Nirupama Sabnis

The role of cholesterol metabolism and cholesterol transport in carcinogenesis: a review of scientific findings, relevant to future cancer therapeutics.

While the unique metabolic activities of malignant tissues as potential targets for cancer therapeutics has been the subject of several recent reviews, the role of cholesterol metabolism in this context is yet to be fully explored. Cholesterol is an essential component of mammalian cell membranes as well as a precursor of bile acids and steroid hormones. The hypothesis that cancer cells need excess cholesterol and intermediates of the cholesterol biosynthesis pathway to maintain a high level of proliferation is well accepted, however the mechanisms by which malignant cells and tissues reprogram cholesterol synthesis, uptake and efflux are yet to be fully elucidated as potential therapeutic targets. High and low density plasma lipoproteins are the likely major suppliers of cholesterol to cancer cells and tumors, potentially via receptor mediated mechanisms. This review is primarily focused on the role(s) of lipoproteins in carcinogenesis, and their future roles as drug delivery vehicles for targeted cancer chemotherapy.

Enhanced solubility and functionality of valrubicin (AD-32) against cancer cells upon encapsulation into biocompatible nanoparticles

Among numerous drug-delivery approaches, reconstituted high-density lipoprotein (rHDL) nanocarriers have proven particularly applicable for delivering highly hydrophobic drugs. In this study, we have investigated the enhancement of the therapeutic impact of valrubicin (AD-32), an antineoplastic agent that has been limited to intravesicular application against bladder cancer, despite the encouraging original preclinical data. Earlier studies validated the superior therapeutic efficacy of AD-32 over doxorubicin. In the present study, rHDL/AD-32 nanoparticles were formulated and characterized with regard to encapsulation efficiency, physicochemical properties, selective toxicity, and receptor-mediated uptake. The half maximal inhibitory concentration values (IC50) for rHDL/AD-32 nanoparticles were 1.8 and 2.6 times lower than the free AD-32 for prostate (PC-3) and ovarian (SKOV-3) cancer cell lines, respectively, whereas nonmalignant cell lines demonstrated 5 and 1.48 times higher IC50 doses with rHDL/AD-32 formulations. The data obtained demonstrated effective receptor- mediated uptake of AD-32 from the rHDL nanocarriers by PC-3 and SKOV-3 cancer cells via a targeted drug-delivery process. The rHDL/AD-32 formulation was stable for 6 months when stored at 4°C or at −20°C, as 92% of the AD-32 was retained in the nanoparticles. The findings from this study show that the rHDL/AD-32 formulation can overcome the solubility barriers of AD-32 and thus serve as an effective systemically administered chemotherapeutic agent.

Pre-Clinical Evaluation of rHDL Encapsulated Retinoids for the Treatment of Neuroblastoma.

Despite major advances in pediatric cancer research, there has been only modest progress in the survival of children with high risk neuroblastoma (NB) (HRNB). The long term survival rates of HRNB in the United States are still only 30–50%. Due to resistance that often develops during therapy, development of new effective strategies is essential to improve the survival and overcome the tendency of HRNB patients to relapse subsequent to initial treatment. Current chemotherapy regimens also have a serious limitation due to off target toxicity. In the present work, we evaluated the potential application of reconstituted high density lipoprotein (rHDL) containing fenretinide (FR) nanoparticles as a novel approach to current NB therapeutics. The characterization and stability studies of rHDL-FR nanoparticles showed small size (<40 nm) and high encapsulation efficiency. The cytotoxicity studies of free FR vs. rHDL/FR toward the NB cell lines SK-N-SH and SMS-KCNR showed 2.8- and 2-fold lower IC50 values for the rHDL encapsulated FR vs. free FR. More importantly, the IC50 value for retinal pigment epithelial cells (ARPE-19), a recipient of off target toxicity during FR therapy, was over 40 times higher for the rHDL/FR as compared to that of free FR. The overall improvement in in vitro selective therapeutic efficiency was thus about 100-fold upon encapsulation of the drug into the rHDL nanoparticles. These studies support the potential value of this novel drug delivery platform for treating pediatric cancers in general, and NB in particular.

