Sequential Drug Delivery in Targeted Cancer Therapy

A pH-responsive polycarbonate nanoplatform enables sequential drug release for enhanced apoptotic cascade synergy in non-small cell lung cancer therapy.

Sequential drug delivery for liver diseases.

Controlled drug delivery systems, that include sequential and/or sustained drug delivery, have been utilized to enhance the therapeutic effects of many current drugs by effectively delivering drugs in a time-dependent and repeatable manner. In this study, with the aid of 3D printing technology, a novel drug delivery device was fabricated and tested to evaluate sequential delivery functionality. With an alginate shell and a poly(lactic-co-glycolic acid) (PLGA) core, the fabricated tubes displayed sequential release of distinct fluorescent dyes and showed no cytotoxicity when incubated with the human embryonic kidney (HEK293) cell line or bone marrow stromal stem cells (BMSC). The controlled differential release of drugs or proteins through such a delivery system has the potential to be used in a wide variety of biomedical applications from treating cancer to regenerative medicine.

According to the World Health Organization, Cancer is one of the world’s deadliest diseases and is the second leading cause of death in the United States. Cancer has been responsible for almost 10 million deaths worldwide in 2020, with the most common forms of cancer being breast, lung, and colon & rectum cancer. To put into scale just how deadly the disease is, the rate of cancer deaths per year is about 158 per 100,000 men and women. Current traditional cancer therapies include chemotherapy, radiation therapy, and surgery. Although these traditional cancer therapy methods have been somewhat effective over the past decades, they come with serious adverse health effects and have been related to very serious long-term side effects. As a result, over the recent years, targeted cancer therapy using small molecule drugs has become a focus in the medical field of cancer treatment. Small molecule drugs have a very advanced and tunable targeting ability which is effective in passing through cell membranes and reaching their designed intracellular targets. Most of these drugs can be administered orally, and due to their very small size, they are able to pass through a variety of obstacles in order to inhibit certain cancer-related biomolecules. In this review, I provide a summary of several different SMIs (small molecule inhibitors) that can be used in cancer therapy and explain recent advances as well as future outlooks in the field of SMIs for cancer treatment.

Nanoparticles (NPs) with easily modified surfaces have been playing an important role in biomedicine. As cancer is one of the major causes of death, tremendous efforts have been devoted to advance the methods of cancer diagnosis and therapy. Recently, magnetic nanoparticles (MNPs) that are responsive to a magnetic field have shown great promise in cancer therapy. Compared with traditional cancer therapy, magnetic field triggered therapeutic approaches can treat cancer in an unconventional but more effective and safer way. In this review, we will discuss the recent progress in cancer therapies based on MNPs, mainly including magnetic hyperthermia, magnetic specific targeting, magnetically controlled drug delivery, magnetofection, and magnetic switches for controlling cell fate. Some recently developed strategies such as magnetic resonance imaging (MRI) monitoring cancer therapy and magnetic tissue engineering are also addressed.

“With diagnosis and therapy combined onto a single platform, theranostics enables real-time monitoring of the status of disease treatment and allows for timely adjustment of type and dose of drugs, paving the way towards personalized medicine.”

