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Hybrid or recombinant protein-polymers, peptide-based biomaterials, and antibody-targeted therapeutics are widely explored for various ocular conditions and vision correction. They have been noted for their potential biocompatibility, potency, adaptability, and opportunities for sustained drug delivery. Unique to peptide and protein therapeutics, their production by cellular translation allows their precise modification through genetic engineering. To a greater extent than drug delivery to other systems, delivery to the eye can benefit from the combination of locally-targeted administration and protein-based specificity. Consequently, a range of delivery platforms and administration methods have been exploited to address the ocular delivery of peptide and protein biomaterials. This review discusses a sample of preclinical and clinical opportunities for peptide-based drug delivery to the eye.

Metastasis is considered the major cause of unsuccessful cancer therapy. The metastatic development requires tumor cells to leave their initial site, circulate in the blood stream, acclimate to new cellular environments at a remote secondary site and endure there. There are several steps in metastasis, including invasion, intravasation, circulation, extravasation, premetastatic niche formation, micrometastasis and metastatic colonization. siRNA therapeutics are appreciated for their usefulness in treatment of cancer metastasis. However, siRNA therapy as a single therapy may not be a sufficient option for control of metastasis. By combining siRNA with targeting, functional agents or small-molecule drugs have shown potential effects that enhance therapeutic effectiveness. This review addresses multidrug resistance and metastasis in breast and ovarian cancers and highlights drug-delivery strategies using siRNA therapeutics.

The delivery of therapeutics to brain tissues is one of the main challenges in neuropathology. For the past two decades, a variety of drug delivery systems has been designed to target components of the blood-brain barrier, including the transferrin receptor, a transmembrane glycoprotein highly expressed in the brain endothelium.In this protocol, we describe the use of transferrin protein to activate the surface of nanoparticles with the aim to direct their uptake in the brain. The molecule is bound by an amide linker to a PEGylated lipid commonly used in the preparation of lipid nanoparticles, micelles, and liposomes.

Achievement of a high dose of drug in the tumor while minimizing its systemic side effects is one of the important features of an improved drug delivery system. Thus, developing responsive carriers for site-specific delivery of chemotherapeutic agents has become a main goal of research efforts. One of the known hallmarks of cancerous tumors is hypoxia, which offers a target for selective drug delivery. The stimuli-sensitive micellar system developed by us, (PEG-azobenzene-PEI-DOPE (PAPD) has proven to be effective in vitro. The proposed construct developed, PAPD, contains an azobenzene group as a hypoxia-sensitive moiety that triggers the shedding of the PEG layer from the nanoparticle surface under conditions of hypoxia to improve cellular uptake. Using microfluidics, we show significantly improved cellular association and penetration under hypoxia in both single cells and in a 3D tumor model. Employing an in vivo model, we demonstrate slower tumor growth that did not induce systemic side effects, including weight loss in an experimental animal model, when compared to the free drug treatment. This complex-in-nature but simple-in-design system for the simultaneous delivery of siRNA to silence the P-glycoprotein and doxorubicin with active tumor targeting and proven therapeutic efficacy represents a universal platform for the delivery of other hydrophobic chemotherapeutic agents and siRNA molecules which can be further modified.

The delivery of therapeutics to brain tissues is one of the main challenges in neuropathology. For the past two decades, a variety of drug delivery systems has been designed to target components of the blood-brain barrier, including the transferrin receptor, a transmembrane glycoprotein highly expressed in the brain endothelium.In this protocol, we describe the use of transferrin protein to activate the surface of nanoparticles with the aim to direct their uptake in the brain. The molecule is bound by an amide linker to a PEGylated lipid commonly used in the preparation of lipid nanoparticles, micelles, and liposomes.

