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Recent developments in nanotechnology, especially in drug delivery systems, are advanced by featuring novel multifunctional nanoparticles that promise safe, specific, and efficient therapeutic delivery for cancer treatment. Multifunctional nanoparticle-based drug delivery systems enable simultaneous delivery of multiple therapeutic agents for effective combination therapy for cancer. In this chapter, we provide detailed protocols for development and application of a multifunctional nanoparticle system for combinatorial delivery of a chemotherapeutic (cisplatin) and small interfering RNA (siRNA) for human antigen R (HuR) mRNA in cancer cells using a polyamidoamine (PAMAM) dendrimer platform. Protocols for nanoparticle functionalization with folic acid (FA) for targeted delivery of therapeutics toward folate receptor (FR)-overexpressing cancer cells are also described. Further, methods employed for physiochemical and functional characterization of the multifunctional nanoparticle system are discussed in detail. Using the methods described in this chapter, researchers would be able to develop PAMAM dendrimer-based multifunctional nanoparticles for targeted delivery of chemotherapeutics and siRNA combinations. We also provide an example showing the dendrimer-polyethyleneimine-cis-diamminedichloroplatinum-siRNA-folic acid (Den-PEI-CDDP-siRNA-FA) nanoparticle system developed was therapeutically effective toward non-small cell lung cancer (NSCLC) cell lines (H1299 and A549) while exhibiting reduced toxicity to normal lung fibroblast (MRC9) cells.

Effective and safe delivery of anticancer agents is among the major challenges in cancer therapy. The majority of anticancer agents are toxic to normal cells, have poor bioavailability, and lack in vivo stability. Recent advancements in nanotechnology provide safe and efficient drug delivery systems for successful delivery of anticancer agents via nanoparticles. The physicochemical and functional properties of the nanoparticle vary for each of these anticancer agents, including chemotherapeutics, nucleic acid-based therapeutics, small molecule inhibitors, and photodynamic agents. The characteristics of the anticancer agents influence the design and development of nanoparticle carriers. This review focuses on strategies of nanoparticle-based drug delivery for various anticancer agents. Recent advancements in the field are also highlighted, with suitable examples from our own research efforts and from the literature., (© 2018 Elsevier Inc. All rights reserved.)

RNA interference (RNAi) is emerging as a powerful approach in cancer treatment. siRNA is an important RNAi tool that can be designed to specifically silence the expression of genes involved in drug resistance and chemotherapeutic inactivity. Combining siRNA and other therapeutic agents can overcome the multidrug resistance (MDR) phenomenon by simultaneously silencing genes and enhancing chemotherapeutic activity. Moreover, the therapeutic efficiency of anticancer drugs can be significantly improved by additive or synergistic effects induced by siRNA and combined therapies. Co-delivery of these diverse anticancer agents, however, requires specially designed nanocarriers. This review highlights the recent trends in siRNA/anticancer drug co-delivery systems under the major categories of liposomes/lipid, polymeric and inorganic nanoplatforms. The objective is to discuss the strategies for nanocarrier-based co-delivery systems using siRNA/anticancer drug combinations, emphasizing various siRNA targets that help overcome MDR and enhance therapeutic efficiency.

Chitosan is a versatile polysaccharide of biological origin. Due to the biocompatible and biodegradable nature of chitosan, it is intensively utilized in biomedical applications in scaffold engineering as an absorption enhancer, and for bioactive and controlled drug release. In cancer therapy, chitosan has multifaceted applications, such as assisting in gene delivery and chemotherapeutic delivery, and as an immunoadjuvant for vaccines. The present review highlights the recent applications of chitosan and chitosan derivatives in cancer therapy.

