Search

Lung cancer is the leading cause of cancer-related deaths with current chemotherapies lacking adequate specificity and efficacy. β-Lapachone (β-lap) is a novel anticancer drug that is bioactivated by NAD(P)H:quinone oxidoreductase 1, an enzyme found specifically overexpressed in non–small cell lung cancer (NSCLC). Herein, we report a nanotherapeutic strategy that targets NSCLC tumors in two ways: (a) pharmacodynamically through the use of a bioactivatable agent, β-lap, and (b) pharmacokinetically by using a biocompatible nanocarrier, polymeric micelles, to achieve drug stability, bioavailability, and targeted delivery. β-Lap micelles produced by a film sonication technique were small (∼30 nm), displayed core-shell architecture, and possessed favorable release kinetics. Pharmacokinetic analyses in mice bearing subcutaneous A549 lung tumors showed prolonged blood circulation (t1/2, ∼28 h) and increased accumulation in tumors. Antitumor efficacy analyses in mice bearing subcutaneous A549 lung tumors and orthotopic Lewis lung carcinoma models showed significant tumor growth delay and increased survival. In summary, we have established a clinically viable β-lap nanomedicine platform with enhanced safety, pharmacokinetics, and antitumor efficacy for the specific treatment of NSCLC tumors. Cancer Res; 70(10); 3896–904. ©2010 AACR.

Supplementary Table 1, Figures 1-3 from β-Lapachone Micellar Nanotherapeutics for Non–Small Cell Lung Cancer Therapy

Cognitive deficits (chemobrain) and peripheral neuropathy occur in ~75% of patients treated for cancer with chemotherapy and persist long-term in >30% of survivors. Without preventive or curative interventions and with increasing survivorship rates, the population debilitated by these neurotoxicities is rising. Platinum-based chemotherapeutics, including cisplatin, induce neuronal mitochondrial defects leading to chemobrain and neuropathic pain. This study investigates the capacity of nasally administered mesenchymal stem cell-derived mitochondria coated with dextran-triphenylphosphonium polymer (coated mitochondria) to reverse these neurotoxicities. Nasally administered coated mitochondria are rapidly detectable in macrophages in the brain meninges but do not reach the brain parenchyma. The coated mitochondria change expression of >2400 genes regulating immune, neuronal, endocrine and vascular pathways in the meninges of mice treated with cisplatin. Nasal administration of coated mitochondria reverses cisplatin-induced cognitive deficits and resolves neuropathic pain at a >55-times lower dose compared to uncoated mitochondria. Reversal of these neuropathologies is associated with resolution of cisplatin-induced deficits in myelination, synaptosomal mitochondrial integrity and neurogenesis. These findings demonstrate that nasally administered coated mitochondria promote resolution of chemobrain and peripheral neuropathy, thereby identifying a novel facile strategy for clinical application of mitochondrial donation and treating central and peripheral nervous system pathologies by targeting the brain meninges.

With a wide variety of biodistribution measurement techniques reported in the literature, it is important to perform side-by-side comparisons of results obtained with different methods on the same particle platform, to determine differences across methods, highlight advantages and disadvantages, and inform methods selection according to specific applications. Inorganic nanostructured particles (INPs) have gained a central role in the development of injectable delivery vectors thanks to their controllable design, biocompatibility, and favorable degradation kinetic. Thus, accurate determination of in vivo biodistribution of INPs is a key aspect of developing and optimizing this class of delivery vectors. In this study, a systematic comparison of spectroscopy (inductively coupled plasma optical emission spectroscopy), fluorescence (in vivo imaging system, confocal microscopy, and plate reader), and radiolabeling (gamma counter)-based techniques is performed to assess the accuracy and sensitivity of biodistribution measurements in mice. Each method is evaluated on porous silicon particles, an established and versatile injectable delivery platform. Biodistribution is evaluated in all major organs and compared in terms of absolute results (%ID/g and %ID/organ when possible) and sensitivity (σ%). Finally, we discuss how these results can be extended to inform method selection for other platforms and specific applications, with an outlook to potential benefit for pre-clinical and clinical studies. Overall, this study presents a new practical guide for selection of in vivo biodistribution methods that yield quantitative results. STATEMENT OF SIGNIFICANCE: The significance of this work lies in the use of a single platform to test performances of different biodistribution methods in vivo, with a strict quantitative metric. These results, united with the qualitative comparison of advantages and disadvantages of each technique, are aimed at supporting the rational choice of each different method according to the specific application, to improve the quantitative description of biodistribution results that will be published by others in the future.

Intratumoral drug delivery is a promising approach for the treatment of glioblastoma multiforme (GBM)., Intratumoral drug delivery is a promising approach for the treatment of glioblastoma multiforme (GBM). However, drug washout remains a major challenge in GBM therapy. Our strategy, aimed at reducing drug clearance and enhancing site-specific residence time, involves the local administration of a multi-component system comprised of nanoparticles (NPs) embedded within a thermosensitive hydrogel (HG). Herein, our objective was to examine the distribution of NPs and their cargo following intratumoral administration of this system in GBM. We hypothesized that the HG matrix, which undergoes rapid gelation upon increases in temperature, would contribute towards heightened site-specific retention and permanence of NPs in tumors. BODIPY-containing, infrared dye-labeled polymeric NPs embedded in a thermosensitive HG (HG–NPs) were fabricated and characterized. Retention and distribution dynamics were subsequently examined over time in orthotopic GBM-bearing mice. Results demonstrate that the HG–NPs system significantly improved site-specific, long-term retention of both NPs and BODIPY, with co-localization analyses showing that HG–NPs covered larger areas of the tumor and the peri-tumor region at later time points. Moreover, NPs released from the HG were shown to undergo uptake by surrounding GBM cells. Findings suggest that intratumoral delivery with HG–NPs has immense potential for GBM treatment, as well as other strategies where site-specific, long-term retention of therapeutic agents is warranted.

Objective Oral squamous cell carcinoma (OSCC) represents 3%-4% of all cancers. Despite the increasing incidence of OSCC distant metastasis and poor prognosis, few animal models of OSCC distant metastasis have been reported. In this study, we established mouse models of OSCC lung metastasis by orthotopic and tail vein injection of new OSCC cell lines. Methods For the tail vein model, we used a novel cell line isolated from lung metastases reproduced in vivo after intravenous injection of HSC-3 GFP/luciferase cells and sorted for GFP expression (HSC-3 M1 GFP/luciferase). Lung metastases were assessed by imaging techniques and further confirmed by histology. For the orthotopic model, HSC-3 GFP/luciferase cells were injected into the tongue of athymic nude mice. The primary tumor and metastases were assessed by in vivo imaging, histology, and immunohistochemistry. Results The orthotopic model presented spontaneous lung metastases in 50% of the animals and lymph node metastases were present in 83% of cases. In the tail vein model, a lung metastasis rate of 60% was observed. Conclusions Lung metastases were successfully reproduced by orthotopic and tail vein injection. Since lymph node metastases were present, the orthotopic model with HSC-3 GFP/luciferase cells may be suitable to investigate metastatic dissemination in OSCC.

