Targetable Clinical Nanoparticles for Precision Cancer Therapy Based on Disease-Specific Molecular Inflection Points - PubMed (original) (raw)
Targetable Clinical Nanoparticles for Precision Cancer Therapy Based on Disease-Specific Molecular Inflection Points
Charalambos Kaittanis et al. Nano Lett. 2017.
Abstract
Novel translational approaches based on clinical modular nanoplatforms are needed in order to treat solid cancers according to their discrete molecular features. In the present study, we show that the clinical nanopharmaceutical Ferumoxytol, which consists of a glucose-based coat surrounding an iron oxide core, could identify molecular characteristics of prostate cancer, corresponding to unique phases of the disease continuum. By affixing a targeting probe for the prostate-specific membrane antigen on its surface, the nanopharmaceutical was able to assess the functional state of the androgen receptor pathway via MRI, guiding therapy and delivering it with the same clinical nanoparticle. In order to simultaneously inhibit signaling from key oncogenic pathways of more advanced forms of prostate cancer, a single-agent therapy for early stage disease to inhibit DNA replication, as well as combination therapy with two drugs co-retained within the nanopharmaceutical's polymeric coating, were tested and resulted in complete tumor ablation. Recalcitrant and terminal forms of the disease were effectively treated with a nanopharmaceutical delivering a combination that upregulates endoplasmic reticulum stress and inhibits metastasis, thereby showing that this multifunctional nanoplatform can be used in the clinic for patient stratification, as well as precision treatment based on the individual's unique disease features.
Keywords: Molecular imaging; PSMA; combination therapy.
Figures
Figure 1
Development of targeted nanopharmaceuticals (TNP) for the recognition of the biomarker FOLH1 (PSMA). (A) Prostate cancer undergoes multiple molecular alterations that give rise to distinct phases. Acquired resistance leads to metastasis, and ultimately to death. (Green circle: hormone deprivation; orange circle: anti-androgens) (B) Schematic representation of the TNP supramolecular architecture. (C) The TNP’s cyclic peptide conferred target specificity. Linearization of the peptide (linP2) abrogated binding to PSMA (LNCaP: PSMA-positive cells; PC3-Ctrl: PSMA-negative cells). (D) Binding of the TNP’s peptide probe occurred at a locus that did not impair PSMA’s enzymatic activity (Glu: glutamic acid; Glu-Fol: monoglutamated folate; 2-PMPA: PSMA inhibitor; ns: not significant; *** P < 0.001; **** P < 0.0001). Means ± SEM.
Figure 2
Multimodal biomarker detection with TNP. (A) In vitro evaluation of the binding of TNP to plasma-membrane-expressed FOLH1 (PSMA), using the TNP’s fluorescence and magnetic resonance signals (PC3-Ctrl: PSMA-negative cells; PC3-PSMA: PSMA-positive cells; **** P < 0.0001). (B) Fluorescence tomography showed homing of TNP’s to the PSMA-positive tumor in nude, male mice. (C) Magnetic resonance imaging revealed reduction in the T2 signal of the biomarker-expressing lesion 24 h after iv administration of the TNP. (D) Quantification of fluorescence and magnetic resonance signal due to TNP accumulation in the animals’ PSMA-expressing tumors (n=5; * P < 0.05, ** P < 0.01). (E) Histological analysis of PC3-Ctrl and PC3-PSMA tumors after TNP administration confirmed accumulation of the TNP within the PSMA-positive tumor (blue: Hoechst 333442 nuclear stain; magenta: Cy5.5 dye of TNP; H&E: hematoxylin and eosin stain; Prussian blue: iron stain). Means ± SEM.
Figure 3
TNP-based evaluation of the androgen receptor pathway in prostate cancer. (A) Treatment with androgens for 96 h decreased the expression of PSMA by LNCaP cells, which assessed with TNP’s fluorescence (Testost.: testosterone; R1881: metribolone; ns: not significant; *** P < 0.001). (B) Inhibition of androgen receptor signaling for 2 weeks upregulated PSMA expression that resulted more TNP binding (Enzalutamide: Xtandi; ** P < 0.01). (C–D) Priming of LNCaP xenografts with enzalutamide caused upregulation of PSMA levels. (Representative images shown. ncontrol = nenz-primed = 6; *** P < 0.001). Means ± SEM.
Figure 4
Improved drug delivery with drug-carrying TNP. (A) Delivery of therapy with TNP caused cell death in the PSMA-expressing LNCaP cells (DoxoTNP: doxorubicin-loaded TNP). (B–C) Selective drug delivery of etoposide, paclitaxel and doxorubicin with TNP (LNCaP: FOLH1-positive cells; PC3-Ctrl: FOLH1-negative cells; *** P < 0.001). (D) The levels of PSMA at the plasma membrane of neoplastic cells dictated response to therapy delivered with TNP. Means ± SEM.
Figure 5
Enhanced tumor response with TNP delivering therapy for castration-resistant disease. (A–B) Co-delivery of the PI3K inhibitor BEZ235 and the anti-androgen enzalutamide achieved tumor regression in athymic, nude male mice with LNCaP xenografts (B: BEZ235; E: enzalutamide; *** P < 0.001). (C–D) Priming with enzalutamide prior to treatment with B/ETNP provided improved response and faster regression (* P < 0.05). Means ± SEM.
Figure 6
Combination therapy of prostate cancer that has acquired resistance with TNP. (A) The gene encoding the heat-shock transcription factor 1 is amplified in samples from cancer patients. (B) Simultaneous delivery of riluzole, which increases the steady-state levels of the heat-shock transcription factor 1, and cabazitaxel with TNP resulted in tumor regression, and (C) robust response with no relapse. Means ± SEM.
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References
- Weissleder R, Schwaiger MC, Gambhir SS, Hricak H. Science translational medicine. 2016;8(355):355ps16. - PubMed
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