Rational Design of Cancer-Targeted BSA Protein Nanoparticles as Radiosensitizer to Overcome Cancer Radioresistance

Radiotherapy displays curative potential for cervical cancer management, but radioresistance occurs during long-term therapy. To overcome this limitation, tumor-targeted nanotechnology has been proposed to enhance the radiosensitivity of solid tumors. Herein, we used biocompatible bovine serum albumin nanoparticles (BSANPs) as carriers of organic selenocompound (PSeD) with folate (FA) as the targeting ligand to fabricate a cancer-targeted nanosystem. The combination of PSeD and BSANPs endowed the nanosystem with higher light absorption and reactive oxygen species (ROS) generation owing to their properties of surface plasmon resonance (SPR) effect, heavy metal effect, high refractive index and nanoparticulate interfacial effect. The combined treatment drastically increased the ROS overproduction, VEGF/VEGFR2 inactivation and inhibition of XRCC-1-mediated repair of DNA damage, thus triggering G2/M phase arrest and apoptosis. Taken together, our findings demonstrate the utility of FA-BSANPs as a promising radiosensitizer to improve cancer radiotherapy

ISAV-NP RNA binding.

<p>(A–C) RNA binding affinity measurements for the <i>wt</i> NP (A), ΔN111 (B) and ΔC16 (C). FA was performed using three RNA oligos each containing 20, 24, and 28 nts. The binding curves are plotted using the same protein concentration range. For the ΔC16 mutant, an inset is added in (C) to provide a more spread-out view at lower protein concentrations. Fully saturated curves for the 20-nt RNA are shown in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003624#ppat.1003624.s003" target="_blank">Fig. S3</a> in Supporting Information. (D–G) RNA binding stoichiometry measurements for the <i>wt</i> NP and the ΔLOOP monomeric mutant. NP:RNA complexes assembled in each experiments are schematically shown with blue handcuffs for NP dimers and grey curves for RNA molecules.</p

ISAV-NP:RNA complexes.

<p>(A–F) EM images of the free NP (A, B), NP bound to a 24-nt RNA (C, D), and NP bound to a 48-nt RNA (E, F). (G) Molecular weights of NP and NP:RNA complexes as determined by DLS. Molecular interpretations were made for each figure with blue handcuffs for the NP dimers and grey curves for RNA molecules.</p

Gel filtration chromatograms for ISAV-NP proteins.

<p>The eluted positions of three protein standards are marked by arrows.</p

Locality maps.

<p><b>A</b>, map of China showing location of Liaoning Province; <b>B</b>, enlarged map of Liaoning Province showing locality of fossil site, south of Lingyuan; <b>C</b>, enlarged map of Lingyuan city showing locality of fossil site at Baishizui village. [planned for page width].</p

Photograph and outline drawing of the skeleton of <i>Chuanqilong chaoyangensis</i>.

<p><b>A</b>, photograph; <b>B</b>, outline drawing. <b>Abbreviations</b>: <b>ca</b>, caudal vertebrae; <b>cb</b>, cervical band; <b>da</b>, dermal armor; <b>dr</b>, dorsal rib; <b>lfe</b>, left femur; <b>lfi</b>, left fibula; <b>lhu</b>, left humerus; <b>lil</b>, left ilium; <b>lis</b>, left ischium; <b>lma</b>, left maxilla; <b>lmd</b>, left mandible; <b>lmt</b>, left metatarsal; <b>lra</b>, left radius; <b>lsc</b>, left scapula; <b>lti</b>, left tibia; <b>lul</b>, left ulna; <b>mc</b>, metacarpals; <b>orb</b>, orbital; <b>pl</b>, plates; <b>q</b>, quadrate; <b>rfe</b>, right femur; <b>rfi</b>, right fibula; <b>rhu</b>, right humerus; <b>ril</b>, right ilium; <b>rma</b>, right maxilla; <b>rmd</b>, right mandible; <b>rmt</b>, right metatarsals; <b>rra</b>, right radius; <b>rsc</b>, right scapula; <b>rti</b>, right tibia; <b>rul</b>, right ulna; <b>sar</b>, sacral rib; <b>te</b>, tendons. [planned for page width].</p

A stratigraphic column of the Jehol Group showing the position of <i>Liaoningosaurus</i> and <i>Chuanqilong</i>.

<p>Modified after <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104551#pone.0104551-Xu3" target="_blank">[64]</a>. [planned for page width].</p

Holotype skull and mandibles of <i>Chuanqilong chaoyangensis</i>.

<p><b>A</b>, photograph in ventral view; <b>B</b>, outline drawing in ventral view; <b>C</b>, close up to maxillary teeth in lateral view. <b>Abbreviations</b>: <b>afe</b>, antorbital fenestra; <b>ar</b>, articular; <b>cv</b>, cervical vertebra; <b>la</b>, lacrimal; <b>ld</b>, left dentary; <b>lma</b>, left maxillary; <b>orb</b>, orbital; <b>ppq</b>, pterygoid process of the quadrate; <b>q</b>, quadrate; <b>rd</b>, right dentary; <b>rma</b>, right maxilla; <b>so</b>, supraorbital; <b>sq</b>, squamosal. [planned for page width].</p

Differential forelimb and hind limb measurements across ankylosaurs.

<p>Symbols for <i>Chuanqilong</i> are in red. A, plot of humeral length versus femoral length. Values for <i>Chuanqilong</i> is fall well below the line of best fit; B, plot of tibial length versus femoral length. <b>Abbreviations</b>: <b>Al</b>, <i>Anodontosaurus lambei</i>; <b>Am</b>, <i>Ankylosaurus magniventris</i>; <b>Ar</b>, <i>Animantarx ramaljonesi</i>; <b>Cbe</b>, <i>Crichtonsaurus benxiensis</i>; <b>Cbo</b>, <i>Crichtonsaurus bohlini</i>; <b>Cc</b>, <i>Chuanqilong chaoyangensis</i>; <b>cfP</b>, <i>cf. Pinacosaurus</i>; <b>Et1</b>, <i>Euoplocephalus tucki</i> UALVP 31; <b>Et2</b>, <i>Euoplocephalus tucki</i> AMNH 5404; <b>Gp</b>, <i>Gargoyleosaurus parkpinoorum</i>; <b>Ht</b>, <i>Hungarosaurus tormai</i>; <b>Lp</b>, <i>Liaoningosaurus paradoxus</i>; <b>ns</b>, nodosaurid scuteling from Paw Paw Formation; <b>Pf</b>, <i>Polacanthus foxii</i>; <b>Pg</b>, <i>Pinacosaurus grangeri</i>; <b>Sc</b>, <i>Scolosaurus cutleri</i>; <b>Se</b>, <i>Sauropelta edwardsi</i>; <b>Tp</b>, <i>Talarurus plicatospineus</i>. [planned for page width].</p

Left ilium and Ischia of <i>Chuanqilong chaoyangensis</i> in lateral view.

<p><b>A</b>, left ilium in ventral view; B, right ischium in lateral view; <b>C</b>, left ischium in lateral view. [planned for column width].</p