Oxygen deficiency after myocardial infarction (MI) leads to massive cardiac cell death. Protection of cardiac cells and promotion of cardiac repair are key therapeutic goals. These goals may be achieved by re-introducing oxygen into the infarcted area. Yet current systemic oxygen delivery approaches cannot efficiently diffuse oxygen into the infarcted area that has extremely low blood flow. In this work, we developed a new oxygen delivery system that can be delivered specifically to the infarcted tissue, and continuously release oxygen to protect the cardiac cells. The system was based on a thermosensitive, injectable and fast gelation hydrogel, and oxygen releasing microspheres. The fast gelation hydrogel was used to increase microsphere retention in the heart tissue. The system was able to continuously release oxygen for 4 weeks. The released oxygen significantly increased survival of cardiac cells under the hypoxic condition (1% O2) mimicking that of the infarcted hearts. It also reduced myofibroblast formation under hypoxic condition (1% O2). After implanting into infarcted hearts for 4 weeks, the released oxygen significantly augmented cell survival, decreased macrophage density, reduced collagen deposition and myofibroblast density, and stimulated tissue angiogenesis, leading to a significant increase in cardiac function.

The major obstacles in intraperitoneal (i.p.) chemotherapy of peritoneal tumors are fast absorption of drugs into the blood circulation, local and systemic toxicities, inadequate drug penetration into large tumors, and drug resistance. Targeted theranostic nanoparticles offer an opportunity to enhance the efficacy of i.p. therapy by increasing intratumoral drug delivery to overcome resistance, mediating image-guided drug delivery, and reducing systemic toxicity. Herein we report that i.p. delivery of urokinase plasminogen activator receptor (uPAR) targeted magnetic iron oxide nanoparticles (IONPs) led to intratumoral accumulation of 17% of total injected nanoparticles in an orthotopic mouse pancreatic cancer model, which was three-fold higher compared with intravenous delivery. Targeted delivery of near infrared dye labeled IONPs into orthotopic tumors could be detected by non-invasive optical and magnetic resonance imaging. Histological analysis revealed that a high level of uPAR targeted, PEGylated IONPs efficiently penetrated into both the peripheral and central tumor areas in the primary tumor as well as peritoneal metastatic tumor. Improved theranostic IONP delivery into the tumor center was not mediated by nonspecific macrophage uptake and was independent from tumor blood vessel locations. Importantly, i.p. delivery of uPAR targeted theranostic IONPs carrying chemotherapeutics, cisplatin or doxorubicin, significantly inhibited the growth of pancreatic tumors without apparent systemic toxicity. The levels of proliferating tumor cells and tumor vessels in tumors treated with the above theranostic IONPs were also markedly decreased. The detection of strong optical signals in residual tumors following i.p. therapy suggested the feasibility of image-guided surgery to remove drug-resistant tumors. Therefore, our results support the translational development of i.p. delivery of uPAR-targeted theranostic IONPs for image-guided treatment of peritoneal tumors.

A7R peptide (ATWLPPR), a ligand of the NRP-1 receptor, regulates the intracellular signal transduction related to tumor vascularization and tumor growth. Here, we designed A7R-cysteine peptide (A7RC) surface modified paclitaxel liposomes (A7RC-LIPs) to achieve targeting delivery and inhibition of tumor growth and angiogenesis simultaneously. The cytotoxicity, inhibiting angiogenesis, and internalization of various liposomes by cells were assessed in vitro to confirm the influence of the peptide modification. The accumulations of A7RC-LIPs in various xenografts in mice were tracked to further identify the function of the peptide on the liposomes' surface. The results confirmed that A7RC peptides could enhance the uptake of vesicles by MDA-MB-231 cells, leading to stronger cytotoxicity in vitro and higher accumulation of vesicles in MDA-MB-231 xenografts in vivo. In addition, A7RC peptides enhanced the inhibitory effects of LIPs on the HUVEC tubular formation on Matrigel. The A7RC-LIPs may be promising drug carriers for anticancer therapy.

Purpose A complete surgical excision with negative tumor margins is the single most important factor in the prediction of long-term survival for most cancer patients with solid tumors. We hypothesized that image-guided surgery using nanoparticle-enhanced photoacoustic and fluorescence imaging could significantly reduce the rate of local recurrence. Methods A murine model of invasive mammary carcinoma was utilized. Three experimental groups were included: (1) control; (2) tumor-bearing mice injected with non-targeted nanoprobe; and (3) tumor-bearing mice injected with targeted nanoprobe. The surgeon removed the primary tumor following the guidance of photoacoustic imaging (PAI), then inspected the surgical wound and removed the suspicious tissue using intraoperative near-infrared (NIR) fluorescence imaging. The mice were followed with bioluminescence imaging weekly to quantify local recurrence. Results Nanoprobe-enhanced photoacoustic contrast enabled PAI to map the volumetric tumor margins up to a depth of 31 mm. The targeted nanoparticles provided significantly greater enhancement than non-targeted nano-particles. Seven mice in the group injected with the targeted nanoprobes underwent additional resections based upon NIR fluorescence imaging. Pathological analysis confirmed residual cancer cells in the re-resected specimens in 5/7 mice. Image-guided resection resulted in a significant reduction in local recurrence; 8.7 and 33.3 % of the mice in the targeted and control groups suffered recurrence, respectively. Conclusions These results suggest that photoacoustic and NIR intraoperative imaging can effectively assist a surgeon to locate primary tumors and to identify residual disease in real-time. This technology has promise to overcome current clinical challenges that result in the need for second surgical procedures.