Treatment of peritoneal surface malignancies with cytoreductive surgery and HIPEC (CRS/HIPEC) has a substantial risk of local recurrence and causes off‐target toxicity. HIPEC is reinvented utilizing a gold nanorod (GNR) platform to provide surgically targeted precision delivery of mild hyperthermia (42 °C) to increase chemotherapeutic efficacy and reduce off‐target toxicity. A biocompatible hydrogel film containing GNRs, mitomycin‐C (MMC), and cisplatin (CisPt) is designed to create controlled, mild hyperthermia generated from NIR laser treatment of GNRs. The concentration of GNRs and duration of hyperthermia is determined using dose‐response curves to titrate goal temperature parameters of mild hyperthermia (42 °C) in a controlled fashion. Loading and release of CisPt and MMC at an inhibitory concentration (IC50) dose is determined to be highly efficient. In vitro and in vivo experiments demonstrate cytotoxicity and reduced tumor growth in murine models of peritoneal malignancy with preferential accumulation of GNRs within peritoneal tumors. Preclinical evidence of efficacy utilizing a biocompatible hydrogel GNR/MMC/CisPt film can lead to clinical trials in patients with peritoneal malignancies. If successful, treatment of other cancers can benefit from this GNR chemotherapy hydrogel film as a method to decrease the incidence of local recurrence in any surgical resection bed.

The liver is a major barrier for site-specific delivery of systemically injected nanoparticles, as up to 90% of the dose is usually captured by this organ. Kupffer cells are thought to be the main cellular component responsible for nanoparticle accumulation in the liver. These resident macrophages form part of the mononuclear phagocyte system, which recognizes and engulfs foreign bodies in the circulatory system. In this study, we have compared two strategies for reducing nanoparticle accumulation in the liver, in order to investigate the specific contribution of Kupffer cells. Specifically, we have performed a comparison of the capability of pegylation and Kupffer cell depletion to reduce liposome accumulation in the liver. Pegylation reduces nanoparticle interactions with all types of cells and can serve as a control for elucidating the role of specific cell populations in liver accumulation. The results indicate that liposome pegylation is a more effective strategy for avoiding liver uptake compared to depletion of Kupffer cells, suggesting that nanoparticle interactions with other cells in the liver may also play a contributing role. This study highlights the need for a more complete understanding of factors that mediate nanoparticle accumulation in the liver and for the exploration of microenvironmental modulation strategies for reducing nanoparticle-cell interactions in this organ.

Vascular remodeling resulting from pulmonary arterial hypertension (PAH) leads to endothelial fenestrations. This feature can be exploited by nanoparticles (NP), allowing them to extravasate from circulation and accumulate in remodeled pulmonary vessels. Hyperactivation of the mTOR pathway in PAH drives pulmonary arterial smooth muscle cell proliferation. We hypothesized that rapamycin (RAP)-loaded NPs, an mTOR inhibitor, would accumulate in diseased lungs, selectively targeting vascular mTOR and preventing PAH progression. RAP poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) NPs were fabricated. NP accumulation and efficacy were examined in a rat monocrotaline model of PAH. Following intravenous (IV) administration, NP accumulation in diseased lungs was verified via LC/MS analysis and confocal imaging. Pulmonary arteriole thickness, right ventricular systolic pressures, and ventricular remodeling were determined to assess the therapeutic potential of RAP NPs. Monocrotaline-exposed rats showed increased NP accumulation within lungs compared to healthy controls, with NPs present to a high extent within pulmonary perivascular regions. RAP, in both free and NP form, attenuated PAH development, with histological analysis revealing minimal changes in pulmonary arteriole thickness and no ventricular remodeling. Importantly, NP-treated rats showed reduced systemic side effects compared to free RAP. This study demonstrates the potential for nanoparticles to significantly impact PAH through site-specific delivery of therapeutics.

Presently, cardiovascular interventions such as stent deployment and balloon angioplasty are performed under x-ray guidance. However, x-ray fluoroscopy has poor soft tissue contrast and is limited by imaging in a single plane, resulting in imprecise navigation of endovascular instruments. Moreover, x-ray fluoroscopy exposes patients to ionizing radiation and iodinated contrast agents. Magnetic resonance imaging (MRI) is a safe and enabling modality for cardiovascular interventions. Interventional cardiovascular MR (iCMR) is a promising approach that is in stark contrast with x-ray fluoroscopy, offering high-resolution anatomic and physiologic information and imaging in multiple planes for enhanced navigational accuracy of catheter-based devices, all in an environment free of radiation and its deleterious effects. While iCMR has immense potential, its translation into the clinical arena is hindered by the limited availability of MRI-visible catheters, wire guides, angioplasty balloons, and stents. Herein, we aimed to create application-specific, devices suitable for iCMR, and demonstrate the potential of iCMR by performing cardiovascular catheterization procedures using these devices. Tools, including catheters, wire guides, stents, and angioplasty balloons, for endovascular interventions were functionalized with a polymer coating consisting of poly(lactide-co-glycolide) (PLGA) and superparamagnetic iron oxide (SPIO) nanoparticles, followed by endovascular deployment in the pig. Findings from this study highlight the ability to image and properly navigate SPIO-functionalized devices, enabling interventions such as successful stent deployment under MRI guidance. This study demonstrates proof-of-concept for rapid prototyping of iCMR-specific endovascular interventional devices that can take advantage of the capabilities of iCMR.

The ultimate goal in the field of drug delivery is to exclusively direct therapeutic agents to pathological tissues in order to increase therapeutic efficacy and eliminate side effects. This goal is challenging due to multiple transport obstacles in the body. Strategies that improve drug transport exploit differences in the characteristics of normal and pathological tissues. Within the field of oncology, these concepts have laid the groundwork for a new discipline termed transport oncophysics. Areas covered: Efforts to improve drug biodistribution have mainly focused on nanocarriers that enable preferential accumulation of drugs in diseased tissues. A less common approach to enhance drug transport involves priming strategies that modulate the biological environment in ways that favor localized drug delivery. This review discusses a variety of priming and nanoparticle design strategies that have been used for drug delivery. Expert opinion: Combinations of priming agents and nanocarriers are likely to yield optimal drug distribution profiles. Although priming strategies have yet to be widely implemented, they represent promising solutions for overcoming biological transport barriers. In fact, such strategies are not restricted to priming the tumor microenvironment but can also be directed toward healthy tissue in order to reduce nanoparticle uptake.

