RGD-Modified Albumin Nanoconjugates for Targeted Delivery of a Porphyrin Photosensitizer

Abstract

Advances in photodynamic therapy of cancer have been restrained by lack of cancer specificity and side effects to normal tissues. Molecularly targeted photodynamic therapy can achieve higher cancer specificity by combination of active cancer targeting and localized laser activation. We aimed to use albumin as a carrier to prepare targeted nanoconjugates that are selective to cancer cells and smaller than conventional nanoparticles for superior tumor penetration. IRDye® 700DX (IR700), a porphyrin photosensitizer, was covalently conjugated to human serum albumin that was also linked with tumor-targeting RGD peptides. With multiple IR700 and RGD molecules in a single albumin molecule, the resultant nanoconjugates demonstrated monodispersed and uniform size distribution with a diameter of 10.9 nm. These targeted nanoconjugates showed 121-fold increase in cellular delivery of IR700 into TOV21G ovarian cancer cells compared to control nanoconjugates. Mechanistic studies revealed that the integrin specific cellular delivery was achieved through dynamin-mediated caveolae-dependent endocytosis pathways. They produced massive cell killing in TOV21G cells at low nanomolar concentrations upon light irradiation, while NIH/3T3 cells that do not express integrin αvβ3 were not affected. Because of their small size, targeted albumin nanoconjugates could penetrate tumor spheroids of SKOV-3 ovarian cancer cells and produced strong phototoxicity in this 3-D model. Owing to their cancer-specific delivery and small size, these targeted nanoconjugates may become an effective drug delivery system for enabling molecularly targeted photodynamic therapy of cancer.

Porphyrinoid biohybrid materials as an emerging toolbox for biomedical light management

“…Li et al described, on the other hand, a covalent hybrid of IR700DX, a commercially available Si(IV)Pc, and HSA bearing tumour targeting RGD peptides, connected through an oligoethylene glycol spacer. 125 Phototoxicity studies in ovarian cancer cells showed that cellular delivery with this conjugate occurred via an endocytosis process. Moreover, this multivalent biohybrid resulted in being highly specific towards carcinogenic cells, while cells that did not express a v b 3 integrin were not affected.…”

Emerging Perspectives on Applications of Porphyrinoids for Photodynamic Therapy and Photoinactivation of Microorganisms

“…[30,31] In other way, a commercially Si(IV)Pc (IR7000DX) has been linked to HSA and RGD peptides, and the production of 1 O 2 was measured in ovarian cancer cells. [32] These bioconjugates demonstrated to be non-toxic to normal cells, and showed good results in cellular penetration and phototoxicity.…”

<p>CXCL12/CXCR4 Axis-Targeted Dual-Functional Nano-Drug Delivery System Against Ovarian Cancer</p>

“…After that, AMD-PEG-BSA was synthesized based on the reaction mechanism that the amino group on BSA surface reacts with the NHS ester of AMD-PEG-NHS could form amide bond when stirring at room temperature, according to procedures reported previously with some modifications. 22 In brief, AMD-PEG-NHS was reacted with BSA at a molar ratio of amino group on BSA and NHS on AMD-PEG-NHS at 1:1.5, the pH of BSA solution was adjusted by NaHCO 3 to around 7.4, followed by adding AMD-PEG-NHS to react for the whole night at room temperature. The obtained product was purified using ultracentrifugal filter tube (MWCO: 5KDa), and the filtrate was lyophilized to calculate the yield.…”