Revisiting Multifunctional Nanomedicines for Cancer Therapy

Abstract

Cancer is one of the primary causes of human deaths worldwide. Most cancer patients receive chemotherapy and radiotherapy, but these therapeutic regimens are usually only partially efficacious and give rise to serious side effects. Therefore, it is necessary to develop new therapeutic strategies to optimize the pattern of cancer treatment. The emergence of nanotechnology has had a profound impact on evolving tumor treatment modalities, facilitated by the development of nanodrug delivery systems that are highly tumor selective and allow for slow release of active anticancer drugs. Vehicles such as liposomes, dendrimers and polymer nanomaterials have been considered as promising carriers for tumor-specific drug delivery, reducing toxicity, and improving biocompatibility. To address the challenges in cancer therapeutics such as poor targeting of first-line chemotherapeutic drugs, easy destruction of nucleic acid drugs, and common immune-related adverse events in immunotherapy, we discuss how nanocarriers can be synergized with these treatment modalities. The future impact of nanomedicine-assisted cancer immunotherapies is also outlined.

1. Introduction

Cancer comprises an array of illnesses that has its roots in practically any organ or tissue of the body. The disease surfaces when abnormal cells multiply in an uncontrolled manner, traversing their normal boundaries to infect nearby healthy cells and/or spread to other organs. The latter process, known as metastasis, significantly contributes to cancer-related mortality. The primary cause of greater mortality rates in the majority of nations is cancer, which is regarded as one of the most dreaded malignant diseases. The term “cancer” refers to the unrestricted division and proliferation of cells. The immense capacity of these cells to multiply uncontrollably, stimulate angiogenesis, and promote invasion and metastasis has earned this condition the title of “the most feared disease” globally. The terms “neoplasm” and “malignant tumor” has also been ascribed to cancer. Any region of the body can be afflicted by cancer; however, the lungs, female breasts, prostate, pancreas, and liver are particularly vulnerable to infection. After ischemic heart disease, cancer is the second worldwide cause of death (8.97 million deaths) and is likely to become the first in 2060 (~18.63 million deaths) [1].

One of cancer’s distinctive characteristics is the unchecked, rapid cell proliferation that occurs in several human organs. This growth leads to malignant tumors, which are the main cause of mortality. The impediments of therapeutic approaches include fatigue, numbness, changes in nails, hair loss, loss of appetite, mouth sores, nausea, weight changes, vomiting, diarrhea, and heart damage. Cancer patients frequently visit hospitals for chemotherapy that results in undesirable side effects. In spite of its enormous potential, chemotherapy remains disadvantageous due to its nonspecific delivery, resulting in off-target adverse consequences [2]. According to the World Health Organization, approximately 50% of cancer deaths can be avoided by adopting three different strategies, viz, consciousness, clinical diagnostic techniques, and care [3, 4]. The treatment of cancer has relied on chemotherapy, radiation, and surgery but these regimens are not bereft of restraints. Conventional chemotherapy, the most popular cancer treatment, is limited in its effectiveness due to fast elimination of most anticancer drugs. When administered more frequently and at higher doses, it results in drug resistance and causes toxicity. Damage to healthy cells is a side effect of chemotherapy that compromises the immune system and causes symptoms like loss of appetite, baldness, and illness. The prime cause of such intense unfavorable fallout and high mortality rates is the excessive dose of chemotherapeutics beyond their remedial limit in normal healthy tissues, originating due to burst release of drugs after administration [5]. As a result, more medication is injected than is necessary to maintain diffusion-controlled phenomena.

Therefore, targeted drug delivery carriers for cancer therapy are currently pertinent, as they can improve remedial efficiency, thereby minimizing adverse side effects [6]. In order to maintain the therapeutic concentration, it is necessary to design and develop controlled drug delivery systems (DDSs) that can release the drug in a regulated manner for prolonged period of time. The therapeutic efficacy of anticancer drugs in various malignant tumors has increased as a result of manifold options available for an individualized approach, tailored to the personal patient profiles [7]. Nonetheless, the quest for new and innovative cancer therapeutics is still urgently needed across the globe. Herein, we review the challenges in cancer therapeutics and development of nanomedicine, focusing on promising nanocarriers, immunomodulatory nanomedicines and nanomedicine-assisted cancer immunotherapies that may help to alleviate the shortcomings in cancer drug delivery.

2. Challenges in cancer therapeutics

The main bottleneck for modern anticancer medications is to target and kill tumor cells while minimizing unwanted effects. In order to decrease uptake by healthy tissues and enhance the payload or drug in the tumor microenvironment (TME), the idea of selective targeting has arisen [8]. Additionally, because more than 40% of anticancer medications are hydrophobic, their ultimate bioavailability and therapeutic effectiveness may suffer. Poorly water-soluble anticancer medicines have traditionally been dissolved using solvents and emulsifiers. However, these have the potential to cause cancer and may be harmful to the liver and neurological system. Tumors also subvert the phenotypic plasticity of the immune compartment to advance disease progression. Tumors may employ strategies to escape immune recognition and repress T-lymphocyte effector functions.