MicroRNAs (miRNAs) are a large family of small noncoding RNAs (~22 nucleotide long) that negatively regulate protein-coding gene expression posttranscriptionally by interacting with messenger RNAs (mRNAs), causing either their degradation or translation inhibition. While miRNAs were first discovered as important regulators of developmental timing, subsequent studies have shown that their deregulations are critically involved in various diseases, including cancer. This is evident from the crucial roles they play in regulating a wide range of cellular processes such as cell survival, apoptosis, cell cycle progression and proliferation, cell-cell interaction, differentiation, and motility. It has been found that miRNA expression levels are altered in all types of cancer and they play important roles in almost all aspects of cancer pathogenesis such as initiation, promotion, metastasis, and responses to drug treatment. These recognitions and other accumulating evidences clearly suggest that miRNAs can serve as novel targets for cancer therapies. Indeed, targeting abnormally-expressed miRNAs has been shown to have great potential in suppressing primary tumor growth, reducing tumor metastasis, and overcoming anticancer drug resistance. It is anticipated that miRNAs can be valuable cancer-specific targets and novel miRNA-based targeted therapies can be formulated to provide effective treatments for cancer. The purpose of this special issue is to provide readers with an overview of research findings on the roles of miRNAs in cancer development, progression, diagnosis and treatment, and how miRNA expression may be regulated. This issue will also update the readers about the challenges and possibilities of miRNAs to emerge as future cancer therapeutics. A. L. Oom et al. first briefly review the potential value of miRNAs as cancer diagnostic markers, which is followed by the detailed discussion on the potential role of miRNAs in cancer therapy. The authors review literatures reporting the role of miRNAs in sensitizing of or mediating resistance to traditional and targeted cancer therapies. A nice summary about studies on miRNAs in combination with traditional cancer therapies is provided in a table. The authors also discuss the current studies on miRNA delivery systems. This review ends with discussion on challenges and perspectives of developing miRNAs as effective cancer therapies. The review paper, authored by K. Otsuka and T. Ochiya, discusses the role of miRNAs in tumor development by uniquely focusing on the interplay between the classic tumor suppressor p53 and the emerging tumor regulatory miRNAs. The authors review recent findings showing both the regulation of expression of various miRNAs by p53 and the direct targeting of p53 by miRNAs. Particularly, this review summarizes up to date research findings about the critical roles of various miRNAs in regulation of cell cycle and apoptosis in the p53 pathways. Y. Fujita, K. Kuwano, T. Ochiya, and F. Takeshita provide an in-depth review of current findings showing the potential of circulating miRNAs as diagnostic biomarkers for lung cancer. This review discusses the general mechanism of miRNA release into extracellular spaces and the impact of extracellular vesicle-encapsulated circulating miRNAs on cancer progression. Moreover, this review also summarizes current studies in detail showing the potential of miRNAs as circulating biomarkers in cancer diagnosis, particularly for lung cancer. N. H. Phuah and N. H. Nagoor review the regulation of miRNAs by natural compounds. Recent studies have shown that natural agents such as curcumin, resveratrol, genistein, epigallocatechin-3-gallate, indole-3-carbinol, and 3,3′-diindolylmethane exert their antiproliferative and/or proapoptotic effects through the regulation of one or more miRNAs. This review summarizes current research findings about the regulation of miRNAs by above natural compounds. The review also discusses the potential of integrating natural agents with conventional chemotherapeutic drugs, thus, enhancing their efficacy. The review article by S. K. Srivastava, S. Arora, C. Averett, S. Singh, and A. P. Singh discusses the effect of naturally occurring phytochemicals on miRNA expression. Particularly, the authors focus on the underlying molecular mechanisms of miRNA regulation by phytochemicals and their functional significance in cancer development and progression. Moreover, the translational potential of the relevant research findings is also discussed. In closing, the guest editors of this special issue would like to thank all the reviewers for their timely and excellent review and journal management team for efficient processing of papers from submission through publication. Chengfeng Yang Yiguo Jiang Ajay P. Singh Fumitaka Takeshita

Nanotechnology in drug delivery has revolutionized modern therapeutics by addressing the limitations of conventional drug delivery methods. This review article explores the significant advancements in nanoparticle-based drug delivery systems, highlighting their role in enhancing therapeutic efficacy and overcoming drug resistance. Nanoparticles, including lipid-based, polymer- based, inorganic, and biological types, offer improved solubility, stability, targeted delivery, and controlled release of therapeutic agents. By enabling precise delivery to specific tissues or cells, these advancements minimize off-target effects and toxicity, particularly in cancer therapy. Additionally, nanomedicine facilitates the delivery of drugs across biological barriers such as the blood-brain barrier, which opens new avenues for treating neurological disorders. The ability to co-encapsulate multiple therapeutic agents in nanoparticles also supports combination therapies that target multiple pathways simultaneously, thereby reducing the development of resistance. As research progresses, the integration of nanotechnology in drug delivery promises to transform healthcare by providing more effective, safer, and personalized treatments. This article advocates for continued exploration and innovation in the field by emphasizing the need for interdisciplinary collaboration to fully realize the potential of nanomedicine in improving patient outcomes and addressing unmet clinical needs.

A sequential drug delivery system based on silk fibroin scaffold for effective cartilage repair.

Controlled and sequential drug delivery is a strategy to enhance the therapeutic effectiveness of drugs in a variety of biological processes and disease states. While many different drug delivery systems are developed recently, most cannot generate temporally complex delivery profiles of multiple therapeutics. These temporally complex profiles are critical for applications such as bone regeneration and cancer chemotherapy, where an orchestrated delivery of multiple drugs is required for an optimal outcome. Here, we developed three distinct biomaterial systems that each enable on-demand controlled or sequential drug release. These systems are based on varying external stimulus such as magnetic stimulation, radiofrequency heating, and near infrared (NIR) laser irradiation. The first system is a dual compartment hydrogel composed of an outer gelatin partition and an inner alginate ferrogel. While the outer compartment could be loaded with a recruitment factor to recruit and harbor cells, the inner compartment was capable of retaining and releasing a differentiation factor on-demand. The inner compartment was a biphasic ferrogel and stimulation was conducted using a custom magnetic stimulation set up. It was shown that delayed differentiation factor delivery can enhance mMSCs’ osteo-differentiation outcomes using 2D and 3D cell cultures. The second system is a magnetoliposome (ML) integrated hydrogel system. In this design, different sizes of magnetic iron oxide nanoparticles (IONPs) were used to develop two different MLs: ML-A and ML-B. Cationic and zwitterionic lipids were used to form positively charged liposomes that could electrostatically adsorb the IONPs on their surfaces and form MLs. The ratio of IONP/lipid was optimized to form stable ML-A and ML-B structures. These structures were integrated within 3D alginate hydrogels to enhance stability and provide localized drug delivery. As the different MLs could be stimulated at different frequencies, complex delivery profiles could be generated using these MLs in hydrogels. Controlled and delayed releases of a model drug (FITC-Dextran) from ML-A and ML-B in hydrogels were demonstrated. The third system is a single-walled carbon nanotube (SWCNT) liposome complex (CLC) integrated hydrogel. Here, unique NIR absorbance properties of SWCNTs were used to achieve drug release from liposomal structures. DNA sequences were used to wrap SWCNTs to uniformly disperse them in an aqueous solution and provide negative charge on their surface. These DNA-SWCNTs were then mixed with cationic liposomes to form CLCs. Optimal SWCNT to lipid ratio to form stable CLCs were determined. CLCs were then integrated within hydrogel structures and drug release was controlled using

