Staphylococcus aureus is a leading cause of biofilm-associated prosthetic joint infection (PJI). A primary contributor to infection chronicity is an expansion of granulocytic myeloid-derived suppressor cells (G-MDSCs), which are critical for orchestrating the antiinflammatory biofilm milieu. Single-cell sequencing and bioinformatic metabolic algorithms were used to explore the link between G-MDSC metabolism and S. aureus PJI outcome. Glycolysis and the hypoxia response through HIF1a were significantly enriched in G-MDSCs. Interfering with both pathways in vivo, using a 2-deoxyglucose nanopreparation and granulocyte-targeted Hif1a conditional KO mice, respectively, attenuated G-MDSC-mediated immunosuppression and reduced bacterial burden in a mouse model of S. aureus PJI. In addition, single-cell RNA-Seq (scRNA-Seq) analysis of granulocytes from PJI patients also showed an enrichment in glycolysis and hypoxia-response genes. These findings support the importance of a glycolysis/HIF1a axis in promoting G-MDSC antiinflammatory activity and biofilm persistence during PJI.

Nanocarriers, more commonly called nanoparticles (NPs), have found increasing use as delivery vehicles which increase the oral bioavailability of poorly water-soluble and peptide therapeutics. Therapeutic bioavailability is commonly assessed by measuring plasma concentrations that reflect the absorption kinetics. This bioavailability is a convolution of the gastrointestinal distribution of the NP vehicle, the release rate of the encapsulated therapeutic cargo, and the absorption-metabolism-distribution kinetics of the released therapeutic. The spatiotemporal distribution of the NP vehicle in the gastrointestinal tract is not well studied and is a buried parameter in PK studies used to measure the effectiveness of an NP formulation. This work is a study of the intestinal distribution and fate of orally dosed NPs in male CD-1 mice over 24 h. NPs have identical hydrophobic cores - composed of poly(styrene) homopolymer, a naphthalocyanine dye, and oleate-coated europium oxide colloids - with one of four different surface stabilizers: neutral poly(styrene)-block-poly(ethylene glycol) (PS-b-PEG), moderately negative hydroxypropyl methylcellulose acetate succinate (HPMCAS), highly negative poly(styrene)-block-poly(acrylic acid) (PS-b-PAA), and highly cationic adsorbed chitosan HCl on PS-b-PAA stabilized NPs. NP hydrodynamic diameters are all below 200 nm, with some variation attributable to the molecular properties of the stabilizing polymer. The encapsulated hydrophobic europium oxide colloids do not release soluble europium ions, enabling the use of highly sensitive inductively coupled plasma mass spectrometry (ICP-MS) to detect NP concentrations in digested biological tissues. Highly anionically-charged PAA and cationically-charged chitosan stabilized NPs showed statistically significant increased retention compared to the neutral PEG-stabilized NPs at p < 0.05 significance and (1-β) > 0.95 power. HPMCAS-stabilized NPs showed statistically insignificant greater retention than PEG-stabilized NPs, and all NP formulations showed clearance from the intestines within 24 h. Different surface charges preferentially reside in different segments of the intestines, where cationic chitosan-stabilized NPs showed increased retention in the small intestines (ileum) and anionic PAA-stabilized NPs in the large intestines (caecum and colon). Modifying the surface charge of a NP can be used to modulate mucoadhesion, total retention, and intestinal segment specific retention, which enables the rational design of delivery vehicles that maximize residence times in appropriate locations.

