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In this review, we emphasize on evolving therapeutic strategies and advances in the treatment of breast cancer (BC). This includes small-molecule inhibitors under preclinical and clinical investigation, phytoconstituents with antiproliferative potential, targeted therapies as antibodies and antibody-drug conjugates (ADCs), vaccines as immunotherapeutic agents and peptides as a novel approach inhibiting the interaction of oncogenic proteins. We provide an update of molecules under different phases of clinical investigation which aid in the identification of loopholes or shortcomings that can be overcomed with future breast cancer research.

Gliomas are highly lethal forms of cancers occurring in the brain. Delivering the drugs into the brain is a major challenge to the treatment of gliomas because of the highly selectively permeable blood-brain barrier (BBB). Tapping the potential of receptor-mediated drug delivery systems using targeted nanoparticles (NPs) is a sought-after step forward toward successful glioma treatment. Several receptors are the focus of research for application in drug delivery. Low-density lipoprotein receptors (LDLR) are abundantly expressed in both healthy brains and diseased brains with a disrupted BBB. In this review, we discuss the LDLR and the types of NPs that have been used to target the brain via this receptor.

Alzheimer's disease (AD) is a complex neurodegenerative disease leading to progressive loss of memory that mainly affects people above 60 years of age. It is one of the leading causes of deaths in the USA. Given its inherent heterogeneity and a still-incomplete understanding of its pathology, biomarkers, and targets available for therapy, it is a challenge to design an effective therapeutic strategy. Several hypotheses have been proposed to understand the disease and to identify reliable markers and targets for treatments. However, none have resulted in strong support from clinical trials. In this review, we objectively discuss the various therapeutic strategies and mechanistic approaches to improve the current clinical outcome of AD therapy.

The delivery of noncoding (nc)RNA to target cancer stem cells and metastatic tumors has shown many positive outcomes, resulting in improved and more efficient treatment strategies. The success of therapeutic RNA depends solely on passing cellular barriers to reach the target site, where it binds to the mRNA of the interest. By 2018, 20 clinical trials had been initiated, most focusing on cancer and diabetes, with some progressing to Phase II clinical trials testing the safety and efficacy of small interfering (si)RNA. Many challenges limit RNA interference (RNAi) and miRNA usage in vivo; therefore, various approaches have been developed to promote ncRNA efficiency and stability. In this review, we focus on targeting the tumor microenvironment (TME) via the modification of delivery systems utilizing nanotechnology-based delivery approaches.

Methicillin-resistant Staphylococcus aureus (MRSA), commonly called a superbug, is a highly alarming antibiotic-resistant population of Staphylococcus aureus (S. aureus) bacteria. Vancomycin (VAN) was first approved by the FDA in 1988, and it is still regarded as the treatment of choice for MRSA. The efficacy of VAN treatment has become less effective due to the development of VAN resistance in MRSA and the potential for nephrotoxicity. This study aims to improve the efficacy of VAN treatment by identifying the folate receptor for MRSA infected tissues and developing folate decorated lipid nanoparticles containing VAN (LVAN). In comparison to conventional VAN, LVAN showed a higher bactericidal effect and a superior ability to inhibit biofilm in MRSA with an enhanced accumulation in MRSA infected thigh tissues and a reduced accumulation in kidney. The results suggested that LVAN is a promising candidate to overcome the current limitations of bacterial resistance and adverse side effects in kidneys found in VAN.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with the lowest survival rate among all solid tumors. The lethality of PDAC arises from late detection and propensity of the tumor to metastasize and develop resistance against chemo and radiation therapy. A highly complex tumor microenvironment composed of dense stroma, immune cells, fibroblast, and disorganized blood vessels, is the main obstacle to current PDAC therapy. Despite the tremendous success of immune checkpoint inhibitors (ICIs) in cancers, PDAC remains one of the poorest responders of ICIs therapy. The immunologically "cold" phenotype of PDAC is attributed to the low mutational burden, high infiltration of myeloid-derived suppressor cells and T-regs, contributing to a significant immunotherapy resistance mechanism. Thus, the development of innovative strategies for turning immunologically "cold" tumor into "hot" ones is an unmet need to improve the outcome of PDAC ICIs therapies. Other smart strategies, such as nanomedicines, sonic Hedgehog inhibitor, or smoothened inhibitor, are discussed to enhance chemotherapeutic agents' efficiency by disrupting the PDAC stroma. This review highlights the current challenges and various preclinical and clinical strategies to overcome current PDAC therapy difficulties, thus significantly advancing PDAC research knowledge.

Cancer is the second highest cause of death worldwide. Several therapeutic approaches, such as conventional chemotherapy, antibodies and small molecule inhibitors and nanotherapeutics have been employed in battling cancer. Amongst them, nanotheranostics is an example of successful personalized medicine bearing dual role of early diagnosis and therapy to cancer patients. In this review, we have focused on various types of theranostic polymer and metal nanoparticles for their role in cancer therapy and imaging concerning their limitation, future application such as dendritic cell cancer vaccination, gene delivery, T-cell activation and immune modulation. Also, some of the recorded patent applications and clinical trials have been illustrated. The impact of the biological microenvironment on the biodistribution and accumulation of nanoparticles have been discussed.

Immunotherapy has gathered momentum in the advanced generation of cancer therapeutics. Many unresectable resistant tumor subtypes are ideal candidates for immunotherapy; however, the efficacy is limited because of heterogeneity of both malignant cells and non-malignant cells of the tumor microenvironment, including stromal and immune cells. The success of immunotherapy is largely dependent on the population of individual immune cell types between patients of the same tumor subtype, and the expression of biomarkers that are expressed by the components of the immune system. Hence, it is imperative to first identify the components of the immune system, visualize these populations in the tumor microenvironment, and then devise specifically targeted immunotherapies. In this review, we have outlined strategies to characterize the cellular components of the immune system with clinically relevant imaging modalities. The importance of high dimensional analyses including mass cytometry and unbiased single-cell RNA sequence analysis in visualizing the ideal candidates for immunotherapy has been discussed. This review stresses the importance of immuno-imaging as a means to further develop targeted immunotherapies for cancer.

The coronaviruses have caused severe acute respiratory syndrome (SARS), the Middle East respiratory syndrome (MERS), and the more recent coronavirus pneumonia (COVID‐19). The global COVID‐19 pandemic requires urgent action to develop anti‐virals, new therapeutics, and vaccines. In this review, we discuss potential therapeutics including human recombinant ACE2 soluble, inflammatory cytokine inhibitors, and direct anti‐viral agents such as remdesivir and favipiravir, to limit their fatality. We also discuss the structure of the SARS‐CoV‐2, which is crucial to the timely development of therapeutics, and previous attempts to generate vaccines against SARS‐CoV and MERS‐CoV. Finally, we provide an overview of the role of nanotechnology in the development of therapeutics as well as in the diagnosis of the infection. This information is key for computational modeling and nanomedicine‐based new therapeutics by counteracting the variable proteins in the virus. Further, we also try to effectively share the latest information about many different aspects of COVID‐19 vaccine developments and possible management to further scientific endeavors., The role of nanotechnology in the detection and the therapeutics of the COVID‐19. The image was created with biorender.com.

