Nanoparticle-based formulation for drug repurposing in cancer treatment

Introduction of nanomedicine

Nanomedicine was first entered the preclinical in the mid-1980s, and the first product is PEGylated adenosine deaminase enzyme that was approved by FDA in early 1990 [ ]. Ever since then, scientists hold great passion in this area and many different types of nanoparticles (NPs) have been produced. Perhaps one of the most famous products is the Doxil (DOX liposomal), which appeared in the United States in 1995 for the treatment of patients with ovarian cancer and AIDS-related Kaposi's sarcoma after the failure of prior other therapy. It can prolong drug circulation time and avoid the reticuloendothelial system due to the PEGylation of the liposomes [ , ].

NPs can have a broad size distribution, ranging from larger than atoms to several hundreds of nanometers. The size of a NP has a significant impact on cellular interaction and in vivo pharmacokinetics, including cellular uptake, biodistribution, and circulation half-life [ ]. NP can be generated from a variety of materials, such as lipid [ ], polymer [ ], protein constructs, carbon dots, and inorganic nanomaterials such as mesoporous silica NPs [ ] and gold nanoclusters [ ]. Nanomedicine has broad applications such as anatomical and functional imaging (CT, MRI, PET), diagnosis (detection of molecules cells, tissues), and therapy (mostly focus on cancer therapy) [ ]. Superparamagnetic iron oxide NPs that are composed of nano-sized iron oxide cores coated with dextran shell have a strong T2 effect and can significantly improve the MRI sensitivity [ ]. Quantum dots were used to develop a fluorescent polarization assay to identify the synthetic peptides' antigenicity. Quantum dots were first conjugated with different peptides and the corresponding antigenicity was measured by using the hepatitis B virus surface antigen as the target. This assay can be completed within a few minutes with high sensitivity and specificity to be 85.4% and 98.6%, respectively [ ].

There are several advantages of NPs over conventional formulations. One of the major benefits of NPs is their high tumor accumulation, which can be achieved through either passive targeting or active targeting. The passive targeting of NPs is exploiting the unique tumor microenvironment. In tumor tissue, the absence of a supporting matrix for the vascular tissue intimates the formation of very leaky vessels and pores (100 nm–2 μm) formed by adjacent endothelial cells [ ]. NPs are accumulated in tumor tissue by taking advantage of this leaky vasculature and poor drainage system, also called EPR (enhanced permeability and retention) effect. While the free drug enters tumor tissue by free diffusion, NPs can extravasate into the leaky tumor blood vessel and remain inside the tumor due to the insufficient lymphatic drainage system [ ]. Vlerken et al. performed the in vivo biodistribution of free drug and the PLGA-based NPs in mice xenografts cancer model and observed a 6.5-fold increase of the NP accumulation in the tumor site compared with its free drug form [ ]. Active targeting is employed to further improve tumor-selective localization of the NP. Conjugating targeting ligands is one of the most popular ways to achieve active targeting. The ligands on the surface of NPs can be recognized and internalized by its corresponding receptors expressed on the surface of cancer cells (e.g., different antibodies, antibody fragments) [ ]. Besides higher tumor targeting, the encapsulation of therapeutic molecules in a NP can improve their solubility, bioavailability, and altered biodistribution and facilitate the cellular uptake.

Despite the advantages, there are several biological and technological challenges yet to be solved for the clinical translation of nanomedicine. One of the main biological challenges is the toxicity of nanomaterials. Other than a few polyethylene glycol (PEG) and PLGA-based polymer, sugar, or protein-based system, there are quite a few synthetic polymers that are eventually proved clinically. Fundamental research is needed to study how the different types of NPs are eliminated from the body. It was proposed that small NPs (smaller than 6 nm) undergo efficient urinary excretion [ , ]. Most of the NPs that cannot be cleared by the renal system will eventually be accumulated in the liver via the mononuclear phagocyte system (MPS). This hepatic processing and biliary excretion are usually slow from several hours to months, which raises the concern of chronic toxicity to the liver [ ]. To overcome the in vivo degradation and toxicity of NP, ideally designed NP should be smaller enough in the circulation system to undergo efficient renal clearance and retain the features that are not favored by the MPS. The technological challenges associated with nanomedicine mainly focus on the scale-up synthesis of polymer and NP. To develop clinically translatable polymers, the synthesis steps should be reproducible and reliable. Nanomanufacturing also requires high-quality control over the size, size distribution, shape, morphology, surface charge, and drug loading efficiency of NP. The overall outlook of NPs is promising, as it is a revolutionary approach to addresses the many disadvantages associated with the free drugs and it is now being expanding to many diseases.