Abstract Prosthetic joint infection (PJI) is a severe complication following hip and knee arthroplasty and is reported to affect 1-2% of total arthroplasties. Staphylococcus aureus (S. aureus) contributes to most PJIs, with a higher treatment failure rate partly due to biofilm formation. Granulocytic myeloid-derived suppressor cell (G-MDSC) expansion and IL-10 secretion are critical for inducing an immunosuppressive environment that supports S. aureus persistence during PJI. Recently, S. aureus-derived lactate was shown to promote IL-10 production by G-MDSCs. However, the importance of G-MDSC metabolism in programming their anti-inflammatory activity is unknown. Single-cell RNA sequencing (scRNA-seq) of infected tissues from a mouse model of S. aureus PJI revealed enrichment of glycolysis and hypoxia pathway genes in G-MDSCs. Increased glycolytic activity in G-MDSCs was confirmed following S. aureus biofilm co-culture and attenuating glycolysis with either 2-deoxyglucose or granulocyte-specific HIF-1a deletion reduced bacterial growth during S. aureus PJI. These changes coincided with less G-MDSC suppressive activity and a transformation towards a proinflammatory phenotype. scRNA-seq of samples from PJI patients revealed heightened glycolysis and hypoxia signatures, supporting findings with the mouse PJI model. Together, these results suggest that glycolysis and HIF-1a pathways are critical for the anti-inflammatory activity of G-MDSCs during S. aureus biofilm infection.

Combination chemotherapeutic drugs administered via a single nanocarrier for cancer treatment provides benefits in reducing dose-limiting toxicities, improving the pharmacokinetic properties of the cargo and achieving spatial-temporal synchronization of drug exposure for maximized synergistic therapeutic effects. In an attempt to develop such a multi-drug carrier, our work focuses on functional multimodal polypeptide-based polymeric nanogels (NGs). Diblock copolymers poly (ethylene glycol)-b-poly (glutamic acid) (PEG-b-PGlu) modified with phenylalanine (Phe) were successfully synthesized and characterized. Self-assembly behavior of the resulting polymers was utilized for the synthesis of NGs with hydrophobic domains in cross-linked polyion cores coated with inert PEG chains. The resulting NGs were small (ca. 70 nm in diameter) and were able to encapsulate the combination of drugs with different physicochemical properties such as cisplatin and neratinib. Drug combination-loaded NGs exerted a selective synergistic cytotoxicity towards EGFR overexpressing ovarian cancer cells. Moreover, we developed ligand-installed EGFR-targeted NGs and tested them as an EGFRoverexpressing tumor-specific delivery system. Both in vitro and in vivo, ligand-installed NGs displayed preferential associations with EGFR (+) tumor cells. Ligand-installed NGs carrying cisplatin and neratinib significantly improved the treatment response of ovarian cancer xenografts. We also confirmed the importance of simultaneous administration of the dual drug combination via a single NG system which provides more therapeutic benefit than individual drug-loaded NGs administered at equivalent doses. This work illustrates the potential of our carrier system to mediate efficient delivery of a drug combination to treat EGFR overexpressing cancers.