Anticancer drug distribution is hampered by a variety of impediments:

2.1 Internal toxicity of the drug

Internal toxicity has the potential to limit the dosage of cancer medications intended for systemic distribution. Systemic toxicity varies depending on the mode of administration and the application site. Local delivery is one of the methods for reducing systemic toxicity since it allows for high drug concentrations and ensures that the drug remains in the local tissue. Systemically administered cancer medications have a higher likelihood of interacting with and being absorbed by the kidney, bone marrow, and central nervous system while in circulation, leading to the death of healthy cells.

2.2 Barrier to tumor microenvironment

Tumors initially rely on the host tissues’ vasculature to supply them with blood. As they grow further, they switch into an angiogenic state in order to meet their increasing metabolic needs. Poor tumor microenvironmental conditions occur because the tumor vascular supply, which develops from the normal host vasculature via angiogenesis, is inadequate to meet the increasing metabolic demands of the growing solid tumor mass, including oxygen and nutrients [9]. An important component of cancer treatment is the inhibition or reduction of tumor angiogenesis.

2.3 Systemic clearance of antitumor drugs

Since anticancer medications may be widely dispersed nonspecifically throughout systemic organs including the heart, brain, liver, kidney, and reticuloendothelial system (RES) organs, delivery to the tumor destination via the systemic route is challenging. The permeability of the membrane, blood flow, and the drug’s capacity to bind to a particularly targeted tumor tissue can all have an impact on how widely the drug is distributed throughout the body. In this scenario, anticancer drugs in blood circulation will interact with systemic organs more often, thereby increasing the likelihood of rapid clearance by the kidney and RES organs. Thus, the body’s normal physiology compromises the systemic delivery of therapeutic agents via hepatic and renal clearance, uptake by cells of the RES and degradation by enzymes in the endosome/lysosome, leading to a lower therapeutic dose of the drug in the tumor cells [10].

2.4 Blockade of access through the blood-brain barrier

The blood-brain barrier (BBB), a natural protective and unique semi-permeable membrane, precludes central nervous system (CNS) from toxins and pathogens in the blood and maintains homeostasis in the brain micromilieu [11]. The cerebrospinal fluid molecules cannot enter the BBB because of the high cell density and strong intracellular gap junctions of endothelial cells. Composed of around a 100 billion capillaries, the 600-km long BBB spans 20 m² of the human brain. Each capillary is approximately 7.5 μm in diameter, allowing for blood supply within 10 μm of each brain cell [12]. The physical barrier shields the brain tumor’s microenvironment from external drugs by impeding the flow of molecules larger than 400 daltons from the bloodstream into the brain. Besides size, hydrophobicity also affects the BBB traversing of any drug for brain tumor delivery. Tight junctions between adjacent vascular endothelial cells restrain paracellular movement and aid transcellular movement [13]. The continuity of the tight junctions, coupled with a lack of fenestrae and efflux transporters, results in the BBB with distinct luminal and abluminal compartments for strict regulation and control between the blood and the brain [14].

2.5 Tumor hypoxia leading to poor milieu

Low oxygenation (hypoxia), a hallmark trait of TME, plays a significant role in effecting the response of tumors to conventional radiation and chemotherapy [15]. Hypoxia also promotes malignant progression in terms of aggressive growth, recurrence of the primary tumor and its metastatic spread. Hypoxia is not a single entity; rather it is multifactorial and often associated with other microenvironmental parameters such as aberrant angiogenesis, impaired blood vessels, dysfunctional lymphatic drainage, elevated interstitial fluid pressure, glycolysis, low pH and reduced bioenergetic status in the solid tumors.

3. Advent of smart nanomedicines for cancer therapy

Nanomedicine is the integration of nanobiotechnology into medical practice. Although the notion of “nano” has been around for four decades, the relationship with drug delivery and its applications in medicine has not received much attention until recent times.

3.1 Development of nanotechnology

The concept of nanoparticles (NPs) was first adapted by Nobel laureate Richard P. Feynman in his famous lecture entitled “There’s plenty of room at the bottom” on 29th December 1959 [16, 17]. The first nanosized colloidal gold particles were prepared by Michael Faraday. This discovery, dating back to more than 150 years, served as a precursor for the development and advancement of DDSs. Surface-modified liposome NPs for sustained circulation was reported for the first time in 1994 [18]. In the years 2004 and 2006, Mihail C. Roco of the U.S. National Nanotechnology Initiative (NNI), projected the timeline encompassing four generations of nanotechnology products and processes—passive nanostructures, active nanostructures, nanosystems, and molecular nanosystems (Figure 1) [19]. Emerging technologies including platforms for quantum information systems, artificial intelligence systems, advanced semiconductors, wireless communication, modern bioeconomy, and advanced manufacturing have opened new horizon to address sustainable society, nanomedicine, personalized learning, and augmented human capabilities [20]. The positive effects of nanotechnology are evident in pharmaceuticals and healthcare [21].

Figure 1.

Timeline for the commencement of industrial prototyping and nanotechnology commercialization: new generations of nanotechnology products and productive processes from 2000 to 2020. Adapted from Roco [19].

3.2 Prerequisites of nanomedicine

Nanomedicine broadly encompasses medical applications of nanomaterials. The following are the general prerequisites for using NPs in nanomedicine, as highlighted by Harry F. Tibbals [22].