In this study, Ag2O3·SnO2·Cr2O3 nanoparticles (NPs) were synthesized via a simple and quick co-precipitation method. The produced materials were characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), Fourier-transform infrared spectroscopy (FTIR), and photoluminescence (PL) spectroscopy. The hydrodynamic size and zeta potential were measured under acidic and basic pH conditions. The photocatalytic activities of the newly synthesized composite were studied considering various parameters. Antibacterial activity tests showed that Ag2O3·SnO2·Cr2O3 is an excellent anti-bacterial agent. A reliable electrochemical sensor probe was designed by depositing the synthesized Ag2O3·SnO2·Cr2O3 NPs onto the flat part of GCE, which showed excellent oxidation activity and selectivity towards 4-aminophenol (4-AP) in a phosphate buffer medium. During electrochemical analysis, the desired 4-AP sensor responded linearly over a large concentration range (0.1 nM–0.01 mM), which is known as the linear dynamic range (LDR), and exhibited appreciable sensitivity (25.1962 μA μM−1 cm−2). Furthermore, it showed a considerably low limit of detection (98.41 ± 4.92 pM), good reproducibility, fast response (20.0 s), and long-term stability in the phosphate buffer medium. This is an efficient method for the fabrication of a selective electrochemical sensor using the electrochemical approach for safety in environmental and healthcare fields.

Currently, various types of nanocarriers have been widely used to deliver bioactive compounds to improve the specificity/effectiveness of the active compound. Among these, dendrimers have gained considerable interest as a delivery system due to their exceptional properties including high water solubility, monodispersity, biocompatibility, and low immunogenicity. These multiple branched monomers have well-defined 3D structures with favorable manufacturing approaches at a large scale. Thus dendrimer-based delivery systems possess unique features that are advantageous for drug delivery in clinics. Various types of drug molecules, including hydrophobic or hydrophilic small molecules and large nucleic acid molecules, can be loaded into dendrimers by either physical or chemical interactions. The enhanced drug solubility and cellular permeation of dendrimer-based delivery systems enable multiple treatment strategies with outstanding efficacy. So far, research has focus on the development of novel delivery strategies using dendrimers for a wide variety of diseases including anticancer, antimicrobial, anti-HIV, and antiosteoarthritis therapies.

In the preceding chapter, the possibilities to couple experiments with computation techniques to characterize and optimize the performance of a drug delivery system have been described. In fact, while it is important to address the problems with the physical properties of a drug delivery system for optimal delivery performance, the impact of the physiological, bio-chemical and chemical barriers within the biological system on the efficiency of systemic drug delivery should not be overlooked, either. Keeping this in mind, in this chapter we will give an overview of the various physiological, chemical and bio-chemical barriers in systemic drug delivery, using oral drug delivery route as an example. We will also discuss the challenges in drug delivery to specific targets such as solid tumors and brain since these targets pose unique barriers that need specific knowledge on to tweak them suitably for enhanced drug delivery and achieve therapeutic benefit for several life-threatening illnesses and incurable disorders. It is hoped that, with more awareness of the various barriers in systemic drug delivery and any issue with the drug property, potential losses of therapeutics in a biological body can be minimized and the efficiency of therapies can be increased at the clinical level.

RNA interference (RNAi) represents a promising therapeutic method that uses siRNA for cancer treatment. Although the RNAi technique has been increasingly used for clinical trials, systemic siRNA delivery into targeted cells is still challenging. The barriers impeding siRNA therapeutics delivery and impacting the treatment outcome must overcome with negligible systemic toxicity for a desirable and successful delivery of siRNA to MDR cancer cells. Nano delivery strategies have been investigated for nanocarrier functionalization, cancer immunotherapy and cancer targeting. Lipid nanoparticles (LNPs), dynamic polyconjugates (DPC™), GalNAc-siRNA conjugates, exosome and RBC systems have shown potential for efficient delivery of siRNA to cancer cells. Delivery of siRNA to tumor cells, immune cells to regulate T cell functions for immunotherapy are promising approaches.