Brain cancer effected around estimated 23 890 adults and 3540 children under the age of 15 in 2020. The chemotherapeutic agents that are already approved by the FDA for brain cancer are proving to be not highly effective because of the interference from the tumor microenvironment as well as their own toxicities. Added to this is the impedance presented by the extremely restrictive permeability of the blood brain barrier (BBB). Targeted nanoparticulate drug delivery systems offer a good opportunity to traverse the BBB and selectively target the tumor cells. Folate receptors are found to be one of the most useful targets for drug delivery to the brain. Hence, this Mini-Review discusses the folate receptors and their application in the treatment of brain cancers using targeted nanoparticles.

Gliomas constitute about 80% of brain tumors and have a meager two-year survival rate. The treatment options available are very few because of poor prognosis and a lack of targeted nanodelivery systems that can cross the blood-brain barrier (BBB) and the blood-tumor barrier. This short review attempts to clarify the challenges for delivery systems designed to cross the BBB, and provides a brief description of the different types of targeted nanodelivery system that have shown potential for success in delivering drugs to the brain. Further, this review describes the most recent studies that have developed nanoparticles for brain delivery in the past five years. We also provide an insight into the most recent clinical trials designed to assess the efficacy of these nanodelivery systems for glioma.

Simple Summary Photodynamic therapy (PDT) has been undertaken with growing focus in recent studies to identify successful anticancer therapies. The field of PDT has evolved rapidly and is continuously being evaluated with new techniques. To make PDT more active and selective, molecular strategies are being developed. In the latest clinical studies on the use of PDT, some challenges are presented. Therefore, the use of nanotechnology-based approaches as delivery tools for PSs may improve their cancer cellular uptake and their toxic properties, as well as the PDT’s therapeutic impact. In addition, photoimmunotherapy (PIT) and photothermal therapy (PTT) might have a significant impact on solid tumor therapeutic strategies. Abstract Current research to find effective anticancer treatments is being performed on photodynamic therapy (PDT) with increasing attention. PDT is a very promising therapeutic way to combine a photosensitive drug with visible light to manage different intense malignancies. PDT has several benefits, including better safety and lower toxicity in the treatment of malignant tumors over traditional cancer therapy. This reasonably simple approach utilizes three integral elements: a photosensitizer (PS), a source of light, and oxygen. Upon light irradiation of a particular wavelength, the PS generates reactive oxygen species (ROS), beginning a cascade of cellular death transformations. The positive therapeutic impact of PDT may be limited because several factors of this therapy include low solubilities of PSs, restricting their effective administration, blood circulation, and poor tumor specificity. Therefore, utilizing nanocarrier systems that modulate PS pharmacokinetics (PK) and pharmacodynamics (PD) is a promising approach to bypassing these challenges. In the present paper, we review the latest clinical studies and preclinical in vivo studies on the use of PDT and progress made in the use of nanotherapeutics as delivery tools for PSs to improve their cancer cellular uptake and their toxic properties and, therefore, the therapeutic impact of PDT. We also discuss the effects that photoimmunotherapy (PIT) might have on solid tumor therapeutic strategies.

Methicillin-resistant Staphylococcus aureus (MRSA) causes serious infections in both community and hospital settings, with high mortality rates. Treatment of MRSA infections is challenging because of the rapidly evolving resistance mechanisms combined with the protective biofilms of S. aureus. Together, these characteristic resistance mechanisms continue to render conventional treatment modalities ineffective. The use of nanoformulations with unique modes of transport across bacterial membranes could be a useful strategy for disease-specific delivery. In this review, we summarize treatment approaches for MRSA, including novel techniques in nanoparticulate designing for better therapeutic outcomes; and facilitate an understanding that nanoparticulate delivery systems could be a robust approach in the successful treatment of MRSA.

Paclitaxel (PTX) encapsulated in albumin (Abraxane®) is an FDA approved frontline nano-formulation for treating advance metastatic pancreatic, lung and breast cancers. Currently in clinic, Abraxane® is being used as a one of the components of combination therapy regimens. On the other hand, difluorinated curcumin (CDF) is a novel and potent synthetic curcumin analogue that is being evaluated for several malignancies including pancreatic, liver, ovarian and breast cancers. To improve the bioavailability and targeting ability of hydrophobic PTX and CDF, we have encapsulated them in folic acid decorated bovine serum albumin nanoparticles, namely FA-BSA-PTX and FA-BSA-CDF, respectively. Both the formulations yielded uniform nano-sized particles with smooth surface morphology, negative surface potential and high drug loading efficiency. Due to heterogeneity and complexity of several cancers, combination regimens are becoming standard arsenals against several deadly cancers. To evaluate the synergistic anti-cancer effect of PTX and CDF, we assessed the combination therapy using intravenously administrable folate decorated albumin bio-conjugate nanoparticles against folate overexpressing ovarian and cervical cancers. Our results demonstrate that combination of FA-BSA-CDF with FA-BSA-PTX produced synergistic anticancer effect, augmented due to folate receptor mediated targeted uptake as well as induction of apoptosis. In conclusion, our preliminary studies show a promising nanomedicine platform for combination therapy for leading gynecological tumor, such as ovarian and cervical cancer.

Nanomedicines can be multifunctional drug delivery agents for cancer therapies. However, they have faced several challenges in clinical trials owing to poor targeting ability, insufficient tumor penetration, difficulty in synthesis and scale up, and limited understanding of interactions between a tumor and nanoparticles. In this regard, tumor muticomponent targeting drug delivery systems are a rational approach for developing tumor-site-specific therapeutics. One of the goals is to arrive at a ready-to-configure, combinatorial, reagent-free click-chemistry-based tumor multicomponent targeting nanoparticle library. The nanoparticles can be co-loaded with drugs, genes and imaging agents, surface decorated with varying targeting ligands that can home to varying tumors and/or tumor multicomponents. This library of nanocarriers could be utilized for early tumor diagnosis and therapy based on individual patient needs for personalized medicine, with a high degree of success in the clinic.

Several cancer immunotherapy approaches have been recently introduced into the clinics and they have shown remarkable therapeutic potentials. The groundbreaking cancer immunotherapeutic agents function as a stimulant or modulator of the body immune system to fight against or kill cancers. Although targeted immunotherapies such as immune check point inhibitors (CTLA-4 or PD-1/PD-L1), DNA vaccination and CAR-T therapy are revolutionizing cancer treatment, the delivery efficacy can be further improved while their off-target toxicity can be mitigated through nanotechnology approaches. Recent research has demonstrated that nanotechnology has multifaceted role for (i) reeducating tumor associated macrophages (TAM) to function as tumor suppressor agent, (ii) serving as an efficient alternative for Chimeric Antigen Receptor (CAR)-T cell generation and transduction, and (iii) selective knockdown of Kras oncogene addiction by nano-Crisper-Cas9 delivery system. The function of host immune stimulatory signals and tumor immunotherapies can further be improved by repurposing of nanomedicine platform. This review summarizes the role of multifunctional polymeric, lipid, metallic and cell based nanoparticles for improving current immunotherapy.

Antibody–drug conjugates (ADCs), a potent class of anticancer therapeutics, comprise a high-affinity antibody (Ab) and cytotoxic payload coupled via a suitable linker for selective tumor cell killing. In the initial phase of their development, two ADCs, Mylotarg®, and Adcetris® were approved by the US Food and Drug Administration (FDA) for treating hematological cancer, but the real breakthrough came with the discovery of the breast cancer-targeting ADC, Kadcyla®. With advances in bioengineering, linker chemistry, and potent cytotoxic payload, ADC technology has become a more powerful tool for targeted cancer therapy. In addition, ADCs with improved safety using humanized Abs with a unified ‘drug:antibody ratio’ (DAR) have been achieved. Concomitantly, there has been a significant increase in the number of clinical trials with anticancer ADCs with high translation potential.