The successful treatment of malignant disease generally requires the use of multiple therapeutic agents that are coordinated in a spatiotemporal manner to enable synergy. Here, a porous silicon-based micro/nano composite (MNC) that is capable of simultaneously delivering chemotherapeutic agents and small interfering RNA (siRNA) to the lungs following intravenous injection is designed. The pores of the silicon microparticles are loaded with B-Raf proto-oncogene serine/threonine kinase (BRAF) siRNA-containing liposomes, while the surface is conjugated with docetaxel-encapsulated polymeric nanoparticles. The synergistic antitumor effect of the MNC is demonstrated in vitro in melanoma cells and in vivo using a mouse model for melanoma lung metastasis. The MNC displays superior therapeutic efficacy and increased accumulation in metastatic melanoma lesions in the lungs in comparison to combination therapy with liposomes and polymers. The results indicate that the MNC can be used as an effective delivery vehicle for simultaneous enrichment of multiple therapeutic agents in the lungs.

INTRODUCTION Chemotherapeutic synergy enhancement can be obtained when drugs are delivered in a sequential manner. However, clinical translation of synergistic combinations is not feasible due to different pharmacokinetic properties arising from distinct drug formulations that negate proper sequential delivery. Our laboratory has developed a platform for temporospatial delivery of agents in a sequential fashion for purposes of enhancing site-specific synergy. The system comprises a drug-containing poly(lactic-co-glycolic acid) (PLGA) core and an outer shell of drug complexed with β-cyclodextrin (β-CD). In this study, we demonstrate the therapeutic potential of this nanoparticle system by encapsulating two drugs, rapamycin (RAP) and paclitaxel (PTX). This combination has been shown to result in cell-killing synergy enhancement in when administered sequentially, and in a time staggered manner, in triple negative breast cancer (TNBC) in in vitro cell-based models. EXPERIMENTAL METHODS The final platform was fabricated by resuspending PLGA-PTX nanoparticles in an aqueous solution of RAP cyclodextrin complexes (RAP-CD) under sonication. Nanoparticles were characterized for size and surface charge. Drug concentration and release kinetics were determined by HPLC. In vitro growth inhibition in SUM159 TNBC cells was determined via MTT assay. Western blotting was used to confirm target knockdown. For in vivo efficacy analysis, SUM159 breast cancer cells (3×106) were inoculated in the mammary fat pads of 4- to 6-week–old female nu/nu mice, and treatments were administered intravenously once a week for a duration of 21 days. RESULTS AND DISCUSSION Nanoparticles had a mean diameter of 140 nm and zeta potential of -30 mV. After complexation with RAP-CD, the surface charge became 25 mV. Release kinetics depicted a fast release of RAP at early timepoints, while PTX showed a prolonged release. Nanoparticles showed concentration dependent cell-killing efficacy in SUM159 breast cancer cells in vitro, with knockdown of pS6, characteristic of RAP treatment, observed. Upon administration of NNPs to murine models of TNBC, NNPs showed significant tumor growth inhibition compared to controls, and knockdown of pS6. CONCLUSION We have developed a novel nanoparticle for the temporospatial release of drugs. The ability to localize agents site-specifically and deliver them sequentially should enable clinical translation of synergistic regimens observed in in vitro scenarios, in turn yielding more efficacious more efficacious outcomes following combination chemotherapy. Citation Format: Segura-Ibarra V, Wu S, Cara FE, Meric-Bernstam F, Ferrari M, Blanco E. Temporospatial delivery of chemotherapeutics from nanoparticles for synergy enhancement. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-14.

Isolated mitochondria are polymerically functionalized for transplantation into metabolically compromised cells. In article number 1700530, Elvin Blanco, Dale J. Hamilton, and co‐workers demonstrate that coating mitochondria with a dextran‐triphenylphosphonium (TPP) conjugate results in longer functional survival of the organelle ex vivo, increased cellular uptake, and an enhanced shift in the metabolic phenotype of cells compared to uncoated mitochondria.

Biological barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biological barriers that a particle encounters upon intravenous administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery.

Oral cavity and oropharyngeal carcinomas (oral cancer) represents a significant cause of morbidity and mortality. Despite efforts in improving early diagnosis and treatment, the 5-year survival rate of advanced stage of the disease is less than 63%. The field of nanomedicine has offered promising diagnostic and therapeutic advances in cancer. Indeed, several platforms have been clinically approved for cancer therapy, while other promising systems are undergoing exploration in clinical trials. With its ability to deliver drugs, nucleic acids, and MRI contrast agents with high efficiency, nanomedicine platforms offer the potential to improve drug efficacy and tolerability. The aim of the present mini-review is to summarize the current preclinical status of nanotechnology systems for oral cancer therapy. The nanoplatforms for delivery of chemopreventive agents presented herein resulted in significantly higher anti-tumor activity than free forms of the drug, even against a chemo-resistant cell line. Impressive results have also been obtained using nanoparticles to deliver chemotherapeutics, resulting in reduced toxicity both in vitro and in vivo. Nanoparticles have also led to improvements in efficacy of photodynamic therapies through the development of targeted magnetic nanoparticles. Finally, gene therapy using nanoparticles demonstrated promising results specifically with regards to inhibition of gene expression. Of the few in vivo studies that have been reported, many of these used animal models with several limitations, which will be discussed herein. Lastly, we will discuss several future perspectives in oral cancer nanoparticle-based therapy and the development of appropriate animal models, distinguishing between oral cavity and oropharyngeal carcinoma.

Site-specific localization is critical for improving the therapeutic efficacy and safety of drugs. Nanoparticles have emerged as promising tools for localized drug delivery. However, over 90% of systemically injected nanocarriers typically accumulate in the liver and spleen due to resident macrophages that form the mononuclear phagocyte system. In this study, the clinically approved antimalarial agent chloroquine was shown to reduce nanoparticle uptake in macrophages by suppressing endocytosis. Pretreatment of mice with a clinically relevant dose of chloroquine substantially decreased the accumulation of liposomes and silicon particles in the mononuclear phagocyte system and improved tumoritropic and organotropic delivery. The novel use of chloroquine as a macrophage-preconditioning agent presents a straightforward approach for addressing a major barrier in nanomedicine. Moreover, this priming strategy has broad applicability for improving the biodistribution and performance of particulate delivery systems. Ultimately, this study defines a paradigm for the combined use of macrophage-modulating agents with nanotherapeutics for improved site-specific delivery.