Targeting the SR-B1 Receptor as a Gateway for Cancer Therapy and Imaging

Malignant tumors display remarkable heterogeneity to the extent that even at the same tissue site different types of cells with varying genetic background may be found. In contrast, a relatively consistent marker the scavenger receptor type B1 (SR-B1) has been found to be consistently overexpressed by most tumor cells. Scavenger Receptor Class B Type I (SR-BI) is a high density lipoprotein (HDL) receptor that facilitates the uptake of cholesterol esters from circulating lipoproteins. Additional findings suggest a critical role for SR-BI in cholesterol metabolism, signaling, motility, and proliferation of cancer cells and thus a potential major impact in carcinogenesis and metastasis. Recent findings indicate that the level of SR-BI expression correlate with aggressiveness and poor survival in breast and prostate cancer. Moreover, genomic data show that depending on the type of cancer, high or low SR-BI expression may promote poor survival. This review discusses the importance of SR-BI as a diagnostic as well as prognostic indicator of cancer to help elucidate the contributions of this protein to cancer development, progression, and survival. In addition, the SR-B1 receptor has been shown to serve as a potential gateway for the delivery of therapeutic agents when reconstituted high density lipoprotein nanoparticles are used for their transport to cancer cells and tumors. Opportunities for the development of new technologies, particularly in the areas of cancer therapy and tumor imaging are discussed.

HDL as a drug and nucleic acid delivery vehicle.

This review is intended to evaluate the research findings and potential clinical applications of drug transport systems, developed based on the concepts of the structure/function and physiological role(s) of high density lipoprotein type nanoparticles. These macromolecules provide targeted transport of cholesteryl esters (a highly lipophilic payload) in their natural/physiological environment. The ability to accommodate highly water insoluble constituents in their core regions enables High density lipoproteins (HDL) type nanoparticles to effectively transport hydrophobic drugs subsequent to systemic administration. Even though the application of reconstituted HDL in the treatment of a number of diseases is reviewed, the primary focus is on the application of HDL type drug delivery agents in cancer chemotherapy. The use of both native and synthetic HDL as drug delivery agents is compared to evaluate their respective potentials for commercial and clinical development. The current status and future perspectives for HDL type nanoparticles are discussed, including current obstacles and future applications in therapeutics.

Photophysical characterization of anticancer drug valrubicin in rHDL nanoparticles and its use as an imaging agent.

Nanoparticles are target-specific drug delivery agents that are increasingly used in cancer therapy to enhance bioavailability and to reduce off target toxicity of anti-cancer agents. Valrubicin is an anti-cancer drug, currently approved only for vesicular bladder cancer treatment because of its poor water solubility. On the other hand, valrubicin carrying reconstituted high density lipoprotein (rHDL) nanoparticles appear ideally suited for extended applications, including systemic cancer chemotherapy. We determined selected fluorescence properties of the free (unencapsulated) drug vs. valrubicin incorporated into rHDL nanoparticles. We have found that upon encapsulation into rHDL nanoparticles the quantum yield of valrubicin fluorescence increased six fold while its fluorescence lifetime increased about 2 fold. Accordingly, these and potassium iodide (KI) quenching data suggest that upon incorporation, valrubicin is localized deep in the interior of the nanoparticle, inside the lipid matrix. Fluorescence anisotropy of the rHDL valrubicin nanoparticles was also found to be high along with extended rotational correlation time. The fluorescence of valrubicin could also be utilized to assess its distribution upon delivery to prostate cancer (PC3) cells. Overall the fluorescence properties of the rHDL: valrubicin complex reveal valuable novel characteristics of this drug delivery vehicle that may be particularly applicable when used in systemic (intravenous) therapy.