Simple Summary Triple-negative breast cancer (TNBC) is one of the most challenging tumors with aggressive behavior, low recovery rate, poor prognosis, high metastatic potential, and rapid relapse compared to other breast cancer subtypes. Conventional therapies currently have minimal effect on TNBC; thus, using combination therapies is a valid strategy to enhance drug activity and minimize the overall adverse effect. Therefore, combining drugs with a different mechanism of actions such as apoptosis inducers and JAK/STAT3 inhibitors improved TNBC cell lines killing activity in vitro and in vivo. To further improve the hydrophobic drug activity, CD44 targeted polymeric nanoparticles (CD44-T-PNPs) were utilized by encapsulating hydrophobic drug (CFM-4.16) in CD44-T-PNPs to enhance the drug solubility, tumor accumulation, and most importantly, enhance drug potency. Tagging our PNPs with Hyaluronic acid (HA) enhanced tumor accumulation, reduced off-target distribution, and improved therapeutic efficacy. Abstract Identified as the second leading cause of cancer-related deaths among American women after lung cancer, breast cancer of all types has been the focus of numerous research studies. Even though triple-negative breast cancer (TNBC) represents 15–20% of the number of breast cancer cases worldwide, its existing therapeutic options are fairly limited. Due to the pivotal role of the presence/absence of specific receptors to luminal A, luminal B, HER-2+, and TNBC in the molecular classification of breast cancer, the lack of these receptors has accounted for the aforementioned limitation. Thereupon, in an attempt to participate in the ongoing research endeavors to overcome such a limitation, the conducted study adopts a combination strategy as a therapeutic paradigm for TNBC, which has proven notable results with respect to both: improving patient outcomes and survivability rates. The study hinges upon an investigation of a promising NPs platform for CD44 mediated theranostic that can be combined with JAK/STAT inhibitors for the treatment of TNBC. The ability of momelotinib (MMB), which is a JAK/STAT inhibitor, to sensitize the TNBC to apoptosis inducer (CFM-4.16) has been evaluated in MDA-MB-231 and MDA-MB-468. MMB + CFM-4.16 combination with a combination index (CI) ≤0.5, has been selected for in vitro and in vivo studies. MMB has been combined with CD44 directed polymeric nanoparticles (PNPs) loaded with CFM-4.16, namely CD44-T-PNPs, which selectively delivered the payload to CD44 overexpressing TNBC with a significant decrease in cell viability associated with a high dose reduction index (DRI). The mechanism underlying their synergism is based on the simultaneous downregulation of P-STAT3 and the up-regulation of CARP-1, which has induced ROS-dependent apoptosis leading to caspase 3/7 elevation, cell shrinkage, DNA damage, and suppressed migration. CD44-T-PNPs showed a remarkable cellular internalization, demonstrated by uptake of a Rhodamine B dye in vitro and S0456 (NIR dye) in vivo. S0456 was conjugated to PNPs to form CD44-T-PNPs/S0456 that simultaneously delivered CFM-4.16 and S0456 parenterally with selective tumor targeting, prolonged circulation, minimized off-target distribution.

Worldwide, the cancer appeared as one of the most leading cause of morbidity and mortality. Among the various cancer types, brain tumors are most life threatening with low survival rate. Every year approximately 238,000 new cases of brain and other central nervous system tumors are diagnosed. The dendrimeric approaches have a huge potential for diagnosis and treatment of brain tumor with targeting abilities of molecular cargoes to the tumor sites and the efficiency of crossing the blood brain barrier and penetration to brain after systemic administration. The various generations of dendrimers have been designed as novel targeted drug delivery tools for new therapies including sustained drug release, gene therapy, and antiangiogenic activities. At present era, various types of dendrimers like PAMAM, PPI, and PLL dendrimers validated them as milestones for the treatment and diagnosis of brain tumor as well as other cancers. This review highlights the recent research, opportunities, advantages, and challenges involved in development of novel dendrimeric complex for the therapy of brain tumor.

We present a case of a 49-year-old woman diagnosed with aquaporin-4 antibody-positive transverse myelitis, who developed a significant transaminitis 2 months after commencing mycophenolate mofetil (MMF) as a steroid-sparing agent. No other risk factors were identified, a blood liver panel was negative and liver biopsy showed features compatible with drug-induced liver injury (DILI). MMF was stopped with a corresponding normalisation of serum alanine aminotransferase over the next 2 months. This case highlights MMF as a rare cause of DILI and provides justification for monitoring of liver biochemistry on therapy.

Immune checkpoint blockade molecules, including antibodies against PD-1 and PD-L1 have gained much clinical recognition in the past few years. These strategies include harnessing the host's immune system to invade cancer cells by inhibiting the interaction between PD-1 and its ligand, PD-L1, thereby facilitating the activation of CD8+ T cells to mount an attack on cancer cells. Triple Negative Breast Cancer (TNBC) accounts for 10-20% of the total breast carcinoma cases. There is no FDA-approved targeted therapy for TNBC due to lack of the major biomarkers: estrogen, progesterone and HER-2. TNBC is difficult to treat, with a high rate of metastasis to nearby organs. We have identified the role of a hypoxia biomarker, carbonic anhydrase IX (CAIX) in proliferation and metastasis of TNBC. Based on this observation, we developed a CAIX-targeted Doxorubicin (Dox) prodrug nanoparticle, abbreviated as CAIX-Dox-NP. CAIX-Dox-NP can deliver the chemotherapeutic, Dox payload selectively in hypoxic tumor microenvironment, thus reducing Dox-associated cardiotoxicity. Most of the advanced stages TNBC solid tumors present themselves with oxygen-deficient, vascularized and matrix-rich core which is impermeable to most of the chemotherapy drugs. CAIX-Dox-NP has the ability to penetrate deep into the TNBC and kill epithelial tumor cells as well as tumor-growth promoting T-cells. CAIX-Dox-NP showed greater penetration in the core of hypoxic TNBC spheroid. Recent studies showed that Immunogenic Cell Death (ICD) has vital role in resurrecting the CD8+ T-cells mediated tumor killing. Combination of anti-PD-1 with inducers of ICD like Dox accentuate the ability of CD8+ T cells in killing of cancer cells. Our approach is to utilize CAIX-Dox for achieving CAIX-mediated targeted delivery and multimodal chemotherapy in addition to induction of ICD. Preliminary studies with CAIX-Dox has profound effect of killing TNBC cells, 4T1, through induction of early phase apoptosis. The Western Blot analysis in 4T1 treated with CAIX-Dox has proved the significant upregulation of ICD biomarkers, HMGB1 and calreticulin, by greater than 3-fold compared to control. To improve the bioavailability of CAIX-Dox, we developed CAIX-Dox-NP that can hitchhike on the circulating plasma albumin. The nanoparticles travel to the tumor and deliver the CAIX-Dox at the hypoxic core of TNBC, resulting in induction of apoptosis and ICD. Inspired from this outcome, we are developing a model for coculture of cancer and T-cells for evaluating if CAIX-Dox treatment can reeducate T-cells in killing cancer cells through ICD pathway. Citation Format: Ketki Bhise, Samaresh Sau, Mohd Ahmar Rauf, Arun K. Rishi, Arun K. Iyer. Hypoxia-targeting prodrug approach for multimodal chemotherapy and immunogenic cell death in aggressive triple negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6263.