• NPs utilized in medical applications must be biodegradable.

• The NPs should remain colloidally stable when combined with physiological buffer solutions and in aqueous environments.

• The NPs should have substantial tissue-relative absorbance or fluorescence at the necessary wavelengths.

• Toxic substances must not be used for nanomedicine synthesis.

• NPs should be easily functionalized using their surface coatings for medical imaging or therapeutics.

3.3 Nanomedicines for cancer therapy

To circumvent the problems associated with current cancer therapeutics, efforts have been concentrated on creating new DDSs for cancer therapy. Over the past few decades, there has been an unprecedented surge in the use of nanomedicines for safer and more efficient tumor targeting, detection, and therapy. To overcome the adverse drawbacks of current cancer therapeutic modalities, nanotechnology-based combinatorial drug delivery has emerged as a possible solution. NP-based DDSs have shown many advantages in cancer treatment, such as improved pharmacokinetic profiles, precise targeting of tumor cells, diminution of adverse side effects and decline in drug resistance [23]. The National Cancer Institute (NCI) of the National Institutes of Health (NIH), U.S. has formed an alliance with the nanotechnology domain in the hope of realizing new breakthroughs in therapeutic and diagnostic modalities for cancer. In alliance with NCI, an array of NPs for therapeutic and diagnostic implications have advanced to the clinical trial stage [24].

The plausible impact of nanotechnology in enhancing tumor treatment and diagnosis is enormous. Because of its potential to revolutionize the synthesis of clinically relevant DDSs, nanotechnology has emerged as an essential game player in modern translational medicine, with clinical applications encompassing contrast agents in bioimaging to carriers for gene and drug delivery into the TME [25]. The size and properties of NPs employed in DDSs are created in accordance with the pathophysiology of the malignancies. Nanotherapy employs nanoscale (10–100 nm) DDS as the therapeutic strategy for intravenous delivery [26]. However, systemically delivered anticancer drugs exhibit weak tumor selectivity and permeate and destroy the normal as well as cancerous cells, resulting in limited therapeutic efficacy coupled with adverse side effects. Renal clearable nanocarriers (RCNs) are newly emerged DDSs, which enable drugs to rapidly penetrate into the tumor cores without the need for prolonged retention in the blood stream, and thereby escape macrophage uptake and also augment the elimination of nontargeted anticancer drugs from the body [27]. RCNs accumulate in the TME with higher selectivity through the enhanced permeability and retention (EPR) effect, resulting in improved therapeutic efficacy of the anticancer drugs with concomitant reduction of side effects. This EPR-based targeting strategy is a fundamental principle in the design of NP-based anticancer drug delivery. By enhancing the delivery of chemotherapeutic medications to tumors and metastatic cancers, nanomedicine normally tries to improve the direct killing of cancer cells.

4. Nanomedicines to circumvent the hurdles in cancer therapy

Penetration of a tumor’s core still represents a formidable barrier for existing DDSs. Nanocarriers may be functionalized with traditional chemotherapeutic agents or nucleic acids, and hence can be a game changer for drug delivery or gene therapy, respectively by enhancing bioavailability and reducing immune system-based side effects, and delivering the cargo accurately [28, 29]. Based on the EPR effect, NPs favorably collect within tumors due to their leaky vessels and limited lymphatic drainage (Figure 2). In addition, NPs can also enter solid tumors by active trans-endothelial processes, particularly notable for human tumors showing rather weak EPR.

Figure 2.

EPR effect in tumors. Unlike normal healthy tissues, in tumor tissues, endothelial cells are poorly aligned with wide fenestrations effecting escalated vascular permeability; lymphatic drainage is impaired and there is absence of a smooth muscle layer, resulting in EPR effect. This results in accumulation of macromolecules (10–200 nm or 40–800 kD) more in tumor tissues than in normal tissues.

Some of the challenges defeated by nanomedicine in generating a new wave of nanoscale drug delivery are:

4.1 Curtailing systemic toxicity

A NP carrier system favors controlled drug targeting and release, in turn, minimizing systemic uptake and is thus crucial for reducing systemic toxicity; thereby, making cancer therapy more efficacious [30]. NPs have been actively explored as carriers to encapsulate and deliver hydrophilic drugs. Placing drug molecules inside or on the surface of a NP carrier allows for controlled release, which offers multiple benefits compared to the conventional dosing forms based on free drugs. Sustained release aims to deliver a drug at a predetermined rate over an extended period of time.

4.2 Attenuation of tumor angiogenesis

NPs play a role in blockage or attenuation of tumor angiogenesis [31]. Extravasation allows NPs to effectively pass the vascular-endothelial barrier via the leaky blood capillaries of the tumor vasculature (inter-endothelial gaps as large as 500 nm), but they still need to navigate the challenging tumor milieu. NPs accumulate at the tumor site as a result of inadequate lymphatic drainage via passive targeting and exert their anticancer effect.

4.3 Tumor tissue retention and inhibition of aggregation

The ideal size of NPs for cancer treatment has been reported to be in the range of 70–200 nm effecting deep tumor tissue penetration, efficient cancer cell internalization coupled with gradual tumor clearance [32]. Smaller NPs get eliminated while the bigger ones are taken up by the RES in the spleen and Kupffer cells of the liver. Nanocarriers of 50 nm have been found to exhibit the maximum tumor tissue retention, integrated over time, thus resulting in the highest efficacy against both primary and metastatic tumors in vivo [32].