Abstract Background: Cancer is a devastating scourge, causing morbidity and mortality in both adult and pediatric populations. In this study, we analyzed the effects of histone deacetylase (HDAC) inhibitors on the MHC class I expression, growth, and migration of cancer cells. Within cancer cells, MHC class I molecules bind to fragments of tumor-associated peptides, and then migrate to the cell surface to present the peptides to T lymphocytes and induce lysis of the tumor cells, thereby preventing further spread of the malignancy. Pancreatic cancer, a disease afflicting older adults, is now the third most common cause of cancer-related death overall in the U.S. Neuroblastoma is the third most common childhood cancer and results in 12% of cancer-associated deaths in children less than 15 years of age. In both of these cancers, HDAC expression has been shown to be dysregulated and abnormally high. Although several HDAC inhibitors have been extensively investigated in preclinical studies and have entered clinical trials, the two HDAC inhibitors that we are evaluating in our research (M344 and RGFP966) have been the focus of only a few prior studies, and much remains to be discovered about their therapeutic effects. Methods: We treated cancer cell lines with HDAC inhibitors over a range of concentrations for multiple timepoints. Our investigations included analysis of MHC class I expression by immunoblotting for total subunit protein levels and flow cytometric monitoring of MHC class I levels at the cell surface, immunoblotting for the co-inhibitory protein PD-L1, transwell assays for migration, and MTT assays for cell growth. New collaborative studies have been initiated to develop two varieties of nanoformulations for optimization of the delivery of these HDAC inhibitors to tumors. Results: Our flow cytometry analysis demonstrated that the expression of the cell-surface human MHC class I molecules detected by antibodies recognizing HLA-A and both HLA-B and –C was elevated on S2-013 cells following M344 treatment. Increased total MHC class I heavy chain protein expression was induced in S2-013 cells by both M344 and RGFP966, and RGFP966 also increased PD-L1 expression. In addition, M344 and RGFP966 reduced S2-013 pancreatic cancer cell growth, and M344 slowed S2-013 migration and Neuro2a neuroblastoma cell growth. Analysis of M344 efficacy in an S2-013 orthotopic xenograft mouse model showed significant reduction of the tumor growth rate. Novel nanoparticles have been generated for M344 delivery using block copolymer and hyaluronic acid formulation strategies. Conclusions: Our evidence indicates that the HDAC inhibitors M344 and RGFP966 have anti-tumor potential via boosting MHC class I molecule expression to improve T cell recognition, as well as by tumor-intrinsic effects (i.e., down-regulation of proliferation and migration). Thus, both of these HDAC inhibitors warrant further analysis in adult and pediatric tumor mouse models, and may have potential for future clinical testing in patients. Citation Format: Shelby M. Knoche, Gabrielle L. Brumfield, Benjamin T. Goetz, Bailee H. Sliker, Cecilia Barbosa, Svetlana Romanova, Tatiana Bronich, Donald W. Coulter, Joyce C. Solheim. Effects of histone deacetylase inhibition on major histocompatibility compatibility complex (MHC) class I expression, growth, and migration of cancer cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P028.

Macrophages are desirable targets for gene therapy of cancer and other diseases. Cationic diblock copolymers of polyethylene glycol (PEG) and poly-L-lysine (PLL) or poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (pAsp(DET)) are synthesized and used to form polyplexes with a plasmid DNA (pDNA) that are decorated with mannose moieties, serving as the targeting ligands for the C type lectin receptors displayed at the surface of macrophages. The PEG-b-PLL copolymers are known for its cytotoxicity, so PEG-b-PLL-based polyplexes are cross-linked using reducible reagent dithiobis(succinimidyl propionate) (DSP). The cross-linked polyplexes display low toxicity to both mouse embryonic fibroblasts NIH/3T3 cell line and mouse bone marrow-derived macrophages (BMMΦ). In macrophages mannose-decorated polyplexes demonstrate an ≈8 times higher transfection efficiency. The cross-linking of the polyplexes decrease the toxicity, but the transfection enhancement is moderate. The PEG-b-pAsp(DET) copolymers display low toxicity with respect to the IC-21 murine macrophage cell line and are used for the production of non-cross-linked pDNA-contained polyplexes. The obtained mannose modified polyplexes exhibit ca. 500-times greater transfection activity in IC-21 macrophages compared to the mannose-free polyplexes. This result greatly exceeds the targeting gene transfer effects previously described using mannose receptor targeted non-viral gene delivery systems. These results suggest that Man-PEG-b-pAsp(DET)/pDNA polyplex is a potential vector for immune cells-based gene therapy.

Targeting androgen receptor (AR) has been shown to be promising in treating glioblastoma (GBM) in cell culture and flank implant models but the mechanisms remain unclear. AR antagonists including enzalutamide are available for treating prostate cancer patients in clinic and can pass the blood–brain barrier, thus are potentially good candidates for GBM treatment but have not been tested in GBM orthotopically. Our current studies confirmed that in patients, a majority of GBM tumors overexpress AR in both genders. Enzalutamide inhibited the proliferation of GBM cells both in vitro and in vivo . Although confocal microscopy demonstrated that AR is expressed but not specifically in glioma cancer stem cells (CSCs) (CD133+), enzalutamide treatment significantly decreased CSC population in cultured monolayer cells and spheroids, suppressed tumor sphere-forming capacity of GBM cells, and downregulated CSC gene expression at mRNA and protein levels in a dose- and time-dependent manner. We have, for the first time, demonstrated that enzalutamide treatment decreased the density of CSCs in vivo and improved survival in an orthotopic GBM mouse model. We conclude that AR antagonists potently target glioma CSCs in addition to suppressing the overall proliferation of GBM cells as a mechanism supporting their repurposing for clinical applications treating GBM.