Pharmacological therapies for cardiovascular diseases are limited by short-term pharmacokinetics and extra-cardiac adverse effects. Improving delivery selectivity specifically to the heart, wherein therapeutic drug levels can be maintained over time, is highly desirable. Nanoparticle (NP)-based pericardial drug delivery could provide a strategy to concentrate therapeutics within a unique, cardiac-restricted compartment to allow sustained drug penetration into the myocardium. Our objective was to explore the kinetics of myocardial penetration and retention after pericardial NP drug delivery. Fluorescently-tagged poly(lactic-co-glycolic acid) (PLGA) NPs were loaded with BODIPY, a fluorophore, and percutaneously administered into the pericardium via subxiphoid puncture in rabbits. At distinct timepoints hearts were examined for presence of NPs and BODIPY. PLGA NPs were found non-uniformly distributed on the epicardium following pericardial administration, displaying a half-life of ~ 2.5 days in the heart. While NPs were mostly confined to epicardial layers, BODIPY was capable of penetrating into the myocardium, resulting in a transmural gradient. The distinct architecture and physiology of the different regions of the heart influenced BODIPY distribution, with fluorophore penetrating more readily into atria than ventricles. BODIPY proved to have a long-term presence within the heart, with a half-life of ~ 7 days. Our findings demonstrate the potential of utilizing the pericardial space as a sustained drug-eluting reservoir through the application of nanoparticle-based drug delivery, opening several exciting avenues for selective and prolonged cardiac therapeutics.

Triple negative breast cancer (TNBC) is known to contain a high percentage of CD44+/CD24−/low cancer stem cells (CSCs), corresponding with a poor prognosis despite systemic chemotherapy. Chloroquine (CQ), an antimalarial drug, is a lysotropic reagent which inhibits autophagy. CQ was identified as a potential CSC inhibitor through in silico gene expression signature analysis of the CD44+/CD24−/low CSC population. Autophagy plays a critical role in adaptation to stress conditions in cancer cells, and is related with drug resistance and CSC maintenance. Thus, the objectives of this study were to examine the potential enhanced efficacy arising from addition of CQ to standard chemotherapy (paclitaxel) in TNBC and to identify the mechanism by which CQ eliminates CSCs in TNBCs. Herein, we report that CQ sensitizes TNBC cells to paclitaxel through inhibition of autophagy and reduces the CD44+/CD24−/low CSC population in both preclinical and clinical settings. Also, we are the first to report a mechanism by which CQ regulates the CSCs in TNBC through inhibition of the Janus-activated kinase 2 (Jak2)—signal transducer and activator of transcription 3 signaling pathway by reducing the expression of Jak2 and DNA methyltransferase 1. Stem Cells 2014;32:2309–2323

Ongoing clinical trials target the aberrant PI3K/Akt/mammalian target of rapamycin (mTOR) pathway in breast cancer through administration of rapamycin, an allosteric mTOR inhibitor, in combination with paclitaxel. However, synergy may not be fully exploited clinically because of distinct pharmacokinetic parameters of drugs. This study explores the synergistic potential of site-specific, colocalized delivery of rapamycin and paclitaxel through nanoparticle incorporation. Nanoparticle drug loading was accurately controlled, and synergistic drug ratios established in vitro. Precise drug ratios were maintained in tumors 48 hours after nanoparticle administration to mice, at levels twofold greater than liver and spleen, yielding superior antitumor activity compared to controls. Simultaneous and preferential in vivo delivery of rapamycin and paclitaxel to tumors yielded mechanistic insights into synergy involving suppression of feedback loop Akt phosphorylation and its downstream targets. Findings demonstrate that a same time, same place, and specific amount approach to combination chemotherapy by means of nanoparticle delivery has the potential to successfully translate in vitro synergistic findings in vivo. Predictive in vitro models can be used to determine optimum drug ratios for antitumor efficacy, while nanoparticle delivery of combination chemotherapies in preclinical animal models may lead to enhanced understanding of mechanisms of synergy, ultimately opening several avenues for personalized therapy.

Nanoparticle-based drug delivery platforms are emerging as powerful chemotherapeutic modalities in breast cancer. Doxorubicin and paclitaxel nanoparticle formulations are currently used clinically, yielding distinct pharmacokinetic parameters that prolong blood circulation times, enhance drug accumulation in tumors, and limit adverse side effects to patients. And while these nanoconstructs have shown substantial improvements in patient tolerability and survival, several emerging trends stand to make a significant impact on future generations of nanoparticle platforms for breast cancer therapy. Firstly, there is a heightened understanding of several processes involved in tumor growth, potentiation, and invasion, resulting in the identification of several attractive molecular targets. This in turn has given rise to antibody-based therapeutics, drug repositioning, and the burgeoning field of RNA interference (RNAi). Secondly, an enhanced understanding of transport phenomena involved in delivery of chemotherapeutics has led to a rethinking and retooling of nanoscale drug carrier designs. Nanoparticle platforms are now incorporating features meant to overcome biological barriers and enhance drug accumulation within tumors, all the while incorporating unique chemistries that enable for controlled release of therapeutic payloads. This review aims to detail the current clinical state of nanoparticle-based therapeutics in breast cancer, as well as highlight several platforms that exemplify the future generation of innovative approaches to chemotherapy in breast cancer.

Cancer cells have high rates of glycolysis and lactic acid fermentation in order to fuel accelerated rates of cell division (Warburg effect). Here, we present a strategy for merging cancer and yeast metabolism to remove pyruvate, a key intermediate of cancer cell metabolism, and produce the toxic compound acetaldehyde. This approach was achieved by administering the yeast enzyme pyruvate decarboxylase to triple negative breast cancer cells. To overcome the challenges of protein delivery, a nanoparticle-based system consisting of cationic lipids and porous silicon were employed to obtain efficient intracellular uptake. The results demonstrate that the enzyme therapy decreases cancer cell viability through production of acetaldehyde and reduction of lactic acid fermentation.

Various nanodelivery systems have been designed to release therapeutic agents upon contact with specific enzymes. However, enzyme-triggered release typically takes place in the tissue interstitium, thereby resulting in the extracellular delivery of drugs. Here, we have designed an enzyme-stimulated multistage vector (ESMSV), which enables stimulus-triggered release of drug-encapsulated nanoparticles from a microparticle. Specifically, polymeric nanoparticles with a surface matrix metalloproteinase-2 (MMP2) peptide substrate were conjugated to the surface of porous silicon microparticles. In the presence of MMP2, the polymeric nanoparticles were released into the tumor interstitium. This platform can be used to attain triggered drug release, while simultaneously facilitating the cellular internalization of drugs. The results indicate that nanoparticle release was MMP2-specific and resulted in improved intracellular uptake of hydrophobic agents in the presence of MMP2. Furthermore, in a mouse model of melanoma lung metastasis, systemic delivery of ESMSVs caused a substantial increase in intracellular accumulation of agents in cancer cells in comparison to delivery with non-stimulus-responsive particles.