Pancreatic ductal adenocarcinoma (PDAC) is the third-highest cause of cancer-related death in the United States. The heterogenicity of the PDAC is a major challenge in the success of anti-PDAC therapy. PDAC is comprised of >90 % dense desmoplastic tumor stroma that impedes the delivery of drugs into the core of the tumor, resulting development of drug resistance. Thus, we developed a nanoparticle pro-drug to overcome the stromal barrier of PDAC. We utilized nanoengineering to target dual CD44 and c-Met biomarkers that have a significant role in developing drug resistance on PDAC. Western blot analysis in various PDAC cell lines, such as PANC-1, AsPc-1, and BxPc3 revealed a high abundance of CD44 and cMet, strongly supporting our hypothesis. Therefore, targeting the CD44 and c-Met biomarker and selectively delivering anti-PDAC drug is a smart strategy to improve the anti-PDAC outcome. We developed dual CD44/c-Met targeted nanoparticle, called D44M that can efficiently penetrate the core of tumor as well as home into CD44 and cMet biomarker. We evaluated tumor selectivity of the near infrared (NIR) fluorescent dye conjugated D44M, D44M-NIR in the orthotopic PDAC model. The biodistribution of D44M-NIR in orthotopic animal model proved superior tumor penetration of D44M-NIR with 7-fold higher than the control NIR dye treatment. Moreover, D44M-NIR treated showed minimum liver accumulation, suggesting an outstanding approach of overcoming nanoparticle mediated liver toxicity. Finally, the D44M was chemically conjugated with gemcitabine (GEM), namely D44M-GEM pro-drug that showed excellent PDAC killing. The PDAC cell killing study of D44M-GEM in combination with Everolimus revealed high synergistic combination effect with CI value of 0.2-0.5. The anti-PDAC therapy in ASPC-1 xenograft model demonstrated significant tumor growth inhibition for treatment of D44M-GEM and D44M-GEM+Everolimus as compared to control. Supported with data, our work provides a perspective towards the implementation of nanotherapeutic to overcome the bottleneck barrier of therapeutic delivery and efficacy of PDAC management. Citation Format: Rami Alzhrani, Samaresh Sau, Amro Aboukameel, Hashem Alsaab, Asfar Azmi, Arun Iyer. Nanoparticle pro-drug to overcome the stromal barrier in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1722.

Pancreatic cancer has very poor prognosis and has a very low five-year survival rate of the order of 5%. This is so because of the lack of major clinical symptoms and reliable detection markers. Recently, it has been realized that hypoxia is one of the major contributors to tumor growth, malignancy, invasion, propagation, metastasis, and resistance to therapy in several solid tumors including the pancreatic cancer. Understandably, it has gained even more importance in pancreatic cancer and is considered as the primary target for its therapy in the recent times since it has been identified as the major determinant of cancer malignancy.

Due to the high rate of gynecologic cancers among females, obtaining structural, functional, and molecular information from reproductive organs can potentially reveal diseases at their early stages of development . In this study, we aimed to develop a miniaturized phased-array ultrasound (US) and photoacoustic (PA) endoscope for potential imaging gynecologic cancer. The developed endoscope is built around a phased-array US transducer coupled to a fiber optic light delivery system. In particular, the proposed endoscope consists of a 64-element phased array US transducer, coupled to a light delivery system that includes six fiber optics. The probe dimensions allow for utilizing this device for imaging various types of gynecologic cancers in which the probe can become close to the pathologic tissue. Given the small imaging aperture, adaptive beamforming was developed to reconstruct co-registered US and PA images in 90-degrees sector scan format. The developed endoscope was tested in a set of tissue-mimicking phantom studies to determine its characteristics and its ability to form form co-registered volumetric US and PA images. In addition, spectroscopic PA (sPA) imaging of biocompatible, folate conjugated dye was tested to demonstrate the possibility of using the developed endoscope in imaging PA molecular contrast agents.

Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeting and codelivery of small interfering RNA (siRNA) and doxorubicin, and to overcome multidrug resistance, we conjugated a cholic acid-polyethylenimine polymer with folic acid, forming CA-PEI-FA micelles. CA-PEI-FA exhibited a low critical micelle concentration (80 μM), small average particle size (150 nm), and positive zeta potential (+ 12 mV). They showed high entrapment efficiency for doxorubicin (61.2 ± 1.7%, w/w), forming D-CA-PEI-FA, and for siRNA, forming D-CA-PEI-FA-S. X-ray photoelectron spectroscopic analysis revealed the presence of external FA on D-CA-PEI-FA micelles. About 25% doxorubicin was released within 24 h at pH 7.4, while more than 30% release was observed at pH 5. The presence of FA enhanced micelle antitumor activity. The D-CA-PEI-FA and D-CA-PEI-FA-S micelles inhibited tumor growth in vivo. No significant differences between their in vitro cytotoxic activities or their in vivo antitumor effects were observed, indicating that the siRNA coloading did not significantly increase the antitumor activity. Histological analysis revealed that tumor tissues from mice treated with D-CA-PEI-FA or D-CA-PEI-FA-S showed the lowest cancer cell density and the highest levels of apoptosis and necrosis. Similarly, the livers of these mice exhibited the lowest level of dihydropyrimidine dehydrogenase among all treated groups. The lowest serum vascular endothelial growth factor level (VEGF) (24.4 pg/mL) was observed in mice treated with D-CA-PEI-FA-S micelles using siRNA targeting VEGF. These findings indicated that the developed CA-PEI-FA nanoconjugate has the potential to achieve targeted codelivery of drugs and siRNA.

In the last couple of decades antioxidant agents have entered the health market as an easy and attractive means of managing diseases. These agents are of enormous interest for an increasingly health-concerned society, and may be particularly relevant for prophylaxis of a number of diseases i.e. arthritis, cancer, metabolic and cardiovascular diseases, osteoporosis, cataracts, brain disorders, etc. Antioxidants are also favorable to vascular healthiness and symbolize useful compounds because they are able to diminish overall cardiovascular risk by acting analogous to first line therapy or as adjuvants in case of failure or in situations where first line therapy cannot be used. Furthermore, well-designed trials are indeed needed to improve the therapeutic efficacy and health benefits of antioxidants. Numerous in vivo proof-of-concepts studies are offered to underline the feasibility of nanostructure system in order to optimizing the delivery of cardiovascular drugs. The present review highlights the recent approaches for management of cardiovascular disease using different vesicular and particulate carriers, including liposomes, nanoparticles, and nanoemulsions, with a primary emphasis on those which are expected to enhance the antioxidants level.