The NP size that obviates aggregation is more likely to prevent thromboembolism, which makes it advantageous for systemic distribution of the NPs when considering the capacity to pass through capillaries [33]. The degree of NP agglomeration at interstitial sites is impacted by surface properties of NPs [34]. For instance, hydrophilic NPs are more likely to interact poorly at the interstitial sites with ground materials.

4.4 Access through the blood-brain barrier

Permeation through the BBB is challenging for any drug, even in the nanosize range. Both size and hydrophobicity represent crucial determinants in the design of nanodrugs for brain tumor delivery [35]. Small, lipophilic molecules diffuse passively into the brain, whereas larger hydrophilic molecules such as peptides or proteins require transport mechanisms [36].

4.5 Targeting tumor hypoxia

Hypoxia-induced chemo-resistance of tumor cells still represents a formidable barrier, as it is difficult for existing DDSs to penetrate the tumor hypoxia core. NPs can modulate hypoxia that is indispensable to tumor angiogenesis, metastasis, and multidrug resistance. Hypoxia-triggered nanovehicles achieve controlled drug release at the target sites and enhance the anticancer activity [37].

5. Nanomedicine as an evolving oncology landscape

Cancer nanomedicine has enabled the improvement of existing cancer therapies by capitalizing on the specialized attributes of nanoparticles (NPs), including their structural features and prolonged circulation in the blood [38]. FDA-approved nanotechnology-based products are on the rise and include synthetic polymers; liposomes and nanoliposomes; micellar NPs; protein NPs; nanocrystals and many others often in combination with drugs or biologics [23]. Three groups of NPs have been engineered for gene delivery applications such as hybrid NPs, organic NPs and inorganic NPs (Figure 3).

Figure 3.

Types of NPs applied to drug delivery systems in cancer therapeutics.

5.1 Organic nanoparticles

Organic NPs have been extensively studied for decades and may be liposome based, polymer based, or dendrimers.

5.1.1 Liposome-based organic nanoparticles

Typically, liposomes have a spherical morphology and are made up of one or two lipid bilayers. Liposomes are primarily utilized to deliver both lipophilic and hydrophilic medications, with the inner aqueous core stabilizing the hydrophilic molecule while the lipid bilayer integrates the former. The effectiveness of liposomes as drug vehicles is related to their pharmacokinetics and depends on the physicochemical conditions, e.g., size, surface charge, membrane lipid packing, steric stabilization, dose, and administration route [39]. The US Food and Drug Administration (FDA) in 1995 approved polyethylene glycol (PEG)ylated liposomes with doxorubicin (DOX), i.e., Doxil®. PEG incorporation on the liposomal surface enhanced the half-life circulation, thus taking advantage of the EPR effect [40]. Besides PEG, various hydrophilic polymers such as poly-N-vinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyoxazoline (Pox), hyperbranched polyglycerol, or zwitterionic polymers, have also been employed [41]. Nano-DDSs such as liposomes also offer an option for drug combination, thereby ameliorating the therapeutic efficacy while reversing drug resistance [42]. An array of liposome-based drugs is currently under clinical translation for cancer therapy.

5.1.2 Lipid or polymeric nanoparticles

Lipid nanocarriers are a burgeoning field for the transport and delivery of a diverse array of therapeutic agents, from biotechnological products to small drug molecules, and significantly improve the therapeutic effectiveness of drugs [43]. Polymeric NPs are small polymeric colloidal particles with a therapeutic drug either dispersed in the polymer matrix (nanosphere) or encapsulated in polymer (nanocapsule) [44]. The advantages of polymeric NPs as drug carriers include their potential for controlled release, their ability to protect drugs and other biologics, couple with improved bioavailability and therapeutic index.

5.1.3 Dendrimers

These synthetic macromolecules resemble trees with multiple branches and sub-branches radiating out from a central core. They are highly branched polymers with easily modifiable surfaces that makes them promising structures for functionalization (for improved delivery and targeting) and conjugation with drugs and nucleic acids. Dendrimers help to enhance the solubility and bioavailability of hydrophobic drugs [45]. The drugs may be encapsulated in the intramolecular cavity of the dendrimers or surface conjugated to their functional groups. Nucleic acids usually form complexes with positively charged surface of cationic dendrimers. The shape, size, charge, and solubility of these nanocarriers can be controlled by different synthesis processes.

5.2 Inorganic nanoparticles

Inorganic NPs include metal and metal oxide NPs such as silver (Ag), iron oxide (Fe₃O₄), titanium oxide (TiO₂), copper oxide (CuO), and zinc oxide (ZnO). Gold NPs, carbon nanotubes, quantum dots, magnetic NPs, and silica NPs are some of the inorganic NPs that have been examined. The advantages of inorganic NPs include a larger surface area-to-volume ratio, ease of preparation, enhanced therapeutic efficacy, reduced drug resistance and other side effects, a wide range of surface conjugation chemistry, albeit at the trade-off of their lower biocompatibility and biodegradability [46]. The major drawback of inorganic NPs is their toxicity. The increased reactive oxygen species (ROS) can be harmful to the normal cells, which can trigger other protective mechanisms like enzymatic and nonenzymatic antioxidant defense mechanism. Further, failure in restoring these protective mechanisms may lead to the damage of proteins, lipids and DNA, resulting in tissue damage, inflammation, and loss of normal cell function.