The efficacy of cancer drugs is often limited because only a small fraction of the administered dose accumulates in tumors. Here we report an injectable nanoparticle generator (iNPG) that overcomes multiple biological barriers to cancer drug delivery. The iNPG is a discoidal micrometer-sized particle that can be loaded with chemotherapeutics. We conjugate doxorubicin to poly(L-glutamic acid) by means of a pH-sensitive cleavable linker, and load the polymeric drug (pDox) into iNPG to assemble iNPG-pDox. Once released from iNPG, pDox spontaneously forms nanometer-sized particles in aqueous solution. Intravenously injected iNPG-pDox accumulates at tumors due to natural tropism and enhanced vascular dynamics and releases pDox nanoparticles that are internalized by tumor cells. Intracellularly, pDox nanoparticles are transported to the perinuclear region and cleaved into Dox, thereby avoiding excretion by drug efflux pumps. Compared to its individual components or current therapeutic formulations, iNPG-pDox shows enhanced efficacy in MDA-MB-231 and 4T1 mouse models of metastatic breast cancer, including functional cures in 40-50% of treated mice.

Background: The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) (PI3k/Akt/mTOR) pathway is dysregulated in certain breast cancers. Ongoing clinical trials aim to therapeutically exploit this pathway through administration of rapamycin (RAP), an mTOR inhibitor, in combination with paclitaxel (PTX). However, actual drug synergy in clinical settings may not be fully realized due to disparate pharmacokinetic parameters of individual drug formulations, wherein drugs or their effects may never be present in the tumor at the same time. Our objective was to generate a nanoparticle platform capable of site-specifically delivering precise amounts of rapamycin and paclitaxel to breast tumors with hopes of increasing synergistic targeting of the PI3k/Akt/mTOR pathway. Materials and Methods: Drug-containing nanoparticles composed of amphiphilic block copolymers of pegylated poly(∈-caprolactone) (PEG-PCL, MW = 5k-5k) were fabricated and nanoparticle size and drug loading efficiency was determined. In vitro growth inhibition of nanoparticle formulations of varying ratios was evaluated in MCF-7 and MDA-MB-468 breast cancer cells via sulforhodamine B assays, after which median-effect plot analyses and combination index calculations were conducted. Antitumor efficacy studies were performed in female nude mice bearing MDA-MB-468 tumors, in which nanoparticles were administered intravenously twice a week for the duration of three weeks. Biodistribution of drug-containing nanoparticles in extracted tumors were examined, as well as reverse phase protein array (RPPA) analysis to gain insights into site-specific synergy. Results: Nanoparticles were spherical, with an average diameter of 9 nm. Both rapamycin and paclitaxel loaded favorably, allowing for customization of different ratios within nanoparticles. Combination indices demonstrated that a 3:1 ratio of RAP:PTX had the most synergy in MDA-MB-468 breast cancer cells in vitro, a synergy found to be preserved in vivo. Significant tumor regression (> 1.5 fold reduction from initial tumor volume) was observed in vivo upon administration of 3:1 RAP:PTX (15:5 mg/kg) nanoparticles. The precise ratio of rapamycin and paclitaxel (3:1) was found maintained in tumors 24 h after administration, an effect not achievable with free drug formulations. RPPA analysis demonstrated effective blocking of mTOR and Akt 24 h after administration of nanoparticles, key events in drug synergy. Discussion: Site-specific delivery of synergistic agents in precisely-controlled drug ratios, possible through their incorporation into nanoparticles, was shown to be highly efficacious against breast tumors. Findings demonstrate the ability to deliver specific drug ratios to tumors, potentially precluding the need to administer maximal doses of both agents in order to achieve synergy, lessening patient side-effects. This study demonstrates the potential for prediction of in vivo therapeutic outcomes from in vitro synergistic findings. Nanoparticle delivery of drugs may also yield enhanced understanding of mechanisms of synergy between molecular-targeted drugs and traditional chemotherapeutics in vivo, resulting in novel and more efficacious treatment regimens. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-03.

Background: A significant challenge for effectively treating cancer is overcoming biological barriers that reduce circulation times and increase degradation of possible treatments. We established an innovative approach to address this issue by embedding drug-containing nanoparticles within the pores of a larger mesoporous silicon particle (MSP) in order to optimize site-specific localization and release of therapeutic agents. The objective is to develop a nanotherapeutic-based multistage platform for breast cancer treatment, wherein paclitaxel, a mitotic inhibitor used in the treatment of breast tumors, will be loaded into polymeric micelles, which in turn will be loaded within MSPs. We hypothesize that this nested incorporation of drugs within MSPs, combined with enhanced tumor transport, will result in a more pronounced and sustained antitumor effect. Materials and Methods: Micelles were assembled from amphiphilic block copolymers consisting of poly(ethylene glycol)-poly(∈-caprolactone) (PEG-PCL, MW = 5k-5k). Nanoparticle size, zeta potential, and morphology was determined, and PTX loading and release kinetics from micelles analyzed. Drug-containing micelles were incorporated into MSPs by a previously established dry-loading method, wherein nanoparticles were incorporated into pores via capillary action. Loading of fluorescent micelles was used to verify loading within MSPs via fluorescence microscopy and flow cytometry analysis. Sulforhodamine B assays were used to evaluate the in vitro antitumor efficacy of the platform in MCF-7 and MDA-MB-468 breast cancer cells. In vivo efficacy was evaluated in MDA-MB-468 breast tumors in female nu/nu mice. Results: Resulting micelles had an average size of 20 nm, as confirmed through TEM, with paclitaxel loaded into micelles very effectively. Release kinetics showed that 50% of the drug was released within 4 hours and 80% released within 24 hours. Loading of micelles into MSPs depended largely on electrostatic interactions, with micelles loading better within pores of MSPs displaying increased positive charge. Micelle loading into MSPs was successful as demonstrated by flow cytometry, and release was significantly retarded (< 30% of drug released over 4 d). Incubation of micelle-containing MSPs with breast cancer cells in vitro showed that MSPs could be internalized by cells, after which a sustained and delayed release of the payload was observed in cells. Breast tumors treated with MSPs demonstrated sustained tumor suppression (169 mm3 compared to initial starting volume of 200 mm3) at day 35 following a single injection. It is important to note that sustained tumor efficacy was achieved with nanoparticle and free drug formulations, however, with the caveat of repeated administrations. Discussion: A novel multistage approach to chemotherapy effectively allows a secondary payload to be loaded and preserved within the MSPs until reaching the tumor site. This prevents premature release of the drug and allows for a sustained release which may potentially result in fewer patient side effects. Future studies will involve loading of multiple nanoparticle types into MSPs and addition of targeting and diagnostic components. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-11.