Successful chemotherapeutic intervention for management of lung cancer requires an efficient drug delivery system. Gold nanoparticles (GNPs) can incorporate various therapeutics; however, GNPs have limitations as drug carriers. Nano-sized cellular vesicles like exosomes (Exo) can ferry GNP-therapeutic complexes without causing any particle aggregation or immune response. In the present study, we describe the development and testing of a novel Exo-GNP-based therapeutic delivery system -'nanosomes'- for lung cancer therapy. This system consists of GNPs conjugated to anticancer drug doxorubicin (Dox) by a pH-cleavable bond that is physically loaded onto the exosomes (Exo-GNP-Dox). The therapeutic efficacy of Dox in nanosomes was assessed in H1299 and A549 non-small cell lung cancer cells, normal MRC9 lung fibroblasts, and Dox-sensitive human coronary artery smooth muscle cells (HCASM). The enhanced rate of drug release under acidic conditions, successful uptake of the nanosomes by the recipient cells and the cell viability assays demonstrated that nanosomes exhibit preferential cytotoxicity towards cancer cells and have minimal activity on non-cancerous cells. Finally, the underlying mechanism of cytotoxicity involved ROS-mediated DNA damage. Results from this study mark the establishment of an amenable drug delivery vehicle and highlight the advantages of a natural drug carrier that demonstrates reduced cellular toxicity and efficient delivery of therapeutics to cancer cells.

The bottleneck in current vector-based cancer therapy is the targeted and controlled release of therapeutics in tumors. Exosomes are submicron-sized vesicles that are secreted by all cell types and are involved in communication and transportation of materials between cells. Analogous in size and function to synthetic nanoparticles, exosomes offer many advantages, rendering them the most promising candidates for targeted drug or gene delivery vehicles. Patient-specific customized therapeutic strategies can be engineered using exosomes derived from the patient's own healthy cells. Therefore, exosome-based cancer therapy has the potential to become an important part of personalized medicine. Interest in exosomes as carrier organelles is relatively recent. Knowledge about exosomal biology and its applications remains limited. The present review is an attempt to describe the current status of the application of exosomes to cancer therapy and the potential challenges associated with their use.

Nanotechnology has enabled the development of novel therapeutic and diagnostic strategies, such as advances in targeted drug delivery systems, versatile molecular imaging modalities, stimulus responsive components for fabrication, and potential theranostic agents in cancer therapy. Nanoparticle modifications such as conjugation with polyethylene glycol have been used to increase the duration of nanoparticles in blood circulation and reduce renal clearance rates. Such modifications to nanoparticle fabrication are the initial steps toward clinical translation of nanoparticles. Additionally, the development of targeted drug delivery systems has substantially contributed to the therapeutic efficacy of anti-cancer drugs and cancer gene therapies compared with nontargeted conventional delivery systems. Although multifunctional nanoparticles offer numerous advantages, their complex nature imparts challenges in reproducibility and concerns of toxicity. A thorough understanding of the biological behavior of nanoparticle systems is strongly warranted prior to testing such systems in a clinical setting. Translation of novel nanodrug delivery systems from the bench to the bedside will require a collective approach. The present review focuses on recent research efforts citing relevant examples of advanced nanodrug delivery and imaging systems developed for cancer therapy. Additionally, this review highlights the newest technologies such as microfluidics and biomimetics that can aid in the development and speedy translation of nanodrug delivery systems to the clinic.

Co-administration of functionally distinct anti-cancer agents has emerged as an efficient strategy in lung cancer treatment. However, a specially designed drug delivery system is required to co-encapsulate functionally different agents, such as a combination of siRNA and chemotherapy, for targeted delivery. We developed a folic acid (FA)-conjugated polyamidoamine dendrimer (Den)-based nanoparticle (NP) system for co-delivery of siRNA against HuR mRNA (HuR siRNA) and cis -diamine platinum (CDDP) to folate receptor-α (FRA) -overexpressing H1299 lung cancer cells. The co-delivery of HuR siRNA and CDDP using the FRA-targeted NP had a significantly greater therapeutic effect than did individual therapeutics. Further, the FRA-targeted NP exhibited improved cytotoxicity compared to non-targeted NP against lung cancer cells. Finally, the NP showed negligible toxicity towards normal MRC9 lung fibroblast cells. Thus, the present study demonstrates FRA-targeted Den nanoparticle system as a suitable carrier for targeted co-delivery of siRNA and chemotherapy agents in lung cancer cells. [ABSTRACT FROM AUTHOR]