With the arrival of the precision medicine and personalized treatment era, targeted therapy that improves efficacy and reduces side effects has become the mainstream approach of cancer treatment. Antibody fragments that further enhance penetration and retain the most critical antigen-specific binding functions are considered the focus of research targeting cancer imaging and therapy. Thanks to the superior penetration and rapid blood clearance of antibody fragments, antibody fragment-based imaging agents enable efficient and sensitive imaging of tumour sites. In tumour-targeted therapy, antibody fragments can directly inhibit tumour proliferation and growth, serve as an ideal carrier for delivery of anti-tumour drugs, or manipulate the immune system to eliminate tumour cells. In this review, the excellent physicochemical properties and the basic structure of antibody fragments are expressly depicted depicted, the progress of antibody fragments in cancer therapy and imaging are thoroughly summarized, and the future development of antibody fragments is predicted.

Combination chemotherapy with a modulator and a chemotherapeutic drug has become one of the most promising strategies for the treatment of multidrug resistance (MDR) in cancer therapy. However, the development of nanocarriers with a high payload and sequential release of therapeutic agents poses a significant challenge. In this work, we report a type of hybrid nanocarriers prepared by polydopamine (PDA) mediated integration of the mesoporous MSN core and the microporous zeolite imidazolate frameworks-8 (ZIF-8) shell. The nanocarriers exploit storage capacities for drugs based on the high porosity and molecular sieving capabilities of ZIF-8 for sequential drug release. Particularly, large amounts of an anticancer drug (DOX, 607 μg mg-1) and a MDR inhibitor curcumin (CUR, 778 μg mg-1) were sequentially loaded in the mesoporous core via π-π stacking interactions mediated by PDA and in the microporous shell via the encapsulation during ZIF-8 growth. The sustained release of DOX was observed to follow earlier and faster release of CUR by acid-sensitive dissolution of the ZIF-8 shell. Furthermore, the nanoparticles showed good biocompatibility and effective cellular uptake in in vitro evaluations using drug-resistant MCF-7/ADR cancer cells. More importantly, the preferentially released CUR inhibited the drug efflux function of the membrane P-glycoprotein (P-gp), which subsequently facilitated the nuclear transportation of DOX released from the PDA-MSN core, and, in turn, the synergistic effects on killing MDR cancer cells. The hybrid mesoporous-microporous nanocarrier holds great promise for combination chemotherapy applications on the basis of sequential drug release.

Drug delivery is an important part of pharmacotherapy of cancer. Merely developing an effective anticancer agent is not enough unless it is delivered to the site of action. Traditional drug development considered formulations for different routes of administration, mostly oral or injectable. Cancer drug delivery is no longer simply wrapping the drug in new formulations for different routes of delivery. Knowledge and experience from other technologies such as nanotechnology, advanced polymer chemistry, and electronic engineering are being brought together in developing novel methods of drug delivery. The focus is on targeted cancer therapy. The newer approaches to cancer treatment not only supplement the conventional chemotherapy and radiotherapy but also aim to prevent damage to the normal tissues and overcome drug resistance. Innovative methods of cancer treatment, e.g., cell and gene therapies, require new concepts of drug delivery in cancer. New biotechnologies have contributed considerably to drug delivery in cancer and some of these have been considered in other chapters: monoclonal antibodies (MAbs) (Chap. 8), nanobiotechnology/nanooncology (Chap. 9), cell therapy (Chap. 10), gene therapy (Chap. 11), and RNAi (Chap. 12).

A nanocapsular combinatorial sequential drug delivery system for antiangiogenesis and anticancer activities

New strategies in melanoma therapy: can nanoparticles overcome chemoresistance?