Due to its late diagnosis and dismal prognosis, pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating solid malignancies, with only 9% of patients surviving after being diagnosed. A multidrug chemotherapeutic regimen FOL-F-IRIN-OX (combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) offers survival benefits superior to that of gemcitabine single agent, but the treatment-related side effects are also severe. To overcome this therapeutic barrier, we developed polymeric micelles bearing active formats of irinotecan and oxaliplatin, SN38 and 1,2-diaminocyclohexane‑platinum (II), DACHPt. Crosslinked micelles were prepared using amphiphilic PEG-b-poly(L-glutamic acid)/SN38 conjugates and subsequently loaded with DACHPt. The dual drug-loaded micelles exhibited improved colloidal stability, prolonged drug release and remarkable cytotoxicity in human pancreatic cancer cell lines and KrasG12D; Trp52R172H/+; Pdx-1 Cre murine tumor organoids models. In vivo, (SN38 + DACHPt)-loaded micelles displayed superior antitumor and antimetastatic activities without impairing safety. Our results suggest that nanomedicine mimicking irinotecan and oxaliplatin as parts of FOLFIRINOX regimen may further improve the feasibility of this multidrug treatment for patients with advanced pancreatic cancer.

Given the superior soft tissue contrasts obtained by MRI and the long residence times of magnetic nanoparticles (MNPs) in soft tissues, MNP-based theranostic systems are being developed for simultaneous imaging and treatment. However, development of such theranostic nanoformulations presents significant challenges of balancing the therapeutic and diagnostic functionalities in order to achieve optimum effect from both. Here we developed a simple theranostic nanoformulation based on magnetic nanoclusters (MNCs) stabilized by a bisphosphonate-modified poly(glutamic acid)-b-(ethylene glycol) block copolymer and complexed with cisplatin. The MNCs were decorated with luteinizing hormone releasing hormone (LHRH) to target LHRH receptors (LHRHr) overexpressed in ovarian cancer cells. The targeted MNCs significantly improved the uptake of the drug in cancer cells and decreased its IC50 compared to the nontargeted formulations. Also, the enhanced LHRHr-mediated uptake of the targeted MNCs resulted in enhancement in the T-2-weighted negative contrast in cellular phantom gels. Taken together, the LHRH-conjugated MNCs show good potential as ovarian cancer theranostics.

Scavenging superoxide (O2•-) via overexpression of superoxide dismutase (SOD) or administration of SOD mimics improves outcomes in multiple experimental models of human disease including cardiovascular disease, neurodegeneration, and cancer. While few SOD mimics have transitioned to clinical trials, MnTnBuOE-2-PyP5+ (BuOE), a manganese porphyrin SOD mimic, is currently in clinical trials as a radioprotector for cancer patients; thus, providing hope for the use of SOD mimics in the clinical setting. However, BuOE transiently alters cardiovascular function including a significant and precipitous decrease in blood pressure. To limit BuOE's acute hypotensive action, we developed a mesoporous silica nanoparticle and lipid bilayer nanoformulation of BuOE (nanoBuOE) that allows for slow and sustained release of the drug. Herein, we tested the hypothesis that unlike native BuOE, nanoBuOE does not induce an acute hypotensive response, as the nanoformulation prevents BuOE from scavenging O2•- while the drug is still encapsulated in the formulation. We report that intact nanoBuOE does not effectively scavenge O2•-, whereas BuOE released from the nanoformulation does retain SOD-like activity. Further, in mice, native BuOE, but not nanoBuOE, rapidly, acutely, and significantly decreases blood pressure, as measured by radiotelemetry. To begin exploring the physiological mechanism by which native BuOE acutely decreases blood pressure, we recorded renal sympathetic nerve activity (RSNA) in rats. RSNA significantly decreased immediately following intravenous injection of BuOE, but not nanoBuOE. These data indicate that nanoformulation of BuOE, a SOD mimic currently in clinical trials in cancer patients, prevents BuOE's negative side effects on blood pressure homeostasis.