Several cancers are highly refractory to conventional chemotherapy. The survival of tumors in several cases is assisted by checkpoint immunomodulation to maintain the imbalance between immune surveillance and cancer cell proliferation. Check point antibody inhibitors, such as anti-PD-1/PD-L1, are a novel class of inhibitors that function as a tumor suppressing factor via modulation of immune cell-tumor cell interaction. These checkpoint blockers are rapidly becoming a highly promising cancer therapeutic approach that yields remarkable antitumor responses with limited side effects. In recent times, more than four check point antibody inhibitors have been commercialized for targeting PD-1, PDL-1, and CTLA-4. Despite the huge success and efficacy of the anti-PD therapy response, it is limited to specific types of cancers, which attributes to the insufficient and heterogeneous expression of PD-1 in the tumor microenvironment. Herein, we review the current landscape of the PD-1/PD-L1 mechanistic role in tumor immune evasion and therapeutic outcome for cancer treatment. We also review the current progress in clinical trials, combination of drug therapy with immunotherapy, safety, and future of check point inhibitors for multiple types of cancer.

Cancer remains a major killer of mankind. Failure of conventional chemotherapy has resulted in recurrence and development of virulent multi drug resistant (MDR) phenotypes adding to the complexity and diversity of this deadly disease. Apart from displaying classical physiological abnormalities and aberrant blood flow behavior, MDR cancers exhibit several distinctive features such as higher apoptotic threshold, aerobic glycolysis, regions of hypoxia, and elevated activity of drug-efflux transporters. MDR transporters play a pivotal role in protecting the cancer stem cells (CSCs) from chemotherapy. It is speculated that CSCs are instrumental in reviving tumors after the chemo and radiotherapy. In this regard, multifunctional nanoparticles that can integrate various key components such as drugs, genes, imaging agents and targeting ligands using unique delivery platforms would be more efficient in treating MDR cancers. This review presents some of the important principles involved in development of MDR and novel methods of treating cancers using multifunctional-targeted nanoparticles. Illustrative examples of nanoparticles engineered for drug/gene combination delivery and stimuli responsive nanoparticle systems for cancer therapy are also discussed.

The interplay between cancer and inflammation has been well documented over the years and the role of nanomedical technologies for treating both these diseases has become evident over the past few decades. With the advances in nanoparticle-based imaging and therapeutic platforms that can exploit the pathological conditions of the tumor and the inflamed sites to effectively deliver drugs, genes and imaging/contrast agents; the management of such conditions with favorable therapeutic outcomes seems plausible. This review will summarize some of the latest advances in the field of targeted nanomedicine development to combat cancer and inflammation. Illustrative examples of multifunctional-targeted nanosystems are presented that highlight their potential in delivering diverse payloads, including small molecule drugs, nucleic acids and imaging agents for simultaneous theranostic interventions.

A new concept for cancer screening has been preliminarily investigated. A cancer targeting agent loaded with a near-infrared (NIR) dye was topically applied on the tissue to highlight cancer-suspect locations and guide optical coherence tomography (OCT) imaging, which was used to further investigate tissue morphology at the micron scale. A pilot study on ApcMin mice has been performed to preliminarily test this new cancer screening approach. As a cancer-targeting agent, poly(epsilon-caprolactone) microparticles (PCLMPs), labeled with a NIR dye and functionalized with an RGD (argenine-glycine-aspartic acid) peptide, were used. This agent recognizes the α(ν)β(3) integrin receptor (ABIR), which is over-expressed by epithelial cancer cells. The contrast agent was administered topically in vivo in mouse colon. After incubation, the animals were sacrificed and fluorescence-guided high resolution optical coherence tomography (OCT) imaging was used to visualize colon morphology. The preliminary results show preferential staining of the abnormal tissue, as indicated by both microscopy and laser-induced fluorescence imaging, and OCT's capability to differentiate between normal mucosal areas, early dysplasia, and adenocarcinoma. Although very preliminary, the results of this study suggest that fluorescence-guided OCT imaging might be a suitable approach for cancer screening. If successful, this approach could be used by clinicians to more reliably diagnose early stage cancers in vivo.

Human antibodies targeting all subtypes of mesothelioma could be useful to image and treat this deadly disease. Here we report tumor targeting of a novel internalizing human single chain antibody fragment (scFv) labeled with 99mTc (99mTc-M40) in murine models of mesothelioma of both epithelioid (M28) and sarcomatoid (VAMT-1) origins. 99mTc-M40 was taken up rapidly and specifically by both subtype tumor cells in vitro, with 68% to 92% internalized within 1 hour. The specificity of binding was evidenced by blocking (up to 95%) with 10-fold excess of unlabeled M40. In animal studies, tumors of both subtypes were clearly visualized by SPECT/CT as early as 1 hour postinjection of 99mTc-M40. Tumor uptake measured as percent of injected dose per gram tissue (%ID/g) at 3 hours was 4.38 and 5.84 for M28 and VAMT-1 tumors, respectively, significantly greater than all organs or tissues studied (liver, 2.62%ID/g; other organs or tissues

Background Biofilms are sophisticated communities of matrix-encased and surface-attached bacteria that exhibit a distinct and specific resistant/tolerant phenotype to almost all antibacterial agents, with activity reduced 10- to 1,000-fold. Interestingly, this augmented resistance rapidly reverts when bacteria detach from the biofilm and return to a planktonic state. However, in this in vitro pharmacokinetic and pharmacodynamic (PK/PD) model we are able to expose biofilms to shear rates that are consistent with human interface and mimic antibiotic penetration and diffusion pathways from serum antibiotic concentration in humans. Methods Methicillin-susceptible ATCC 29213 and MRSA 494 strains were evaluated. Initial susceptibility tests were performed by broth microdilution method. Time kill studies were performed to identify synergy patterns for liposomal and commercial antibiotics. Biofilm eradication was investigated using antibiotics vancomycin (VAN) (commercial) vs. liposomal VAN (VAN-L) (Patent#17-1460) and also combination of VAN- cefazolin (commercial) vs. liposomal vancomycin and liposomal cefazolin (CFZ-L) (Patent# 17-1460) in biofilms for strain MRSA 494. Biofilms were generated overnight using the BioFlux Microfluidic system (Fluxion BioSciences) at constant and continuous shear rates to optimize biofilm attachment and creation. Perfusion of antibiotic solutions (free peak concentration) was applied over a 24 h time period. Time lapse pictures were recorded to determine antibiotic biofilm eradication rates over 18h of incubation and pictures were analyzed using Bioflux Montage software. Results MIC values demonstrated a 2-fold reduction for liposomal vancomycin vs. commercial vancomycin. Also, combination of liposomal VAN MIC in presence of CFZ-L showed a 15.87-fold reduction in comparison to commercial VAN for 494. Overall, our biofilm results demonstrated a 43.6% improved eradication using VAN-L and CFZ-L combination in comparison to commercial VAN-CFZ combination. We also observed 5.7% improved eradication using VAN-L vs. commercial VAN. Conclusion Liposomal form of VAN and CFZ combinations are a promising approach to improved efficacy and reduced VAN resistance in S. aureus biofilms. Disclosures M. J. Rybak, Allergan: Consultant, Grant Investigator and Speaker’s Bureau, Research grant and Research support. Achaogen: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Bayer: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Melinta: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Theravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Sunovian: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Zavante: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. NIAID: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support.

