Design of a Simple and Practical Nanosystem Coordinates Tumor Targeting and Penetration for Improved Theranostics

Abstract

A novel amphiphilic peptide PA (APPA) containing two functional motifs is designed to coordinate the targeting to integrin αvβ3 and neuropilin-1(NRP-1) on cell membrane. The cooperation of the two motifs fulfills the penetration of APPA-based nanosystem deep into tumor tissue and accumulates there. The APPA can be easily synthesized and self-assembled into spherical nanoparticles in the presence of doxorubicin (DOX) (PAD), or can be used for construction of fluorescent nanoprobe in the presence of DiR (PA-DiR). In vitro and in vivo studies demonstrate that the self-assembled PAD and PA-DiR nanosystems show a surprisingly high affinity for and penetration into αvβ3 and NRP-1 positive tumors. The PA-DiR nanoprobe can be specifically recruited to 4T1 xenograft tumors. The signal of PA-DiR enriched in the tumor was more than 10 times higher than that of the negative control PC-DiR. The high affinity and specificity of the PA-DiR nanoprobe in in vivo fluorescence imaging, the profound therapeutic efficacy of PAD nanosystem in solid tumor models, and the low toxicity of APPA-based nanosystem demonstrate the great potential of this well-designed and simple nanosystem for application in the diagnosis and therapy of αvβ3 and NRP-1 positive tumors, with minimal side effects.

Peptosome Coadministration Improves Nanoparticle Delivery to Tumors through NRP1-Mediated Co-Endocytosis

“…APPA and APPC self-assembled peptosomes containing fluorescence probes were prepared by using the same method as described in our previous work [24] and the procedure described in the methods. The transmission electron microscopy (TEM) images of DiR- (DilC18(7) dialkyl carbocyanine membrane label) [29,30] containing APPA or APPC peptosome (PADiR or PCDiR), the DOX-containing APPA peptosome (PAD), and the tetramethylrhodamine isothiocyanate (TRITC)-containing APPA self-assembled peptosome (PAT) were shown in Figure S1A.…”

“…DMSO was added to bring up the solution to 10 uL, and 1 mL of PBS was added to the mixture and ultrasonicated (50 W) for 10 min, followed by incubation at room temperature for 1 h. The final solution was centrifuged at 5500× g for 5 min and the aqueous solution was collected. Transmission electron microscopy (TEM, HT7700, Hitachi, Japan) was used to characterize the morphology and the size of APPA and APPC self-assembled peptosomes [24]. Briefly, the collected aqueous solution was dropped onto a carbon grid, dried, and negatively stained with uranyl acetate for TEM.…”

“…The mice in each group were intravenously administered with LipoCy5 (100 µL), PAT (100 µL), PAT (100 µL) + free Cy5 (2 μM, 100 µL), and PAT (100 µL) + LipoCy5 (Cy5: 2 μM, 100 µL), respectively. Six hours after the injection, the tumors were excised and slices were prepared as the procedure described in our previous study [24]. The cell membranes were stained with FITC labeled anti-Na + /K + ATPase antibody and the nuclei with DAPI.…”

“…The nanosystem homes to tumor vessels through the binding of RGD with integrin αvβ3 and then penetrates into tumor tissue through the interaction of the CendR motif with NRP1 receptor [12]. Since both αvβ3 and NRP1 are highly expressed in many tumors [24] the nanosystem could have wide applications in cancer therapy. In this study, we further demonstrate that the APPA self-assembled peptosomes can be used as an adjuvant to improve the delivery of antibodies, nanoprobes, and nanodrugs to tumors.…”

Polymer Architecture Alters Tissue Distribution and Enhances Cytotoxicity Profiles in Orthotopic Models of Triple Negative Breast Cancers

“…Nevertheless, important studies have shown that polymer or nanoparticle size, surface-displayed functionality and ability to break down into smaller fragments when in target sites, are all important factors enhancing penetration into tumours. [29][30][31][32][33][34][35][36] Recent work has elegantly shown that pHPMA polymers with a variety of side-chain and backbone architectures can exhibit marked variations in their ability to transport into tumours and other tissues. [37] Up to ~ 4-5 fold differences in tumour accumulation in a murine EL4 T cell lymphoma model were observed for pHPMA polymers varying in dendron or dendritic architectures, even though the primary polymer chemistries and therapeutic payloads were very similar.…”