The Potential Role of Nanotechnology in Therapeutic Approaches for Triple Negative Breast Cancer

Triple Negative Breast Cancer, TNBC, a highly aggressive and metastatic type of breast cancer, is characterized by loss of expression of the estrogen receptor (ER), progesterone receptor (PR), and a lack of overexpression of the human epidermal growth factor receptor 2 (HER2). It is a heterogeneous group of tumors with diverse histology, molecular uniqueness and response to treatment. Unfortunately, TNBC patients do not benefit from current anti-HER2 or hormone positive targeted breast cancer treatments; consequently, these patients rely primarily on chemotherapy. However, the 5-year survival rate for woman with metastatic TNBC is less than 30%. As a result of ineffective treatments, TNBC tumors often progress to metastatic lesions in the brain and lung. Brain metastases of invasive breast cancer are associated with 1 and 2 year survival rate of 20% and <2% respectively. Because the only current systemic treatment for TNBC is chemotherapy, alternative targeted therapies are urgently needed to improve the prognosis for TNBC patients. This review is focused on opportunities for developing new approaches for filling the current void in an effective treatment for TNBC patients.

Superparamagnetic reconstituted high-density lipoprotein nanocarriers for magnetically guided drug delivery

Current cancer chemotherapy is frequently associated with short- and long-term side effects, affecting the quality of life of cancer survivors. Because malignant cells are known to overexpress specific surface antigens, including receptors, targeted drug delivery is often utilized to reduce or overcome side effects. The current study involves a novel targeting approach using specifically designed nanoparticles, including encapsulation of the anti-cancer drug valrubicin into superparamagnetic iron oxide nanoparticle (SPION) containing reconstituted high-density lipoprotein (rHDL) nanoparticles. Specifically, rHDL–SPION–valrubicin hybrid nanoparticles were assembled and characterized with respect to their physical and chemical properties, drug entrapment efficiency and receptor-mediated release of the drug valrubicin from the nanoparticles to prostate cancer (PC-3) cells. Prussian blue staining was used to assess nanoparticle movement in a magnetic field. Measurements of cytotoxicity toward PC-3 cells showed that rHDL–SPION–valrubicin nanoparticles were up to 4.6 and 31 times more effective at the respective valrubicin concentrations of 42.4 µg/mL and 85 µg/mL than the drug valrubicin alone. These studies showed, for the first time, that lipoprotein drug delivery enhanced via magnetic targeting could be an effective chemotherapeutic strategy for prostate cancer.

Studies on solvatochromic properties of aminophenylstyryl-quinolinum dye, LDS 798, and its application in studying submicron lipid based structure.

The styryl group of dyes has been used in cellular studies for over 20 years because of their solvatochromic and/or electrochromic properties. Here we report characterization of solubility and solvatochromic properties of a near infra-red styryl dye, styryl 11 or LDS 798. We have extended our studies to small unilamellar vesicles and lipid based nanoparticles and found that solvatochromic properties of this dye used in tandem with fluorescence correlation spectroscopy can be used to efficiently determine the diffusion coefficient and hence the size of the submicron lipid based particles. This technique has the potential to provide essential information about liposomal and vesicular structures and their movement in vitro and in situ.

Targeted nanoparticles for pediatric leukemia therapy

The two major forms of leukemia, acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), account for about one-third of the malignancies diagnosed in children. Despite the marked successes in ALL and AML treatment, concerns remain regarding the occurrence of resistant disease in subsets of patients, the residual effects of therapy that often persist for decades beyond the cessation of treatment. Therefore, new approaches are needed to reduce or to avoid off target toxicities, associated with chemotherapy and their long-term residual effects. Recently, nanotechnology has been employed to enhance cancer therapy, via improving the bioavailability and therapeutic efficacy of anti-cancer agents. While in the last several years, numerous review articles appeared detailing the size, composition, assembly, and performance evaluation of different types of drug carrying nanoparticles, the description and evaluation of lipoprotein-based drug carriers have been conspicuously absent from most of these major reviews. The current review focuses on such information regarding nanoparticles with an emphasis on high density lipoprotein-based drug delivery systems to examine their potential role(s) in the enhanced treatment of children with leukemia.