Renal cell carcinoma (RCC) is very difficult to treat as the cells are mostly resistant to many current therapies. Therefore, newer treatments including better ways of drug delivery are urgently needed to fight this malignant disease efficiently. The ongoing work was done by generating and characterizing RCC cells that are resistant to everolimus, a front-line mTOR-targeted therapy, and tested whether a class of CARP-1 functional mimetic (CFM) compounds inhibits parental and everolimus-resistant RCCs in combination with sorafenib. CFMs inhibited RCC cell viability in a dose-dependent manner that was comparable to everolimus treatments as well as the combination with sorafenib. CFM-4.16 inhibited viabilities of everolimus-resistant RCC cells, albeit CFM-4.16 combined with sorafenib was more effective than CFM-4.16 alone. CFM-dependent loss of RCC cell viabilities was due in part to reduced cyclin B1 levels, activation of pro-apoptotic, stress-activated protein kinases (SAPKs), and apoptosis. However, CFMs and sorafenib are hydrophobic, and their dose escalation for in vivo studies remains challenging. We addressed the solubility and delivery concerns of CFM-4.16 and sorafenib by utilizing a nanotechnology-based approach. Our data thus far revealed that we have been successful in overcoming the solubility concerns of CFM-4.16 and sorafenib by encapsulating it in water-soluble vitamin E TPGS-based micellar nanoformulation that enables high drug loading and affords its intravenous administration for animal testing. We also use our polymeric NPs formulation for in vitro efficacy in parental, wild-type and everolimus-resistant RCC. After confirming the anticancer activity of CFM-4.16-loaded nanoformulations in vitro, we finally examined the intravenous (i.v.) administration of the CFM-4.16-loaded polymeric NPs in a clinically relevant RCC mouse model. The CFM-4.16 formulation inhibited the viability of parental and everolimus-resistant RCC cells in vitro and suppressed the growth of parental A498 RCC-cell-derived xenografts (RCC animal model), in part by stimulating apoptosis. After optimizing its potency and biologic stability, we performed imaging of animal inoculated with RCC tumor and PDX model by conjugation with NIR dye. The results showed high binding affinity and specific tumor uptake, faster normal tissue clearance and less non-target organ uptake. These findings make CFM-4.16 an important potential therapeutic in combination with sorafenib using nanoformulation in the treatment of RCCs. Citation Format: Hashem O. Alsaab, Samaresh Sau, Vino T. Cheriyan, Ulka Vaishampayan, Arun K. Rishi, Arun K. Iyer. Tumor multifunctional targeting polymeric nanomicelles with polypharmacy payload for effective therapy and imaging of resistant renal cell carcinoma [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 4107.

Renal Cell Carcinoma (RCC) contributes >90% of the most common form of kidney tumor and remains one of the ten leading causes of cancer death in the US. Tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors have increased therapeutic possibilities for treating RCC. Although the impact on disease progression is encouraging, a substantial proportion of patients do not respond adequately, and therapy resistance almost inevitably occurs. Eventually, new strategies have emerged that include immunotherapy such as PD-1 inhibitor (Nivolumab) and the combination of chemo-immune therapy. Possibly, combination treatment aimed at different, non-related pathways may be advantageous. In this regard, we would like to come up with synergistic therapeutic strategies for nonresponsive, highly aggressive tumor types to tackle the current clinical challenges. We have worked on different RCCs tumor models that in general have a poor prognosis with conventional therapies. We also pursued different combination regimens, including drugs that work on the mTOR inhibition (everolimus), inhibit RTK-inhibitor or VEGFR (cabozantinib or sorafenib). Also, there is a critical need to develop safe and effective delivery vehicles that can carry the payload to the right target tissue and cell. Thus, different types of nanoparticles have been designed to deliver a variety of therapeutic agents to target hypoxic tumor microenvironment by using carbonic anhydrase-9 (CA9); FRα for targeting cancer epithelial cells; and FRβ for targeting tumor-associated macrophages (TAM) and combination delivery of RTK-inhibitor Cabozantinib (CB) and sorafenib with our own apoptosis inducer/CARP-1 protein activator CFM-4.16 (C4.16) for overcoming drug resistance and reprograming TAM for RCC therapy. The current work also focused on multimodal approaches, including (a) Optimization of hypoxia marker conjugated targeted polymer-lipid nano-formulation (PLNP) using copper-free click chemistry; (b) In vitro and in vivo pre-clinical testing of targeted -PLNP loaded with polypharmacy in inhibiting RCCs using mice bearing resistant RCCs and patient-derived xenografts (PDX). The results of efficacy and biodistribution of targeted PLNPs in animals bearing RCC xenografts and PDX model showed higher accumulation of drugs at tumor sites with higher tumor growth inhibition. Also, the targeted formulation showed high binding affinity and specific tumor uptake, faster normal tissue clearance, and less non-target organ uptake. These findings portent promising therapeutic potential of hypoxia-targeted -PLNPs for treating RCCs. Citation Format: Hashem O. Alsaab, Samaresh Sau, Vino T. Cheriyan, Rami Alzhrani, Ulka Vaishampayan, Arun K. Rishi, Arun K. Iyer. Tumor multicomponent targeting nano-micelles with synergistic combination to overcome drug resistance and reprogramming of macrophages in renal cell carcinoma [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 3716.

The fundamental limitations of conventional cancer treatment have promoted the development and application of nanoengineering platforms for achieving effective patient outcomes. Over a time, considerable clinical success has been accomplished in nanotechnology field but there are many challenges limiting the progress of nanomedicine from bench to the beside. The highly heterogeneous tumor environment, an inadequate understanding of interactions between tumor biomarkers and nanomedicine, and reproducibility in synthesis required for clinical translation are some of the major challenges. Thus, there is an urgent need to redirect our focus of nano-drug carrier that can target multiple components of tumor including, tumor epithelial cells, tumor angiogenic vessels, tumor hypoxia and stromal cells. To achieve this, we developed a library of various tumor biomarker targeting ligands, and drug and imaging agents encapsulated in nanoparticles (NPs). Finally, the library of targeting ligands was conjugated with NPs using reagent free ‘click' chemistry. This strategy will serve as an “off-the-shelf ready to configure drug formulation" that can be engineered based on a mix-and-match strategy for individual patient needs. It is envisaged that the patient can walk in the clinic and be given the targeted drug that is personalized to their need. For the proof-of-concept, we evaluated tumor selectivity of multiple cancer biomarker targeting oligo-micelles (OMs), iron oxide and lipid NPs in various patient derived tumor xenograft (PDx) models, such as non-small cell lung and triple negative breast cancer. We observed that the dual tumor hypoxia and cancer stem cell (CSC) targeting rod shaped OM has 8-fold higher tumor core penetration compared to non-targeted OM in these PDx tumors, as obtained from NIR-fluorescence imaging. This OM has significantly higher tumor vs. liver ratio and they follow tumor specific receptor competition. The tumor growth inhibition of drug loaded OM is superior compared to free drug. This approach demonstrated significant improvement of tumor stroma penetration with low healthy organ uptake of NPs portending more promising potentials for selective cancer treatment. Citation Format: Samaresh Sau, Hashem Alsaab, Katyayani Tatiparti, Ketki Bhise, Arun Rishi, Arun K. Iyer. Tumor multicomponent targeting nanoparticle library for personalized cancer therapy & imaging [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 4660.