5.2.1 Gold nanoparticles

Gold (Au) NPs are frequently used as nanosized diagnostic and therapeutic agents. Colloid Au has shown potential in medication delivery owing to its unique physicochemical characteristics such as strong tunable surface plasmon resonance (SPR) which can be detected using multiple imaging modalities, capacity to bind amine and thiol groups, enable surface modification and ability to passively accumulate on tumor cells [47]. Efforts have been made to entrap Au NPs into a lipid carrier to enhance its antitumor potential. Au porphyrin has been documented as a very potent antitumor drug [48]. Au NPs have been widely used as one of the leading nanomaterials for combinatorial cancer therapy [49].

5.2.2 Silica nanoparticles

Mesoporous silica nanoparticles (MSNPs) exhibit mechanical, thermal, chemical stability, high surface area and ordered porous interior to store anticancer therapeutics with high loading capacity and tunable drug release mechanisms [50]. Furthermore, the surface of MSNPs can be easily decorated or modified by attaching ligands for specific targeting to the cancer cells exploiting their overexpressed receptors. The controlled release of drugs at the target site without any leakage to the healthy tissues can be achieved by employing environment responsive gatekeepers for end-capping of MSNPs.

5.2.3 Magnetic nanoparticles

Magnetic nanoparticles (MNPs) offer high magnetic moments and surface-area-to-volume ratios that make them attractive for hyperthermia-mediated therapy of cancer as well as targeted drug delivery. MNPs are directed at the target tissue by means of an external magnetic field. Materials most commonly used for magnetic drug delivery contain metal or metal oxide NPs, such as superparamagnetic iron oxide NPs (SPIONs). SPIONs are conjugated with drugs, in combination with an external magnetic field to target the nanoparticles [51]. Due to their high osmotic pressure and ease of separation from water by a magnetic field, magnetic NPs functionalized with highly water-soluble and ionic strength groups have attracted attention in recent years as promising DDSs. Recently, a study reported the use of folic acid-conjugated poly(amidoamine) dendrimer-grafted magnetic chitosan as a smart drug delivery platform for doxorubicin, targeting human breast cancer cell lines [52]. This multifunctional system can address the limitations of conventional chemotherapeutic agents by utilizing pH-triggered drug release, which enables targeted cytotoxicity against cancer cells.

5.2.4 Carbon nanotubes

Carbon nanotubes (CNTs) are categorized into single-walled CNTs, consisting of a single piece of graphene and multiwalled CNTs comprising of a multilayer of graphene sheet that caries peptides, proteins and genes. They can pass through membranes, carrying therapeutic drugs, vaccines or nucleic acids deep into the cellular targets [53]. They are safe, nontoxic vehicles and increase the solubility of the attached drug, resulting in greater therapeutic efficacy. Multiwalled CNTs modified by dendrimer have been used for the delivery of doxorubicin.

5.2.5 Quantum dots

Quantum dots (QDs) are semiconductor NPs that have optical and electronic (optoelectronic) capabilities depending on their size and composition. Compared with conventional drug carriers, QD nanocarriers for drugs have become a hotspot in the field of nanomedicine as they are small in size with large surface area [54]. These carriers have a unique mode of drug release with an initial burst followed by a constant release over a prolonged period of time, thereby increasing the effectiveness of drugs at a limited concentration, with negligible side effects. Since the drug-loaded carriers have the property of adhesion and small particle size, they can improve the absorption, bioavailability, and stability of drugs; lengthen circulation time in vivo; enhance targeted absorption of the drug; improve biodistribution; enhance the efficacy and reduce side effects of drug; and improve the therapeutic index of the drugs.

5.3 Hybrid-based nanoparticles

Owing to the advantages and disadvantages of organic and inorganic NPs, combination of the two in a single hybrid DDS endows the multifunctional carrier with superior biological properties that can augment therapeutic efficacy as well as lessen drug resistance [55].

5.3.1 Lipid polymer hybrid nanoparticle

The most commonly used matrices in these nanocarriers are polymers and lipids. Among the polymeric nanosystems, polymeric NPs, polymeric micelles, and polymer-drug conjugates have been distinguished, while the lipid-based nanosystems include liposomes, solid lipid NPs, and nanostructured lipid vectors [56]. Lipid-based nanocarriers offer several advantages such as low production cost, high trapping efficiency of the therapeutic agent; however, they tend to display reduced stability, a fast load release, and high polydispersity.

5.3.2 Organic-inorganic hybrid nanoparticles

One popular approach to creating NPs is to combine organic and inorganic hybrid NPs to integrate their merits and minimize their intrinsic drawbacks. A liposome-silica hybrid (LSH) NP comprising of a silica core encapsulated by a lipid bilayer has been reported to be effectual in delivering drugs to kill prostate and breast cancer cells [57]. The LSH NP has also been shown to offer a platform for the synergistic drug delivery, such as gemcitabine and paclitaxel to pancreatic cancer in a mouse model of the disease [23].