HPMA copolymer-based dexamethasone prodrug (P-Dex) and PEG-based dexamethasone prodrug (PEG-Dex, ZSJ-0228) were previously found to passively target the inflamed kidney and provide potent and sustained resolution of nephritis in NZB/WF1 lupus-prone mice. While both prodrug nanomedicines effectively ameliorate lupus nephritis, they have demonstrated distinctively different safety profiles. To explore the underlining mechanisms of these differences, we conducted a head-to-head comparative PK/BD study of P-Dex and PEG-Dex on NZB/WF1 mice. Overall, the systemic organ/tissue exposures to P-Dex and Dex released from P-Dex were found to be significantly higher than those of PEG-Dex. The high prodrug concentrations were sustained in kidney for only 24 h, which cannot explain their lasting therapeutic efficacy (>1 month). P-Dex showed sustained presence in liver, spleen and adrenal gland, while the presence of PEG-Dex in these organs was transient. This difference in PK/BD profiles may explain PEG-Dex' superior safety than P-Dex.

Biofilm-associated prosthetic joint infections (PJIs) cause significant morbidity due to their recalcitrance to immune-mediated clearance and antibiotics, with Staphylococcus aureus (S. aureus) among the most prevalent pathogens. We previously demonstrated that S. aureus biofilm-associated monocytes are polarized to an anti-inflammatory phenotype and the adoptive transfer of pro-inflammatory macrophages attenuated biofilm burden, highlighting the critical role of monocyte/macrophage inflammatory status in dictating biofilm persistence. The inflammatory properties of leukocytes are linked to their metabolic state, and here we demonstrate that biofilm-associated monocytes exhibit a metabolic bias favoring oxidative phosphorylation (OxPhos) and less aerobic glycolysis to facilitate their anti-inflammatory activity and biofilm persistence. To shift monocyte metabolism in vivo and reprogram cells to a pro-inflammatory state, a nanoparticle approach was utilized to deliver the OxPhos inhibitor oligomycin to monocytes. Using a mouse model of S. aureus PJI, oligomycin nanoparticles were preferentially internalized by monocytes, which significantly reduced S. aureus biofilm burden by altering metabolism and promoting the pro-inflammatory properties of infiltrating monocytes as revealed by metabolomics and RT-qPCR, respectively. Injection of oligomycin alone had no effect on monocyte metabolism or biofilm burden, establishing that intracellular delivery of oligomycin is required to reprogram monocyte metabolic activity and that oligomycin lacks antibacterial activity against S. aureus biofilms. Remarkably, monocyte metabolic reprogramming with oligomycin nanoparticles was effective at clearing established biofilms in combination with systemic antibiotics. These findings suggest that metabolic reprogramming of biofilm-associated monocytes may represent a novel therapeutic approach for PJI.

Successful treatment of pancreatic cancer remains a challenge due to desmoplasia, development of chemoresistance, and systemic toxicity. Herein, we synthesized (6-(3-hydroxy-4-methoxylphenyl)pyridin-2-yl) (3,4,5-trimethoxyphenyl)methanone (CH-3-8), a novel microtubule polymerization inhibitor with little susceptible to transporter-mediated chemoresistance. CH-3-8 binding to the colchicine-binding site in tubulin protein was confirmed by tubulin polymerization assay and molecular modeling. CH-3-8 disrupted microtubule dynamics at the nanomolar concentration in MIA PaCa-2 and PANC-1 pancreatic cancer cell lines. CH-3-8 significantly inhibited the proliferation of these cells, induced G2/M cell cycle arrest, and led to apoptosis. CH-3-8 is hydrophobic with an aqueous solubility of 0.97 ± 0.16 μg/mL at pH 7.4. We further conjugated it with dodecanol through diglycolate linker to increase hydrophobicity and thus loading in lipid-based delivery systems. Hence, we encapsulated CH-3-8 lipid conjugate (LDC) into methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol) (mPEG-b-PCC-g-DC) polymeric nanoparticles (NPs) by solvent evaporation, resulting in a mean particle size of 125.6 ± 2.3 nm and drug loading of 10 ± 1.0% (w/w) while the same polymer could only load 1.6 ± 0.4 (w/w) CH-3-8 using the same method. Systemic administration of 6 doses of CH-3-8 and LDC loaded NPs at the dose of 20 mg/kg into orthotopic pancreatic tumor-bearing NSG mice every alternate day resulted in significant tumor regression. Systemic toxicity was negligible, as evidenced by histological evaluations. In conclusion, CH-3-8 LDC loaded NPs have the potential to improve outcomes of pancreatic cancer by overcoming transporter-mediated chemoresistance and reducing systemic toxicity.

