗利什曼原虫的潜力，而且在利什曼原虫的光灭活中，它们可以产生一种安全的载体来表达和传递具有增强细胞介导免疫的特定抗原。
Photodynamic therapy, unlikely to elicit drug-resistance, deserves attention as a strategy to counter this outstanding problem common to the chemotherapy of all diseases. Previously, we have broadened the applicability of this modality to photodynamic vaccination by exploiting the unusual properties of the trypanosomatid protozoa, Leishmania, i.e., their innate ability of homing to the phagolysosomes of the antigen-presenting cells and their selective photolysis therein, using transgenic mutants endogenously inducible for porphyrin accumulation. Here, we extended the utility of this host-parasite model for in vitro photodynamic therapy and vaccination by exploring exogenously supplied photosensitizers. Seventeen novel phthalocyanines (Pcs) were screened in vitro for their photolytic activity against cultured Leishmania. Pcs rendered cationic and soluble (csPcs) for cellular uptake were phototoxic to both parasite and host cells, i.e., macrophages and dendritic cells. The csPcs that targeted to mitochondria were more photolytic than those restricted to the endocytic compartments. Treatment of infected cells with endocytic csPcs resulted in their accumulation in Leishmania-containing phagolysosomes, indicative of reaching their target for photodynamic therapy, although their parasite versus host specificity is limited to a narrow range of csPc concentrations. In contrast, Leishmania pre-loaded with csPc were selectively photolyzed intracellularly, leaving host cells viable. Pre-illumination of such csPc-loaded Leishmania did not hinder their infectivity, but ensured their intracellular lysis. Ovalbumin (OVA) so delivered by photo-inactivated OVA transfectants to mouse macrophages and dendritic cells were co-presented with MHC Class I molecules by these antigen presenting cells to activate OVA epitope-specific CD8+T cells. The in vitro evidence presented here demonstrates for the first time not only the potential of endocytic csPcs for effective photodynamic therapy against Leishmania but also their utility in photo-inactivation of Leishmania to produce a safe carrier to express and deliver a defined antigen with enhanced cell-mediated immunity.
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影响因子：
1.5
作者：
LIU, X;CHANG, KP
通讯作者：
CHANG, KP
影响因子：
9.7
作者：
CANTI, G;LATTUADA, D;VALENTINI, G
通讯作者：
VALENTINI, G
影响因子：
13.8
作者：
Gardlo, K;Horska, Z;Fritsch, C
通讯作者：
Fritsch, C
影响因子：
5.5
作者：
Llanos-Cuentas, Alejandro;Calderon, Wessmark;Piazza, Franco M.
通讯作者：
Piazza, Franco M.
影响因子：
4.1
作者：
Asilian, A.;Davami, M.
通讯作者：
Davami, M.