5.3.3 Cell membrane-coated nanoparticles

This strategy for NP design involves hybridization of natural biomaterials with organic or inorganic NPs. Cell membrane-covered drug-delivery nanoplatforms have been garnering attention because of their enhanced biointerfacing capabilities that originate from the source cells. In this top-down strategy, NPs are covered by various membrane coatings, including membranes from specialized cells or hybrid membranes from different types of cell membranes. NPs coupled with a hybrid membrane derived from macrophage and cancer cells could treat breast cancer-derived lung metastases and accumulated at sites of inflammation, targeting specific metastasis, with homogenous tumor targeting abilities and exhibited excellent chemotherapeutic potential with inhibitory effects on cell viability, motility, and invasion and no overt cardiotoxicity [58]. This hybrid cell membrane-disguised nanoplatform is a promising strategy for specific targeted therapy of tumor metastasis.

6. Mechanism of targeting with nanodrugs

A crucial aspect of nanocarriers for drug delivery is their ability to target cancer cells specifically to boost therapeutic effectiveness while shielding normal cells from damage. Owing to their specific cell uptake and trafficking mechanisms, NPs permit the delivery of sensitive therapeutics in sufficient concentration to their target site in active form, and prevent accumulation in undesired organs. Hence, proper NP formulation and optimization is pertinent to enable cellular/nuclear targeting. Active and passive targeting are the two basic categories into which the NP targeting systems can be categorized (Figure 4).

Figure 4.

Targeting of NPs to cancer cells to enhance therapeutic efficacy and minimize systemic toxicity. Active targeting is affected through interaction between ligands on NPs and overexpressed receptors on cancer cells. Passive targeting of NPs is enabled by EPR effect, which exploits escalated vascular permeability and impaired lymphatic drainage of cancer cells and NPs enter the tumor vasculature through leaking blood capillaries. Adapted from Yao et al. [23].

6.1 Active targeting

Active targeting precisely targets the cancer cells through direct interaction between ligands decorated on the surface of NPs with their receptors that are overexpressed on cancer cells. Internalized NPs successfully release therapeutic medications by receptor-mediated endocytosis. This strategy promotes the affinities of the nanocarriers for the surface of cancer cell and thus enhances the drug penetration. Since proteins and small interfering RNAs (siRNAs) are macromolecular drugs, active targeting is particularly suited for their delivery. The frequently studied receptors include the transferrin receptor, folate receptor, glycoproteins (such as lectins), epidermal growth factor receptor (EGFR) and Human epidermal growth factor receptor 2 (HER2). These ligands precisely bind to receptors on target cells [59].

6.2 Passive targeting

Under certain conditions such as inflammation and hypoxia, characteristic of tumors, the endothelium of blood vessels becomes more permeable than in the healthy state. NPs extravasate from blood arteries that nourish the tumor and concentrate in tumor tissue as a result of rapid and efficient angiogenesis. The rapidly growing tumors capitalize on hypoxia to recruit new blood vessels or engulf the existing ones. The newly formed leaky vessels allow selective enhanced permeation of macromolecules larger than 40 kD and nanocarriers to the tumor stroma. Furthermore, poor lymphatic drainage in tumor contributes to retention of drug-encapsulated nanosized drug carriers, enhancing the pharmacokinetics (prolonged systemic circulation) of the drug, providing tumor selectivity and minimizing adverse effects. Nanocarriers then distribute their therapeutic contents to tumor cells and this biodistribution of NPs promotes the EPR effect. Drugs after being successfully delivered to the target site, unveil their therapeutic magic. This type of tumor targeting termed “passive” relies on carrier characteristics (size, circulation time) and tumor biology (vascularity, leakiness) but does not possess a ligand for specific tissue or organ binding unlike active targeting [59].

The tumor microenvironment plays a significant role in the passive distribution of nanomedicines in addition to the EPR effect. Glycolytic cancer cell metabolism and hypoxia yield an acidic tumor microenvironment. Subsequently, the low pH environment triggers some pH-sensitive NPs to release chemotherapeutic drugs in the vicinity of the cancer cell [60]. However, there are some limitations with respect to passive targeting, such as nonspecific drug distribution, nonuniversal existence of the EPR effect and varying vascular permeability across various tumors.

7. Smart nanoparticles for cancer gene therapeutics

The massive data available from human genome sequencing has accelerated the identification of target genes, making gene and nucleic acid therapeutics the next generation of medicine. In the past decades, gene therapy has undergone a notable progress, and is now poised to become a first-line therapy for cancer. By cellular administration of therapeutic nucleic acid, gene therapy modifies gene expression with the goal of treating a disease.