The daunting task for drug molecules to reach pathological lesions has fueled rapid advances in Nanomedicine. The progressive evolution of nanovectors has led to the development of multi-stage delivery systems aimed at overcoming the numerous obstacles encountered by nanovectors on their journey to the target site.This review summarizes major findings with respect to silicon-based drug delivery vectors for cancer therapeutics and imaging. Based on rational design, well-established silicon technologies have been adapted for the fabrication of nanovectors with specific shapes, sizes, and porosities. These vectors are part of a multi-stage delivery system that contains multiple nano-components, each designed to achieve a specific task with the common goal of site-directed delivery of therapeutics.Quasi-hemispherical and discoidal silicon microparticles are superior to spherical particles with respect to margination in the blood, with particles of different shapes and sizes having unique distributions in vivo. Cellular adhesion and internalization of silicon microparticles is influenced by microparticle shape and surface charge, with the latter dictating binding of serum opsonins. Based on in vitro cell studies, the internalization of porous silicon microparticles by endothelial cells and macrophages is compatible with cellular morphology, intracellular trafficking, mitosis, cell cycle progression, cytokine release, and cell viability. In vivo studies support superior therapeutic efficacy of liposomal encapsulated siRNA when delivered in multi-stage systems compared to free nanoparticles. This article is part of a Special Issue entitled Nanotechnologies - Emerging Applications in Biomedicine.

Specificity as the major limitation of combination chemotherapy Efficacious patient outcomes in cancer increasingly rely on chemotherapeutic regimens comprising multiple drugs. The criteria for polychemotherapy, as outlined by Seidman and coworkers, simply state that component drugs should possess single-agent activity, work synergistically with one another, and have non-overlapping safety profiles [1]. Unfortunately, these criteria are rarely met. While survival benefits have been observed, clinically approved combination regimens fail to bring about significant improvements in patient outcomes, and more importantly, result in substantial morbidity. As an example, anthracyclines and taxanes are administered concomitantly to metastatic breast cancer patients. However, no clear mechanism of synergy warrants their combination, and both elicit significant deleterious effects, hindering their use at appropriate doses required to bring about efficacy. Combination chemotherapy has indeed evolved substantially in recent years, driven in large part by an enhanced understanding of the molecular machinery responsible for tumor growth and spread. Consequently, several aberrant pathways and overexpressed moieties have become attractive targets for therapy. As an example, the discovery that the human epidermal growth factor receptor 2 (HER2) is overexpressed in 20–30% of breast cancers resulted in the development of the antibody trastuzumab. Since its approval, trastuzumab has been used in combination with taxanes and platinum-based drugs, and is currently being explored in more than 70 different combination clinical trials. Recent efforts are also aimed at targeting dysregulated signaling cascades, such as the PI3K/Akt/mTOR pathway. Several rapamycin analogues exist that inhibit mTOR and are currently being explored clinically in combination with taxanes. Likewise, similar approaches are underway for agents that potentially target IGF, FGF, MAPK and MET pathways [2]. Combination chemotherapy regimens are thus becoming more personalized and rationally designed, pairing novel or repositioned agents that act specifically on molecular targets with traditional chemotherapeutics, all with the hope of maximizing antitumor efficacy while minimizing patient side effects. The incorporation of agents that are capable of discriminating between healthy and malignant cells indeed represents a giant leap forward in improving patient responses. However, this only partially addresses the major problem facing combination chemotherapy, which is the same age-old limitation facing single-agent therapy – delivery. The series of biological barriers that impede adequate delivery of drugs to tumor sites, including enzymatic degradation and nonspecific uptake in healthy organs, are now well known, and unfortunately remain a formidable challenge for present-day drug formulations. Importantly, this non-specificity severely limits the bioavailability of drugs at Nanoparticle-based polychemotherapy: optimizing drug synergy for efficacious cancer treatment

Background: Current chemotherapeutic strategies are not without substantial shortcomings, including non-specific drug distribution and toxicity to normal cells. Breakthroughs in the understanding of underlying molecular mechanisms of tumorigenesis has led to the discovery and design of several drugs capable of exerting effects on key targets essential for tumor propagation. Consider rapamycin and LY294002, drugs that target the PI3K/mammalian target of rapamycin (mTOR) signaling pathway, a pathway found to be dysregulated in breast cancer. The objective is to generate a nanoscale platform capable of site-specifically delivering a powerful payload of PI3K/mTOR inhibitors for the synergistic treatmentof breast tumors. The novel, injectable nanocarrier consists of three components: 1) mesoporous silicon particles (MSPs) that will be injected into the bloodstream and housing; 2) nanoparticles (polymer micelles) loaded with; 3) PI3K/mTOR inhibitors. We hypothesize that this platform will provide for enhanced bioavailability and drug synergy at tumor sites. Materials and Methods: The amphiphilic block copolymers that comprise the micelles consist of a pegylated formulation of poly(ε-caprolactone) (PEG-PCL, MW = 5k-1k). Drug-containing micelles were fabricated using a film sonication technique. The yield, loading efficiency, and percentage of loaded drug was calculated. Nanoparticle size and zeta potential was determined using dynamic light scattering (DLS), while size and morphology was corroborated via TEM. Release studies of drugs from micellar formulations was performed to determine the kinetics of release. Dried APTES-modified MSPs were incubated with the micellar formulations for ∼3 h. Nanoparticle loading and release was analyzed via HPLC. The in vitro antitumor efficacy of the platform was evaluated in MCF-7 and MDA-MB-468 breast cancer cells via a sulforhodamine B assay. Results: Micelles produced by the film sonication technique were found to have an average zeta potential of -9.29 mV, and an average diameter of 34.4 ± 2.7 nm. This size was confirmed via TEM. Drug loading densities of paclitaxel, rapamycin, and LY294002 within polymer micelles was shown to be 4.6 ± 0.4, 4.1 ± 0.6, and 3.2 ± 0.6 %, respectively. Factoring in a theoretical loading of 5% for all drugs, the loading efficiency using this procedure is very high. The release kinetics were shown to be slow for rapamycin and paclitaxel (20% release over 4 days) while very fast for LY294002 (>60%). Loading of micelles within the MSPs was shown to be approximately 40%. Upon incubation of the micelles with MCF-7 and MDA-MB-468 breast cancer cells, the multistage platform was effective at suppressing tumor growth after a 4 d incubation. Discussion: We have proposed herein a novel nanotherapeutic platform that aims to effectively target the PI-3K/mTOR pathway in breast tumors, bringing about tumor eradication by delivering drugs in a site-specific fashion in order to maximize drug synergy. We believe that the long blood circulation and the site-specific delivery afforded by the nanocarrier platform will translate in vitro synergy findings to the in vivo setting. Current work is underway to examine the in vivo efficacy of the platform. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-10.