Antibody drug conjugates (ADCs) are a new form of targeted therapy to cancer, consisting of an antibody, a conditionally stable linker, and a cytotoxic drug. Immune checkpoint molecule, such as programmed death ligand-1 (PD-L1) overexpressed in various solid tumors including triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) and it has a crucial role in tumor immune evasion. Blocking the interaction between PD-L1 and PD-1 (programmed death-1 receptor) resurrects tumor immune surveillance, resulting CD8+ cytotoxic T cells activation to attack the tumor cells. This is an emerging anticancer mechanism and more than four antibody inhibitors have been recently FDA approved against PD-1 or PD-L1 biomarker. Targeting PD-L1 in TNBC and NSCLC is an excellent approach for tumor immunotherapy. However, the major challenges of anti-PD-L1 therapy (Atezolizumab) are (i) the transient expression of PD-L1 in tumor microenvironment, (ii) development of anti-PD-L1 resistance, (iii) difficulty of tumor stroma penetration that retard its clinical outcome. To overcome these challenges, we chemically conjugated Atezolizumab (ATZ) with potent chemotherapeutic payload, such as Doxorubicin (Dox) through polyethylene glycol (PEG) linkers. The role of Dox is to break the tumor stroma so that PD-L1 antibody can penetrate to the core of the tumor. Introduction of PEG-linker with high molecular weight ATZ (155 kD) has drastically improved the solubility of ADC and successful chemical conjugation of between ATZ and PEG-Dox was evaluated by MALDI-TOF analysis. Our data has revealed significantly tumor cell killing effect and induction of apoptosis in PD-L1-Dox treated MDA-MB-231 cells. The near infrared imaging of PD-L1 dye conjugate in TNBC and NSCLC patient derived xenograft (PDx) supports the selective tumor targetability. Based on the synergistic anticancer effect and selective tumor targetability demonstrated in this study build a strong rational of using PD-L1 ADC approach for cancer immune-chemo therapy and diagnosis. Citation Format: Samaresh Sau, Alex Petrovici, Hashem Alsaab, Arun K. Iyer. PD-L1 antibody drug conjugate for cancer immune-chemo combination therapy [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 3707.

Heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a stress-related anti-apoptotic molecule, that has been implicated in enhanced survival of neoplastic cells and in drug-resistance. We here show that Hsp32 is expressed in most solid tumors and hematopoietic neoplasms and may be employed as a new therapeutic target as evidenced by experiments using specific siRNA and a Hsp32-targeting pharmacologic inhibitor. This Hsp-32 targeting drug, SMA-ZnPP, was found to inhibit the proliferation of neoplastic cells with IC(50) values ranging between 1 and 50 microM. In addition, SMA-ZnPP induced apoptosis in all neoplastic cells examined. Furthermore, SMA-ZnPP was found to synergize with other targeted and conventional drugs in producing growth-inhibition. Resulting synergistic effects were observed in all tumor and leukemia cells examined. Interestingly, several of the drug partners, when applied as single agents, induced the expression of Hsp32 in neoplastic cells, suggesting that synergistic effects resulted from SMA-ZnPP-induced ablation of a Hsp32-mediated survival-pathway that is otherwise used by tumor cells to escape drug-induced apoptosis. Together, Hsp32 is an important survival factor and target in solid tumors and hematopoietic neoplasms, and may be used to optimize anticancer therapy by combining conventional or targeted drugs with Hsp32-inhibitors. Based on these data, it seems desirable to explore the value of Hsp32-targeting drugs as anti-cancer agents in clinical trials.

Background: Doxorubicin is a commonly used chemotherapy limited by cardiotoxicity. Pirarubicin, derived from doxorubicin, selectively targets tumors when encapsulated in styrene maleic acid (SMA), forming the macromolecular SMA pirarubicin. Selective targeting is achieved because of the enhanced permeability and retention (EPR) effect. SMA-pirarubicin inhibits the growth of colorectal liver metastases, but tumor destruction is incomplete. The role played by the tumor microcirculation is uncertain. This study investigates the pattern of microcirculatory changes following SMA-pirarubicin treatment. Methods: Liver metastases were induced in CBA mice using a murine-derived colon cancer line. SMA-pirarubicin (100 mg/kg total dose) was administered intravenously in 3 separate doses. Twenty-four hours after chemotherapy, the tumor microvasculature was examined using CD34 immunohistochemistry and scanning electron microscopy. Tumor perfusion and permeability were assessed using confocal in vivo microscopy and the Evans blue method. Results: SMA-pirarubicin reduced the microvascular index by 40%. Vascular occlusion and necrosis were extensive following treatment. Viable cells were arranged around tumor vessels. Tumor permeability was also increased. Conclusion: SMA-pirarubicin damages tumor cells and the tumor microvasculature and enhances tumor vessel permeability. However, tumor necrosis is incomplete, and the growth of residual cells is sustained by a microvascular network. Combined therapy with a vascular targeting agent may affect residual cells, allowing more extensive destruction of tumors.

CNS disorders still prevail to be one of the largest disease areas where current treatment options are limited and there has been growing interest among academia, industry, and research organizations to explore novel options to deliver therapeutics to the brain. Novel strategies encompassing invasive and noninvasive approaches for CNS delivery, to overcome physiological and technical challenges has been the current norm. CNS imaging offers improved diagnosis of disorders and techniques like X-ray computed tomography (CT), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) have proved to be promising for cerebral imaging. Combinations of functional and structural imaging modalities such as PET/MRI and SPECT/MRI are known to be used for preclinical and clinical imaging. The concept of image-guided targeted delivery of therapeutics to the CNS is seen to be an effective strategy to compliment the current diagnosis regimen with a therapeutic end goal. Combination of nanoparticulate drug delivery with an imaging component has shown initial promise to improve targeting of therapeutics to the CNS.

One of the most challenging aspects of lung cancer therapy is the rapid acquisition of multidrug-resistant (MDR) phenotype. One effective approach would be to identify and downregulate resistance-causing genes in tumors using small interfering RNAs (siRNAs) to increase the sensitivity of tumor cells to chemotherapeutic challenge. After identifying the overexpressed resistance-related antiapoptotic genes (survivin and bcl-2) in cisplatin-resistant cells, the siRNA sequences were designed and screened to select the most efficacious candidates. Modifications were introduced in them to minimize off-target effects. Subsequently, the combination of siRNA and cisplatin that gave the maximum synergy was identified in resistant cells. We then demonstrated that the combination treatment of the selected siRNAs and cisplatin encapsulated in CD44-targeting hyaluronic acid (HA)-based self-assembling nanosystems reversed the resistance to cisplatin and delayed the tumor growth significantly (growth inhibition increased from 30 to 60%) in cisplatin-resistant tumors. In addition, no abnormalities in body weights, liver enzyme levels or histopathology of liver/spleen tissues were observed in any of the treatment groups during the study period. Overall, we demonstrate that the combination of siRNA-mediated gene-silencing strategy with chemotherapeutic agents constitutes a valuable and safe approach for the treatment of MDR tumors.Molecular Therapy-Nucleic Acids (2013) 2, e110; doi:10.1038/mtna.2013.29; published online 30 July 2013.

