Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy

Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it has poor pharmacokinetic properties, and unfavorable bioavailability has hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4+ monocytic myeloid-derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long-term survival, with ∼60% of GBM tumor-bearing mice remaining tumor free after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability.Fil: Alghamri, Mahmoud S.. University Of Michigan Medical School; Estados UnidosFil: Banerjee, Kaushik. University Of Michigan Medical School; Estados UnidosFil: Mujeeb, Anzar A.. University Of Michigan Medical School; Estados UnidosFil: Mauser, Ava. University of Michigan; Estados UnidosFil: Taher, Ayman. University Of Michigan Medical School; Estados UnidosFil: Thalla, Rohit. University Of Michigan Medical School; Estados UnidosFil: McClellan, Brandon L.. University Of Michigan Medical School; Estados UnidosFil: Varela, Maria L.. University Of Michigan Medical School; Estados UnidosFil: Stamatovic, Svetlana M.. University Of Michigan Medical School; Estados UnidosFil: Martinez Revollar, Gabriela. University Of Michigan Medical School; Estados UnidosFil: Andjelkovic, Anuska V.. University Of Michigan Medical School; Estados UnidosFil: Gregory, Jason V.. University of Michigan; Estados UnidosFil: Kadiyala, Padma. University Of Michigan Medical School; Estados UnidosFil: Calinescu, Alexandra. University Of Michigan Medical School; Estados UnidosFil: Jiménez, Jennifer A.. University of Michigan; Estados UnidosFil: Apfelbaum, April A.. University of Michigan; Estados UnidosFil: Lawlor, Elizabeth R.. University of Washington; Estados UnidosFil: Carney, Stephen. University of Michigan; Estados UnidosFil: Comba, Andrea. University Of Michigan Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Faisal, Syed Mohd. University Of Michigan Medical School; Estados UnidosFil: Barissi, Marcus. University Of Michigan Medical School; Estados UnidosFil: Edwards, Marta B.. University Of Michigan Medical School; Estados UnidosFil: Appelman, Henry. University Of Michigan Medical School; Estados UnidosFil: Sun, Yilun. Case Western Reserve University; Estados UnidosFil: Gan, Jingyao. University of Michigan; Estados UnidosFil: Ackermann, Rose. University of Michigan; Estados UnidosFil: Schwendeman, Anna. University of Michigan; Estados UnidosFil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Olin, Michael R.. University of Minnesota; Estados UnidosFil: Lahann, Joerg. University of Michigan; Estados UnidosFil: Lowenstein, Pedro R.. University of Michigan; Estados UnidosFil: Castro, Maria G.. University of Michigan; Estados Unido

The complete chloroplast genome of Miliusa glochidioides (Annonaceae) and phylogenetic analysis

The chloroplast (cp) genome of Miliusa glochidioides has been fully sequenced. The cp genome of this species has a typical quadripartite structure comprised of four parts: a large single copy (LSC; 88,782 bp) region, a small single copy (SSC; 18,949 bp) region, and two inverted repeat (IR; 26,029 bp each) regions. The full length of the cp genome is 159,789 bp; its GC content is 36.7%, and it encodes a total of 129 genes including 84 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. Among the protein-coding genes, nine (rps16, rpl2, rpl16, atpF, rpoC1, petB, petD, ndhA, and ndhB) contain one intron, and three (rps12, clpP, and ycf3) have two introns. A maximum-likelihood (ML) phylogenetic tree shows that M. glochidioides is a sister to Chieniodendron hainanense

Analysis of Demodex infection of facial hair follicles and skin biophysical parameters in different subtypes of rosacea

Objective To analyze the Demodex infection in facial hair follicles and the changes in skin biophysical properties in different subtypes of rosacea. Methods A total of 32 patients with erythematotelangiectatic rosacea (ETR) and 40 cases with papulopustular rosacea (PPR) were enrolled in this study. A reflectance confocal microscopy (RCM) was used to examine Demodex folliculorum infection on the forehead and the cheeks. The rate of Demodex folliculorum infection, the number of infected hair follicles, total Demodex count per scanned area, the number of Demodex per hair follicle and number of Demodex per infected hair follicle were analyzed. A non-invasive skin physiological device was used to measure the stratum corneum hydration, TEWL, sebum, melanin and erythema indices, and skin elasticity. Skin biophysical parameters and Demodex infection were compared between ETR and PPR. Results In subjects aged >31 years and disease duration of >3 years, the rate of Demodex infection, the number of infected hair follicles, total Demodex count per scanned area, the number of Demodex per hair follicle and number of Demodex per infected hair follicle were higher in PPR patients than in ETR patients (P0.05). Moreover, skin biophysical properties, including melanin and erythema indices, sebum and stratum corneum hydration levels, elasticity, and TEWL, were comparable in ETR and PPR patients (P>0.05). Conclusion Demodex folliculorum infection, but not skin biophysical properties, is influenced by patients′ age, disease duration and the subtypes of rosea