Individualized medicine is the healthcare strategy that rebukes the idiomatic dogma of 'losing sight of the forest for the trees'. We are entering a new era of healthcare where it is no longer acceptable to develop and market a drug that is effective for only 80% of the patient population. The emergence of "-omic" technologies (e.g. genomics, transcriptomics, proteomics, metabolomics) and advances in systems biology are magnifying the deficiencies of standardized therapy, which often provide little treatment latitude for accommodating patient physiologic idiosyncrasies. A personalized approach to medicine is not a novel concept. Ever since the scientific community began unraveling the mysteries of the genome, the promise of discarding generic treatment regimens in favor of patient-specific therapies became more feasible and realistic. One of the major scientific impediments of this movement towards personalized medicine has been the need for technological enablement. Nanotechnology is projected to play a critical role in patient-specific therapy; however, this transition will depend heavily upon the evolutionary development of a systems biology approach to clinical medicine based upon "-omic" technology analysis and integration. This manuscript provides a forward looking assessment of the promise of nanomedicine as it pertains to individualized medicine and establishes a technology "snapshot" of the current state of nano-based products over a vast array of clinical indications and range of patient specificity. Other issues such as market driven hurdles and regulatory compliance reform are anticipated to "self-correct" in accordance to scientific advancement and healthcare demand. These peripheral, non-scientific concerns are not addressed at length in this manuscript; however they do exist, and their impact to the paradigm shifting healthcare transformation towards individualized medicine will be critical for its success.

Biodistribution detection methods currently hold a central role in evaluating clinical potential of new drugs and nanomedicine in vivo, either through therapeutic efficacy or toxicity assays. However, the explorative nature of these methods makes it practically difficult to validate them for clinical studies to comply with regulations as determined by the Food and Drug Administration. This work proposes a new systematic comparison of biodistribution methods to facilitate clinical validation and employment in pre-clinical and early stage clinical studies. Several optical methods (detection through IVIS, confocal microscopy, fluorescence emission), direct detection methods (detection through ICP-OES), and radiation-based methods (detection through gamma counter) are systematically tested and validated on cGMP grade microparticles. The classification here proposed quantitatively highlights the advantages and disadvantages of each method, expressing them in terms of: limit of detection, recovery rate, reproducibility, and sensitivity. As a result, this quantitative evaluation of several preclinical biodistribution detection methods leads to a new rational and objective classification of biodistribution methods based on quantitative characteristics, which is essential to facilitate clinical translation of pre-clinical data collection. Their different characteristics and application-specific advantages are also discussed based in light of the results presented. Overall, this work proposes a new and rational quantitative comparison of biodistribution detection methods with the goal to provide a guide to facilitate clinical translation of on-going and future pre-clinical and early-stage clinical studies. Citation Format: Sara Nizzero, Feng Li, Alessandro Venuta, Guodong Zhang, Carlotta Borsoi, Joy Wolfram, Junhua Mai, Haifa Shen, Zheng Li, Elvin Blanco, Mauro Ferrari. Empowering preclinical studies: A systematic and quantitative analysis of biodistribution methods to facilitate clinical translation of new drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-019.

Polymeric micelles are supramolecular, core-shell nanoparticles that offer considerable advantages for cancer diagnosis and therapy. Their relatively small size (10–100 nm), ability to solubilize hydrophobic drugs as well as imaging agents, and improved pharmacokinetics provide a useful bioengineering platform for cancer applications. Several polymeric micelle formulations are currently undergoing phase I/II clinical trials, which have shown improved antitumor efficacy and reduced systemic toxicity. This minireview will focus on recent advancements in the multifunctional design of micellar nanomedicine with tumor targeting, stimulated drug release, and cancer imaging capabilities. Such functionalization strategies result in enhanced micellar accumulation at tumor sites, higher drug bioavailability, as well as improved tumor diagnosis and visualization of therapy. Ultimately, integrated nanotherapeutic systems (e.g., theranostic nanomedicine) may prove essential to address the challenges of tumor heterogeneity and adaptive resistance to achieve efficacious treatment of cancer.

Purpose: β-Lapachone (ARQ 501, a formulation of β-lapachone complexed with hydroxypropyl-β-cyclodextrin) is a novel anticancer agent with selectivity against prostate cancer cells overexpressing the NAD(P)H:quinone oxidoreductase-1 enzyme. Lack of solubility and an efficient drug delivery strategy limits this compound in clinical applications. In this study, we aimed to develop β-lapachone–containing polymer implants (millirods) for direct implantation into prostate tumors to test the hypothesis that the combination of a tumor-specific anticancer agent with site-specific release of the agent will lead to significant antitumor efficacy. Experimental Design: Survival assays in vitro were used to test the killing effect of β-lapachone in different prostate cancer cells. β-Lapachone release kinetics from millirods was determined in vitro and in vivo. PC-3 prostate tumor xenografts in athymic nude mice were used for antitumor efficacy studies in vivo. Results: β-Lapachone killed three different prostate cancer cell lines in an NAD(P)H:quinone oxidoreductase-1–dependent manner. Upon incorporation of solid-state inclusion complexes of β-lapachone with hydroxypropyl-β-cyclodextrin into poly(d,l-lactide-co-glycolide) millirods, β-lapachone release kinetics in vivo showed a burst release of ∼0.5 mg within 12 hours and a subsequently sustained release of the drug (∼0.4 mg/kg/d) comparable with that observed in vitro. Antitumor efficacy studies showed significant tumor growth inhibition by β-lapachone millirods compared with controls (P < 0.0001; n = 10 per group). Kaplan-Meier survival curves showed that tumor-bearing mice treated with β-lapachone millirods survived nearly 2-fold longer than controls, without observable systemic toxicity. Conclusions: Intratumoral delivery of β-lapachone using polymer millirods showed the promising therapeutic potential for human prostate tumors.