The toxicity of anticancer agents and the difficulty in delivering drugs selectively to tumor cells pose a challenge in overcoming multidrug resistance (MDR). Recently, nanotechnology has emerged as a powerful tool in addressing some of the barriers to drug delivery, including MDR in cancer, by utilizing alternate routes of cellular entry and targeted delivery of drugs and genes. However, it is unclear whether doxorubicin (Dox) can be delivered by nanotechnologic approaches.We asked whether (1) Dox-loaded lipid-functionalized dextran-based biocompatible nanoparticles (Dox/NP) can reverse MDR, (2) Dox/NP has more potent cytotoxic effect on MDR tumors than poly(ethylene glycol)-modified liposomal Dox (PLD), and (3) multidrug resistance protein 1 (MDR1) small interfering RNA loaded in these nanoparticles (siMDR1/NP) can modulate MDR.To create stable Dox/NP and siMDR1/NP, we used two different lipid-modified dextran derivatives. The effect of Dox or Dox/NP was tested on drug-sensitive osteosarcoma (KHOS) and ovarian cancer (SKOV-3) cell cultures in triplicate and their respective MDR counterparts KHOS(R2) and SKOV-3(TR) in triplicate. We determined the effects on drug retention, transfection efficacy of siMDR1/NP, and P-glycoprotein expression and the antiproliferative effect between Dox/NP and PLD in MDR tumor cells.Fluorescence microscopy revealed efficient uptake of the Dox/NP and fluorescently tagged siMDR1/NP. Dox/NP showed five- to 10-fold higher antiproliferative activity at the 50% inhibitory concentration than free Dox in tumor cells. Dox/NP showed twofold higher activity than PLD in MDR tumor cells. siMDR1/NP (100 nM) suppressed P-glycoprotein expression in KHOS(R2).Dextran-lipid nanoparticles are a promising platform for delivering Dox and siRNAs.Biocompatible dextran-based nanoparticles that are directly translatable to clinical medicine may lead to new potential therapeutics for reversing MDR in patients with cancer.

Current challenges in early detection, limitations of conventional treatment options, and the constant evolution of cancer cells with metastatic and multi-drug resistant phenotypes require novel strategies to effectively combat this deadly disease. Nanomedical technologies are evolving at a rapid pace and are poised to play a vital role in diagnostic and therapeutic interventions - the so-called "theranostics" - with potential to advance personalized medicine. In this regard, nanoparticulate delivery systems can be designed with tumor seeking characteristics by utilizing the inherent abnormalities and leaky vasculature of solid tumors or custom engineered with targeting ligands for more specific tumor drug targeting. In this review we discuss some of the recent advances made in the development of multifunctional polymeric nanosystems with an emphasis on image-guided drug and gene delivery. Multifunctional nanosystems incorporate variety of payloads (anticancer drugs and genes), imaging agents (optical probes, radio-ligands, and contrast agents), and targeting ligands (antibodies and peptides) for multi-pronged cancer intervention with potential to report therapeutic outcomes. Through advances in combinatorial polymer synthesis and high-throughput testing methods, rapid progress in novel optical/radiolabeling strategies, and the technological breakthroughs in instrumentation, such as hybrid molecular and functional imaging systems, there is tremendous future potential in clinical utility of theranostic nanosystems.

Background The use of neo-adjuvant chemotherapy in treating osteosarcoma has improved patients' average 5 year survival rate from 20% to 70% in the past 30 years. However, for patients who progress after chemotherapy, its effectiveness diminishes due to the emergence of multi-drug resistance (MDR) after prolonged therapy. Methodology/Principal Findings In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure resulting from MDR, we designed and evaluated a novel drug delivery system for MDR1 siRNA delivery. Novel biocompatible, lipid-modified dextran-based polymeric nanoparticles were used as the platform for MDR1 siRNA delivery; and the efficacy of combination therapy with this system was evaluated. In this study, multi-drug resistant osteosarcoma cell lines (KHOSR2 and U-2OSR2) were treated with the MDR1 siRNA nanocarriers and MDR1 protein (P-gp) expression, drug retention, and immunofluoresence were analyzed. Combination therapy of the MDR1 siRNA loaded nanocarriers with increasing concentrations of doxorubicin was also analyzed. We observed that MDR1 siRNA loaded dextran nanoparticles efficiently suppresses P-gp expression in the drug resistant osteosarcoma cell lines. The results also demonstrated that this approach may be capable of reversing drug resistance by increasing the amount of drug accumulation in MDR cell lines. Conclusions/Significance Lipid-modified dextran-based polymeric nanoparticles are a promising platform for siRNA delivery. Nanocarriers loaded with MDR1 siRNA are a potential treatment strategy for reversing MDR in osteosarcoma.

Human antibodies targeting prostate cancer cell surface epitopes may be useful for imaging and therapy. The objective of this study was to evaluate the tumor targeting of an internalizing human antibody fragment, a small-size platform, to provide high contrast in a mouse model of human prostate carcinoma.A prostate tumor-targeting single-chain antibody fragment (scFv), UA20, along with a nonbinding control scFv, N3M2, were labeled with (99m)Tc and evaluated for binding and rapid internalization into human prostate tumor cells in vitro and tumor homing in vivo using xenograft models. For the in vitro studies, the labeled UA20 scFv was incubated at 37 degrees C for 1 h with metastatic prostate cancer cells (DU145) to assess the total cellular uptake versus intracellular uptake. For the animal studies, labeled UA20 and N3M2 scFvs were administered to athymic mice implanted subcutaneously with DU145 cells. Mice were imaged with small-animal SPECT/CT with concomitant biodistribution at 1 and 3 h after injection.The UA20 scFv was labeled in 55%-65% yield and remained stable in phosphate buffer within 24 h. The labeled UA20 scFv was taken up specifically by prostate tumor cells. Internalization was rapid, because incubation at 37 degrees C for less than 1 h resulted in 93% internalization of total cell-associated scFvs. In animal studies, SPECT/CT showed significant tumor uptake as early as 1 h after injection. At 3 h after injection, tumor uptake was 4.4 percentage injected dose per gram (%ID/g), significantly greater than all organs or tissues studied (liver, 2.7 %ID/g; other organs or tissues,1 %ID/g), except the kidneys (81.4 %ID/g), giving tumor-to-blood and tumor-to-muscle ratios of 12:1 and 70:1, respectively. In contrast, the control antibody exhibited a tumor uptake of only 0.26 %ID/g, similar to that of muscle and fat. Tumor-specific targeting was evidenced by reduced tumor uptake of nearly 70% on administration of a 10-fold excess of unlabeled UA20 scFv. Kidney uptake was nonspecific, consistent with the route of excretion by scFvs.The UA20 scFv showed rapid and specific internalization in prostate tumor cells in vitro and accumulation in prostate tumor xenografts in vivo, demonstrating the potential for future development for prostate cancer imaging and targeted therapy.

Tetrahydropyranyladriamycin (THP or pirarubicin) destroys tumors via several mechanisms; one of which involves the production of ROS that requires molecular oxygen for its generation. SMA forms stable self-assembled associated micelles with pirarubicin (SMA-pirarubicin), and confers macromolecular characteristics to pirarubicin. This micellar macromolecular drug is selectively delivered to solid tumors via the EPR effect and its preferential tumor accumulation suppresses the systemic toxicity whilst its prolonged high concentration at the site of tumor enhances its efficacy much higher compared to free pirarubicin. Administration of SMA-pirarubicin micelle under HBO can further enhance the delivery of molecular oxygen that facilitates tumor selective generation of ROS, thus augmenting its antitumor potency. In this study, we evaluated the efficacy of SMA-pirarubicin micelles either as single drug or in combination with HBO in a mouse metastatic colorectal cancer model. At or below the maximum tolerated dose, SMA-pirarubicin remarkably reduced metastatic tumor nodules and it was far more effective than free pirarubicin. The data also suggests a potential benefit of combined therapy of HBO with micellar anthracyclins.