Neuroblastoma is the most commonly diagnosed extracranial solid tumor in children. The patients with aggressive metastatic disease or refractory/relapsed neuroblastoma currently face a dismally low chance of survival. Thus, there is a great need for more effective therapies for this illness. In previous studies, we, as well as others, showed that the immune cell chemoattractant C-C motif chemokine ligand 21 (CCL21) is effective as an intratumoral therapy able to slow the growth of cancers. In this current study, we developed and tested an injectable, slow-release, uniform, and optimally loaded alginate nanoformulation of CCL21 as a means to provide prolonged intratumoral treatment. The alginate-nanoformulated CCL21, when injected intratumorally into mice bearing neuroblastoma lesions, significantly prolonged survival and decreased the tumor growth rate compared to CCL21 alone, empty nanoparticles, or buffer. Notably, we also observed complete tumor clearance and subsequent full protection against tumor rechallenge in 33% of nanoformulated CCL21-treated mice. Greater intratumoral presence of nanoformulated CCL21, compared to free CCL21, at days 1 and 2 after treatment ended was confirmed through fluorescent labeling and tracking. Nanoformulated CCL21-treated tumors exhibited a general pattern of prolonged increases in anti-tumor cytokines and relatively lower levels of pro-tumor cytokines in comparison to tumors treated with CCL21 alone or buffer only. Thus, this novel nanoformulation of CCL21 is an effective treatment for neuroblastoma, and may have potential for the delivery of CCL21 to other types of solid tumors in the future and as a slow-release delivery modality for other immunotherapies

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. A combination of cisplatin (CDDP) and gemcitabine (Gem) treatment has shown favorable clinical results for metastatic disease; both are limited by toxicities and nontargeted delivery. More than 80% of PDAC aberrantly expresses the sialyl Tn (STn) antigen due to the loss of function of the core 1 beta 3-Gal-T-specific molecular chaperone, a specific chaperone for the activity of core 1 beta 3-galactosyltransferase or Cl GaIT. Here, we report the development of polymeric nanogels (NGs) loaded with CDDP and coated with an anti-STn antigen-specific antibody (TKH2 monoclonal antibody) for the targeted treatment of PDAC. TKH2-functionalized, CDDP-loaded NGs delivered a significantly higher amount of platinum into the cells and tumors expressing STn antigens. We also confirmed that a synergistic cytotoxic effect of sequential exposure of pancreatic cancer cells to Gem followed by CDDP can be mimicked by the codelivery of CDDP-loaded NGs (NG/CDDP) and free Gem. In a murine orthotopic model of PDAC, combined simultaneous treatment with Gem and targeted NG/CDDP significantly attenuated tumor growth with no detectable acute toxicity. Altogether, these results suggest that combination therapy consisting of Gem followed by TKH2-conjugated CDDP NGs induces highly synergistic therapeutic efficacy against pancreatic cancer. Our results offer the basis for development of combination drug regimens using targeted nanomedicines to increase treatment effectiveness and improve outcomes of PDAC therapy.