Recently, it has been discovered that the PEG layer on nanoparticle surface can create steric hindrance, preventing efficient cellular uptake of PEGylated nanoparticles. Thus, it would be ideal to have a nanoparticle system that sheds the PEG layer upon reaching the tumor microenvironment. Hypoxia, which is a hallmark of cancerous tumors, can be used as a trigger to shed the PEG layer from the nanoparticle surface. In this study, a hypoxia-sensitive PEG-azobenzene-PEI-DOPE (PAPD) construct, with an azobenzene group as a hypoxia-sensitive moiety, was prepared. The feasibility of co-delivering Doxorubicin (Dox) and anti-P-gp siRNA (siPgp) using the PAPD nanoparticles was evaluated in monolayers of the Adriamycin-resistant human ovarian cancer cell line, A2780 ADR, and in 3D spheroids of the multidrug-resistant human breast cancer cell line, MCF7 ADR. Under hypoxic conditions, the PAPD nanoparticles showed up to a 60% increase in cellular uptake by monolayers and a significantly greater tumor penetration in a spheroid model. siPgp, when delivered using PAPD nanoparticles, showed up to a 60% P-gp downregulation under hypoxic conditions. The combination of siPgp and Dox delivered using PAPD nanoparticles led to an 80% cytotoxicity in cell monolayers and 20% cytotoxicity in spheroids under hypoxic conditions. In this research, a novel hypoxia-sensitive nanoparticle system was developed that demonstrated improved delivery of an encapsulated cargo and augmented cytotoxicity on multidrug-resistant cancer cells under hypoxic conditions.

Folic acid is often used for active targeting of tumor cells to enhance therapeutic outcomes. Here, folic acid was conjugated with chitosan and folate-conjugated chitosan-lipid hybrid nanoparticles were prepared by ionic gelation method using anionic lipid. These nanoparticles were in size range of 200 to 400 nm with spherical shape. In vitro drug release data suggested a sustained release of cisplatin. The therapeutic efficacy of the folate-conjugated hybrid nanoparticles was evaluated in SK-OV-3, A2780 and MCF-7 cancer cell lines. A significant increase in cytotoxicity was observed with folate targeted LPHNPs compared to non-targeted LPHNPs. Significantly enhanced cellular uptake and cell cycle arrest resulting from folate-targeted nanoparticles were confirmed using fluorescence microscopy and flow cytometry. The therapeutic efficacy and tumor penetration were further evaluated in 3D spheroid tumor models. These studies suggest that folate-conjugated lipid-chitosan nanoparticles could enhance therapeutic activity and may represent a promising platform for active targeting of tumor cells.

7558 Background: Prolymphocytic leukemia (PLL) compromises two subsets; B-cell and T-cell, accounting for less than 2% of mature lymphocytic leukemia. Both of them are rare lymphoid neoplasms with a very aggressive clinical course and poor prognosis. Methods: We used SEER program dataset between 1998 and 2016. We divided the patients into 2 groups: B-PLL and T-PLL and identified them using ‘ICD-O-3 histology recode: 9833/3 and 9834/3 respectively. We used SPSS software (version 26, IBM, NY, USA) to calculate overall survival using Kaplan-Meier methods and compare the survival between the two subtypes using the log-rank test. We also used multivariable covariate-adjust cox models to determine the impact of age, sex, race, cause of death, and associated primary malignancies on survival in both types. Results: A retrospective cohort study of 783 patients (295 B-PLL and 488 T-PLL) with overall survival rate of 22.5% (30.2% B-PLL and 18% T-PLL). The overall median survival for PLL was 16 months (95 CI, 13.745-18.255). The median survival of B-PLL (25 months, 95%CI, 15.733-34.267) was much better than T-PLL (14 months, 95%CI, 11.922-16.078). The mean age was 68.7±15.3. Patient age was an independent factor in determining the survival and inversely associated with survival time in both types (p < 0.0001). The survival rate was worst ) among age groups older than 79, between 70-79 years (8.9%, 18.9%) respectively. Although white male patients were more affected in both types, neither sex nor race significantly affected survival (P 0.554, 0.062 respectively). 64.7% of PLL patients died due to cancer. Patients with cancer-related death had significantly shorter survival time in both T-PLL group (HR = 0.351, 95% CI 0.241-0.512) and B-PLL group (HR = 0.682, 95% CI 0.491-0.945). We also found that 24.4% of B-PLL and 19% of T-PLL patients have another associated primary malignancy. Among hematological malignancies, non-hodgkin lymphoma was the commonest. Although associated solid tumors were less common, Prostate cancer and breast cancer were the commonest for both types and lung/bronchus malignancies were more associated with T-PLL. Conclusions: T-PLL subtype has worse prognosis. Age is the most important independent predictor of survival in both types. Although most of affected patients were white males, race and gender have no impact on survival. Non-hodgkin lymphoma is the commonest primary associated malignancy followed by breast and prostate cancer in both types.