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Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum-sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic.

Dual pretargeting with anti-CD20 and anti–HLA-DR allows effective therapeutic delivery of a BEZ235 nanoformulation to NHL cells., Overactivation of the PI3K/mTOR signaling has been identified in non-Hodgkin’s lymphoma. BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity. Here, we developed a nanoparticle (NP)–based pretargeted system for the therapeutic delivery of BEZ235 to CD20- and HLA-DR–expressing lymphoma cells for targeted therapy. The pretargeted system is composed of dibenzocyclooctyne-functionalized anti-CD20 and anti-Lym1 antibodies as the tumor-targeting components and azide-functionalized BEZ235-encapsulated NPs as the effector drug carrier. Using lymphoma cell lines with different CD20 and HLA-DR antigen densities as examples, we demonstrate that the dual antibody pretargeted strategy effectively raises the number of NPs retained on the target tumor cells and improves the in vitro and in vivo antitumor activity of BEZ235 through the inhibition of the PI3K/mTOR pathway. Our data demonstrate that the NP-based pretargeted system improves the therapeutic window of small-molecule kinase inhibitor.

Collagen IV-targeting peptide-conjugated basement membrane-targeting nanoparticles are successfully engineered to identify early-stage blood vessel injury induced by high-dose radiotherapy.

Chemosensitizers can improve the therapeutic index of chemotherapy and overcome treatment resistance. Successful translation of chemosensitizers depends on the development of strategies that can preferentially deliver chemosensitizers to tumors while avoiding normal tissue. We hypothesized that nanoparticle (NP) formulation of chemosensitizers can improve their delivery to tumors which can in turn improve their therapeutic index. To demonstrate the proof of principle of this approach, we engineered NP formulations of two chemosensitizers, the PI3-kindase inhibitor wortmanin (Wtmn) and the PARP inhibitor olaparib. NP Wtmn and NP olaparib were evaluated as chemosensitizers using lung cancer cells and breast cancer cells respectively. We found Wtmn to be an efficient chemosensitizer in all tested lung-cancer cell lines reducing tumor cell growth between 20 and 60% compared to drug alone. NP formulation did not decrease its efficacy in vitro. Olaparib showed less consistent chemosensitization as a free drug or in NP formulation. NP Wtmn was further evaluated as a chemosensitizer using mouse models of lung cancer. We found that NP Wtmn is an effective chemosensitizer and more effective than free Wtmn showing a 32% reduction in tumor growth compared to free Wtmn when given with etoposide. Importantly, NP Wtmn was able to sensitize the multi-drug resistant H69AR cells to etoposide. Additionally, the combination of NP Wtmn and etoposide chemotherapy did not significantly increase toxicity. The present study demonstrates the proof of principle of using NP formulation of chemosensitizing drugs to improve the therapeutic index of chemotherapy.

Combining molecularly targeted agents and chemotherapeutics is an emerging strategy in cancer treatment. We engineered sub-50 nm diameter diblock copolymer nanoparticles (NPs) that can sequentially release wortmannin (Wtmn, a cell signaling inhibitor) and docetaxel (Dtxl, genotoxic anticancer agent) to cancer cells. These NPs were studied in chemoradiotherapy, an important cancer treatment paradigm, in the preclinical setting. We demonstrated that Wtmn enhanced the therapeutic efficacy of Dtxl and increased the efficiency of radiotherapy (XRT) in H460 lung cancer and PC3 prostate cells in culture. Importantly, we showed that NPs containing both Wtmn and Dtxl release the drugs in a desirable sequential fashion to maximize therapeutic efficacy in comparison to administering each drug alone. An in vivo toxicity study in a murine model validated that NPs containing both Dtxl and Wtmn do not have a high toxicity profile. Lastly, we demonstrated that Dtxl/Wtmn-coencapsulated NPs are more efficient than each single-drug-loaded NPs or a combination of both single-drug-loaded NPs in chemoradiotherapy using xenograft models. Histopathological studies and correlative studies support that the improved therapeutic efficacy is through changes in signaling pathways and increased tumor cell apoptosis. Our findings suggest that our nanoparticle system led to a dynamic rewiring of cellular apoptotic pathways and thus improve the therapeutic efficiency.

We report the use of near-infrared (NIR) radiation to trigger the irreversible flocculation of poly(oligo(ethylene glycol) methacrylate)-stabilised polypyrrole nanoparticles in physiological buffer.

Optical coherence tomography (OCT) is a modern high resolution subsurface medical imaging technique. Herein we describe: (i) the synthesis of a thiophene-functionalized oligo(ethylene glycol) methacrylate (OEGMA)-based statistical copolymer, denoted poly(2TMOI–OEGMA); (ii) the preparation of sterically-stabilized polypyrrole (PPy) nanoparticles of approximately 60 nm diameter; (iii) the evaluation of these nanoparticles as a NIR-absorbing optical contrast agent for high-resolution OCT imaging. We show that poly(2TMOI–OEGMA)-stabilized PPy nanoparticles exhibit similar optical properties to poly(vinyl alcohol) (PVA)-stabilized PPy nanoparticles of comparable size prepared using commercially available PVA. Spectroscopic measurements and Mie calculations indicate that both types of PPy nanoparticles strongly absorb NIR radiation above 1000 nm, suggesting their potential use as OCT contrast agents. In vitro OCT studies indicate that both types of PPy nanoparticles reduce NIR backscattering within homogeneous intralipid tissue phantoms, offering almost identical contrast performance in this medium. However, PVA-stabilized PPy nanoparticles became colloidally unstable when dispersed in physiological buffer and immersed in a solid biotissue phantom and hence failed to generate a strong contrast effect. In contrast, the poly(2TMOI–OEGMA)-stabilized PPy nanoparticles remained well-dispersed and hence exhibited a strong rapid onset contrast effect within the biotissue phantom under identical physiological conditions. Ex vivo studies performed on excised chicken and porcine skin tissue demonstrated that topical administration of a low concentration of poly(2TMOI–OEGMA)-stabilized PPy nanoparticles rapidly enhances OCT image contrast in both cases, allowing key tissue features to be readily identified.

A near-infrared (NIR) absorbing contrast agent based on polypyrrole nanoparticles is described. Quantitative optical coherence tomography studies on tissue phantoms and Mie scattering calculations indicate their potential application for early-stage cancer diagnosis.