Proteasome inhibitors (PIs) have markedly improved response rates as well as the survival of multiple myeloma (MM) patients over the past decade and have become an important foundation in the treatment of MM patients. Unfortunately, the majority of patients either relapses or becomes refractory to proteasome inhibition. This report describes that both PI sensitive and resistant MM cells display enhanced sensitivity to PI in the presence of synthetic amphiphilic block copolymers, Pluronics (SP1017). SP1017 effectively overcomes both acquired resistance and tumor microenvironment-mediated resistance to PIs. The combination of bortezomib and SP1017 augments accumulation of ubiquitinated proteins, increases markers of proteotoxic and ER stress, and ultimately induces both the intrinsic and extrinsic drug-induced apoptotic pathways in MM cells. Notably, co-treatment of bortezomib and SP1017 intensifies SP1017-induced disorganization of the Golgi complex and significantly reduces secretion of paraproteins. Using a human MM/SCID mice model, the combination of bortezomib and SP1017 exerted enhanced antitumor efficacy as compared to bortezomib alone, delaying disease progression, but without additional toxicity. Collectively, these findings provide proof of concept for the utility of combining PI with SP1017 and present a new approach to enhance the efficacy of current treatment options for MM patients.

Although the prognosis of patients with breast cancer continues to improve, breast cancer metastasis to bones remains high in incidence and challenging to manage. Here, we report the development of bone-homing alendronate (ALN)-anchored biodegradable polymeric micelles for the targeted treatment of metastatic cancer to bone. These micelles exhibited bone protective capacity including the recruitment, differentiation, and resorption activity of the osteoclasts. Encapsulation of docetaxel (DTX), the first-line chemotherapeutic for treatment of metastatic breast cancer, in ALN-modified micelles results in a sustained release, enhanced cytotoxicity, and improved pharmacokinetics. In the syngeneic animal model of late-stage disseminated breast cancer bone metastasis, the treatment with targeted DTX-loaded micelles attenuated the tumorigenesis and significantly improved animal lifespan compared to the conventional surfactant-based formulation (free DTX). These findings indicate potential applications of the osteotropic nanomedicines for bone metastasis treatment.

The discipline of neurotheranostics was forged to improve diagnostic and therapeutic clinical outcomes for neurological disorders. Research was facilitated, in largest measure, by the creation of pharmacologically effective multimodal pharmaceutical formulations. Deployment of neurotheranostic agents could revolutionize staging and improve nervous system disease therapeutic outcomes. However, obstacles in formulation design, drug loading and payload delivery still remain. These will certainly be aided by multidisciplinary basic research and clinical teams with pharmacology, nanotechnology, neuroscience and pharmaceutic expertise. When successful the end results will provide "optimal" therapeutic delivery platforms. The current report reviews an extensive body of knowledge of the natural history, epidemiology, pathogenesis and therapeutics of neurologic disease with an eye on how, when and under what circumstances neurotheranostics will soon be used as personalized medicines for a broad range of neurodegenerative, neuroinflammatory and neuroinfectious diseases.

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer-related death in the United States, is highly aggressive and resistant to both chemo- and radiotherapy. It remains one of the most difficult-to-treat cancers, not only due to its unique pathobiological features such as stroma-rich desmo-plastic tumors surrounded by hypovascular and hypoperfused vessels limiting the transport of therapeutic agents, but also due to problematic early detection, which renders most treatment options largely ineffective, resulting in extensive metastasis. To elevate therapeutic effectiveness of treatments and overt their toxicity, significant enthusiasm was generated to exploit new strategies for combating PDAC. Combination therapy targeting different barriers to mitigate delivery issues and reduce tumor recurrence and metastasis has demonstrated optimal outcomes in patients' survival and quality of life, providing possible approaches to overcome therapeutic challenges. This paper aims to provide an overview of currently explored multimodal therapies using either conventional therapy or nanomedicines along with rationale, up-to-date progress, as well as the key challenges that must be overcome. Understanding the future directions of the field may assist in the successful development of novel treatment strategies for enhancing therapeutic efficacy in PDAC.