7.1 Cancer gene therapeutics

Opposed to conventional treatment paradigms, with the advancements in cancer genomics, gene therapy has the potential to treat cancer by directly targeting or focusing on the culprit genes. Gene therapy leverages a multitude of advantages for anticancer therapeutics such as high potency and specificity, low off-target toxicity and delivery of multiplex genes that can concurrently target cancer tumorigenesis, recurrence and drug resistance. Strategies for cancer gene therapy comprise of: (i) suicidal gene therapy, wherein an enzyme expressing transgene is introduced into the cell, thereby converting inactive prodrug into metabolites cytotoxic to the host cells [61]; (ii) gene silencing, whereby gene expression is suppressed by RNA interference (RNAi) techniques such as siRNA, small hairpin RNA (shRNA), antisense oligonucleotides, micro RNA (miRNA) [62]; and (iii) DNA/messenger RNA (mRNA) vaccination, wherein specific tumor antigen-encoding plasmid DNA/mRNA is introduced into the cell to induce an immune response [63, 64].

7.2 Cancer genes and nanotechnology: a promising alliance for next generation cancer therapeutics

Novel delivery methods are required in furtherance of this rapidly evolving field of cancer genomics to be translated into clinically viable gene therapy for patients. Among the numerous gene delivery strategies, NP-based anticancer gene therapy has attracted significant attention due to low toxicity profiles, well-controlled and high gene delivery efficiency, and multifunctionalities [65]. Magnetic NPs have unleashed the potential to achieve selective and efficient delivery of therapeutic genes and transform the challenge of gene therapy into a new frontier for cancer treatment [66, 67]. mRNA vaccine nanoformulations have been used to maximize cellular immunity for cancer treatment [68]. Nano-RNAi-based biodrugs have been engineered to inhibit the target genes in cancer patients [69]. Iron oxide and gold NP carriers for RNAi therapy have also been explored for targeted delivery and RNA payload release, coupled with auxiliary properties supporting imaging functionality for theranostic application. Moreover, the RNAi gene delivery may be paired with combination therapies such as chemotherapy, photothermal therapy, immunotherapy, and radiotherapy [70].

8. Harnessing the combined potential of cancer nanomedicine and immunotherapy: a new paradigm in immunotherapeutic nanomedicines

The immune system is a vital determinant of cancer, suppressing or promoting its development and progression and thus shapes the cancer trajectory. It may polarize to an immune-stimulatory state, enabling T cell immune-surveillance or orchestrate a tolerogenic immunosuppressive niche, interfering with the cytotoxic potential of tumor antigen-specific T cells [71]. Thus, novel therapeutic strategies are needed that aim to restore the TME to an immune-reactive state.

8.1 Immune evasion as a hallmark of cancer

Cancer cells are known to elude the host’s immune system’s defensive machinery and avert immunological killing. The concept of cancer immunoediting underpins this hallmark and comprises three key phases, namely: elimination, equilibrium and escape [72]. Immunosurveillance is shaped by the interplay between innate and adaptive arms of immunity, working in tandem to eliminate dysregulated cancer cells.

8.2 Cancer immunotherapy targeting immune cells versus tumor cells

To counter the immunosuppressive TME, cancer immunotherapy seeks to either activate immune cells (within peripheral lymphoid organs or the TME) or remove immunodeficient cells in the TME, ultimately resulting in the killing of tumor cells [73]. Currently, FDA approved antiangiogenic drugs have shown modest levels of clinical success owing to tumor hypoxia, antiangiogenic therapeutic resistance, and poor targeting of TME. To defeat these constraints, targeting angiogenesis synergistically with immunosuppressive TME could offer potential therapeutic opportunities [31]. Cancer immunotherapy can be augmented with toll-like receptor agonist (TLRa) as adjuvants which elicit potent immune activation. Despite their potential, their clinical translation is limited due to lack of pharmacokinetic control, causing systemic toxicity from unregulated systemic cytokine storm [74].

8.3 Immune checkpoint blockade therapy

Immune checkpoints are the gate-keepers of immune response that maintain self-tolerance. Stimulatory immune checkpoint molecules promote T-cell activation and potentiate immunological response; concomitantly, immune checkpoint inhibitors (ICIs) suppress the body’s immune response and prevent onset of autoimmunity. Immune checkpoint blockade therapy (ICBT) strengthens immune response to fight against tumors by modulating immunological checkpoint signaling pathways, aids antiangiogenesis by lowering vascular endothelial growth factor expression and alleviating hypoxia [75]. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) on the surface of activated T cells, as well its ligand on tumor cells, programmed cell death-ligand1 (PD-LI), are the principal targets of clinically accessible ICIs. Other immune checkpoint molecules include lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) structural domain proteins, T cell immunoglobulin mucin-3 (TIM-3), variable domain of immunoglobulin suppressor of T cell activation (VISTA), to name a few. Until recently, as many as 70 ICIs are in phase III and IV clinical trials; while seven ICIs have been FDA-approved [76]. The first immune checkpoint targeting agent, ipilimumab, a monoclonal antibody (mAb) targeting CTLA-4, was approved by FDA in 2011 which opened the domain of ICBT. Subsequently, mAbs blocking other checkpoints such as PD-1 or PD-L1 have received FDA approvals to treat a number of tumor types.

Despite the unprecedented durable clinical responses observed in subsets of patients, most patients do not respond, and few develop resistance to therapy after initial response. Furthermore, ICBTs can result in life-threatening toxicities, known as immune-related adverse events (irAE).