To overcome multidrug resistance (MDR) existing in tumor chemotherapy, polymeric micelles encoded with folic acid on the micelle surface were prepared with the encapsulation of a potent MDR modulator, FG020326. The micelles were fabricated from diblock copolymers of poly(ethylene glycol) (PEG) and biodegradable poly(e-caprolactone) (PCL) with folate attached to the distal ends of PEG chains. The folate-conjugated copolymers, folate-PEG-PCL, were synthesized by multistep chemical reactions. First, allyl-terminated copolymer (allyl-PEG-PCL) was synthesized through a ring-opening polymerization of e-caprolactone in bulk employing monoallyl-PEG as a macroinitiator. Second, the allyl terminal groups of copolymers were converted into primary amino groups by a radical addition reaction, followed by conjugation of the carboxylic group of folic acid. In vitro studies at 37°C demonstrated that FG020326 release from micelles at pH 5.0 was faster than that at pH 7.4. Cytotoxicity studies with MTT assays indicated that folate-functionalized and FG020326-loaded micelles resensitized the cells approximately five times more than their folate-free counterparts (p < 0.01) in human KBv200 cells treated with vincristine (VCR). The in vitro Rhodamine 123 efflux experiment using MDR KBv200 cells revealed that when cells were pretreated with folate-attached and FG020326-loaded micelles, the P-glycoprotein (P-gp) drug efflux function was significantly inhibited. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res 2008

Previously, biodegradable polymer implants (polymer millirods) to release chemotherapeutic agents directly into tumors have been developed. The purpose of this study is to evaluate local drug distribution from these implants in liver tumors treated with radiofrequency (RF) ablation and determine if the implants provide a therapeutic improvement over RF ablation alone. Cylindrical implants were fabricated using 65% poly(D,L-lactide-co-glycolide) (PLGA), 21.5% NaCl, and 13.5% doxorubicin. Control or drug-containing millirods were implanted inside VX2 liver tumors (11 mm diameter) in rabbits after RF ablation. Therapeutic efficacy was assessed 4 and 8 days after treatment using tumor size, histology, and fluorescence measurement of drug distribution. Tumors in both test groups recurred at the boundary of the ablated region. Therapeutic doxorubicin concentrations were found in more than 80% of the ablated area, but concentrations declined rapidly at the boundary between normal and ablated tissue. This region was characterized by a developing fibrous capsule with resolving inflammation, which restricted drug transport out of the ablated zone. The intratumoral doxorubicin implants delivered high concentrations of drug within the ablated region but only limited amounts outside the ablation zone. Future studies will focus on overcoming the fibrotic transport barrier and enhancing drug delivery to the periphery of the ablation region to prevent tumor progression.

The purpose of this study was to evaluate the antitumor efficacy and local drug distribution from doxorubicin-containing poly(D,L-lactide-co-glycolide) (PLGA) implants for intratumoral treatment of liver cancer in a rabbit model. Cylindrical polymer millirods (length 8 mm, diameter 1.5 mm) were produced using 65% PLGA, 21.5% NaCl, and 13.5% doxorubicin. These implants were placed in the center of VX2 liver tumors (n = 16, 8 mm in diameter) in rabbits. Tumors were removed 4 and 8 days after millirod implantation, and antitumor efficacy was assessed using tumor size measurements, tumor histology, and fluorescent measurement of drug distribution. The treated tumors were smaller than the untreated controls on both day 4 (0.17 +/- 0.06 vs. 0.31 +/- 0.08 cm(2), p = 0.048) and day 8 (0.14 +/- 0.04 vs. 1.8 +/- 0.8 cm(2), p = 0.025). Drug distribution profiles demonstrated high doxorubicin concentrations (>1000 microg/g) at the tumor core at both time points and drug penetration distances of 2.8 and 1.3 mm on day 4 and 8, respectively. Histological examination confirmed necrosis throughout the tumor tissue. Biodegradable polymer millirods successfully treated the primary tumor mass by providing high doxorubicin concentrations to the tumor tissue over an eight day period.

Polymer micelles are rapidly becoming a powerful nanomedicine platform for cancer therapeutic applications due to their small size (10-100 nm), in vivo stability, ability to solubilize water insoluble anticancer drugs, and prolonged blood circulation times. Recent data from clinical trials with three micelle formulations have highlighted these and other pharmacokinetic advantages with reduced systemic toxicity and patient morbidity compared to conventional drug formulation. While the initial anti-tumor efficacy of these systems seems promising, a strong research impetus has been placed on micelle functionalization in order to achieve tumor targeting and site-specific drug release, with the hope of reaching a more pronounced tumor response. Hence, the purpose of this review is to draw attention to the new developments of multi-functional polymer micelles for cancer therapy with special focus on tumor targeting and controlled drug release strategies.

Frequent mass exchange takes place in a heterogeneous environment among several phases, where mass partitioning may occur at the interface of phases. Analytical and computational methods for diffusion do not usually incorporate molecule partitioning masking the true picture of mass transport. Here we present a computational finite element methodology to calculate diffusion mass transport with a partitioning phenomenon included and the analysis of the effects of partitioning. Our numerical results showed that partitioning controls equilibrated mass distribution as expected from analytical solutions. The experimental validation of mass release from drug-loaded nanoparticles showed that partitioning might even dominate in some cases with respect to diffusion itself. The analysis of diffusion kinetics in the parameter space of partitioning and diffusivity showed that partitioning is an extremely important parameter in systems, where mass diffusivity is fast and that the concentration of nanoparticles can control payload retention inside nanoparticles. The computational and experimental results suggest that partitioning and physiochemical properties of phases play an important, if not crucial, role in diffusion transport and should be included in the studies of mass transport processes.

Aims Ongoing inflammation and endothelial dysfunction occurs within the local microenvironment of heart failure, creating an appropriate scenario for successful use and delivery of nanovectors. This study sought to investigate whether cardiovascular cells associate, internalize, and traffic a nanoplatform called mesoporous silicon vector (MSV), and determine its intravenous accumulation in cardiac tissue in a murine model of heart failure. Methods and results In vitro cellular uptake and intracellular trafficking of MSVs was examined by scanning electron microscopy, confocal microscopy, time-lapse microscopy, and flow cytometry in cardiac myocytes, fibroblasts, smooth muscle cells, and endothelial cells. The MSVs were internalized within the first hours, and trafficked to perinuclear regions in all the cell lines. Cytotoxicity was investigated by annexin V and cell cycle assays. No significant evidence of toxicity was found. In vivo intravenous cardiac accumulation of MSVs was examined by high content fluorescence and confocal microscopy, with results showing increased accumulation of particles in failing hearts compared with normal hearts. Similar to observations in vitro, MSVs were able to associate, internalize, and traffic to the perinuclear region of cardiomyocytes in vivo. Conclusions Results show that MSVs associate, internalize, and traffic in cardiovascular cells without any significant toxicity. Furthermore, MSVs accumulate in failing myocardium after intravenous administration, reaching intracellular regions of the cardiomyocytes. These findings represent a novel avenue to develop nanotechnology-based therapeutics and diagnostics in heart failure.