8.4 Cancer nanoimmunotherapy as a renaissance of cancer nanomedicine

Immunotherapeutic approaches have been revisited with the advent of nanotechnology that can target the peripheral immune system as well as the key cellular components of TME and tumor cells more precisely. Thus, nanoplatforms have been engineered to improve the delivery efficiency of cancer nanomedicines that can target immune cells such as dendritic cells (DCs) for peripheral immune activation or inhibit immunosuppressive cells within the TME. These nanoimmunomedicines have brought a paradigm shift in cancer therapy by embracing cancer nanomedicine and immunotherapy, resulting in synergistic effects such as the immune system activation to remove immunosuppression as well as induction of immunological memory [77].

Several cancer nanomedicines have been shown to boost anticancer immunity by working in concert with clinically proven immune therapeutics [78]. Nanoimmunomedicines can also repurpose cancer nanomedicine to reduce the toxicity of various immunotherapies (Figure 5). Integration of antiangiogenic therapy with immunotherapy in a single nanoplatform has been reported as a promising nanotechnological advancement oriented to modulate the immunosuppressive TME without eliciting systemic toxicity [31]. NPs have been found to constitute a modular platform to deliver TLRa that potently synergized with PD-L1 checkpoint blockade to slow tumor growth while potentially diminishing the encapsulated dosage to achieve therapeutic efficacy, resulting in increased potency, reduced systemic cytokine release and decreased toxicity [74].

Figure 5.

Nanomedicine-based immunotherapy: a promising solution for cancer therapeutics.

8.5 Nanotechnology to enhance immune checkpoint blockade therapy

As checkpoint inhibitors targeting the principal inhibitory axes alone do not elicit adequate response in patients bearing poorly immunogenic tumors, a combination of ICIs with nanotechnology-driven immunostimulatory treatment, such as nano-chemo/photo/thermo therapy has been implemented as a viable strategy to break immune tolerance locally and enhance systemic antitumor immunity. To improve the long-lasting response rate of ICBT, nanotechnology was employed for the delivery of single immune checkpoint inhibitor that unfortunately led to resistance and a restricted period of response. However, ICBT (targeting different inhibitory pathways or both inhibitory as well as costimulatory pathways) in concert with nanotechnology delivery systems has generated promising results [79].

The creation of novel NPs, such as lipid nanoparticles, nanoscale metal-organic frameworks, polymeric NPs/micelles/nanogels, inorganic NPs, and nanocarriers derived from cell membranes, has provided efficient solutions for the targeted delivery of the cargoes, stimulation of antitumor immune responses, sensitization of tumors to immunotherapy, and/or reduction of side effects. Nanomedicines can even achieve sequential release of various treatments to generate a cascade immune response, induce immunogenic cell death (ICD) of cancer cells to improve cancer immunotherapy, and modify the tumor immune-microenvironment.

Particularly in pre-clinical settings, the synergism of nanomedicine with immunotherapy has yielded impressive results. Nevertheless, molecularly targeted small molecule anticancer treatments, as well as nanotherapeutics and immune therapeutics, only perform well in specific patient subpopulations. As a result, methods for patient stratification in clinical trials need to be developed that may be crucial for ensuring rapid and effective clinical translation of nanoimmunotherapy.

9. Conclusion

For the treatment of cancer, nanotechnology has been developed as effective DDS. The development of nanocarriers for controlled drug delivery and targeted therapy has increased the efficacy of cancer medicines, lowering off-target adverse effects. Few of these active anticancer medicines are FDA approved while others have progressed onto clinical trials. Cancer treatment effectiveness is also enhanced by employing strategies such as immunotherapy that prime our bodies to attack cancer. Additionally, nanocarrier delivery technologies offer enhanced platforms for combination therapy, which aids in overcoming drug resistance due to efflux transporter overexpression, faulty apoptotic pathway, and hypoxic TME. With rational therapeutic combinations, next-generation multifunctional cancer nanomedicine and NP-mediated integrated gene therapy and/or ICI immunotherapy are needed to support “multitargeted therapy” by obstructing adaptive chemo-resistance, immune escape and amplifying the impact of therapeutic combinations. Nanoimmunomedicines may be clinically translated and may lead to a paradigm shift in cancer treatment.

10. Future perspectives and challenges ahead

NP carriers penetrate tumors and exert efficient antitumor effect. An ideal carrier would be “theranostic nanocarrier” that can carry the antitumor medicine while also being coated with particles for tumor surveillance and imaging to integrate the therapeutic and diagnostic procedures in the same NP carrier provided the medication has strong imaging potential. A few of these are undergoing clinical trials. Nanotechnology is anticipated to form alliance with pharmacogenomics and revolutionize pharmacotyping and “personalized medicine” to predict anticancer pharmacotherapeutic outcomes. It is further necessary to create novel platforms that combine cancer biology and “antimetastatic nanotechnology” while considering the biological mechanisms of different stages of cancer metastasis. A merger of these disciplines may hasten cancer diagnosis at a very early stage, excluding the need for costly late-stage emergency therapies for metastatic cancer. To realize the clinical potential, a focused therapeutic intervention specific to TME is preferred. Through minimally invasive surgery, “implantable devices” can be directly put into tumors, releasing the nanomedicines/chemotherapeutics and increasing the in vivo efficacy of chemotherapy, making it more cost-effective.