Combinational nanomedicine: two or more drugs in one particle

Drug combination includes two or more drugs in a single dosage form at a fixed dose, which needs to take into account the diverse pharmacokinetics, physiological varieties, and different drug dose regime. Cancer is intrinsic heterogenic, even to the same tumor of different patients or the different cells within the same tumors. Frequently, the intrinsic or acquired cancer drug resistance to a single chemotherapeutics due to multiple-drug resistance, apoptosis suppression, or enhancing DNA repairing is the main reason for a quick cancer relapse or incurability [ ]. Therefore, the addition of combinational therapy to chemotherapy regimen is particularly beneficial as different drugs can target different pathways or genes that can greatly reduce the number of cancer cells that survived the treatment and significantly delayed the cancer recurrence or even eradicate it. Combinational nanomedicine is providing even greater advantages for cancer treatment and offering superior therapeutic outcomes to the current drug cocktail therapy. Especially in the field of immunotherapy, compared with conventual therapies or cancer nanomedicine, the combinational nanoimmunotherapy substantially improves the patient's overall survival and long-term memory responses ( Fig. 13.1 ) [ , ].

Figure 13.1, Potential clinical benefits of combination nanoimmunotherapy.

By taking advantage of NPs, drugs can be delivered simultaneously to the target of interests and be maintained at the optimum drug ratio. Different drugs can be loaded at desired molar ratios and released in a controlled manner based on nature of the nanomaterials' properties despite the physicochemical property difference of the individual drugs. CPX-351 is a liposome formulation encapsulating cytarabine and daunorubicin at the 5:1 molar ratio. CPX-351 exhibited a prolonged t _1/2 of 40.4 h for cytarabine and 31.5 h for daunorubicin, markable different than their nonliposomal formulation (1–3 h for cytarabine and 18.5 h for daunorubicin). It has been used in several Phase I and II clinical trials for treating acute myeloid leukemia and myelodysplastic syndrome and was exhibited an increased overall patient survival rate. After the IV infusion, the optimized dosage was well maintained for 24 h [ ]. Secondly, combinational nanomedicine can enhance tumor therapeutic efficacy. One advantage of nanomedicine versus conventional medication is EPR effect. Therefore, the bioavailability of the payloads in tumor will be higher, and less drug dose was required to achieve the same therapeutic effect, which in turn would reduce the drug dose and inhibit side effects. Irinotecan is a potent anticancer drug, but its application is hindered by its severe side effects of severe diarrhea, and even life-threatening hematological and GI toxicity [ ]. The combinational of liposomal irinotecan, 5-FU and leucovorin can significantly improve the overall survival of metastatic pancreatic cancer patients compared with 5-FU and leucovorin or liposomal irinotecan alone, together with very acceptable toxicity [ ]. Thirdly, combinational nanomedicine can overcome multiple-drug resistance (MDR).

MDR is a major obstacle for cancer eradication and plays a crucial role in cancer relapse and metastasis. Combination chemotherapy holds great potential in overcoming MDR by targeting mechanisms for cancer. MDR can be developed due to the incidence of excess drug efflux, increase DNA repair, malfunctional checkpoints, and activation of prosurvival pathways [ ]. Some nanomaterials themselves can function as P-gp inhibitors in nature, including the polysaccharides, PEG, and various Pluronic-based polymers [ ]. Pluronic P85 has been widely used in inhibiting P-gp in brain endothelial cells by increasing ATP depletion, inducing membrane fluidization, and inhibiting P-gp ATPase activity [ ]. NPs can also reverse the MDR by increasing cellular uptake, thus bypassing the efflux pumps [ ]. By codelivering doxorubicin (DOX) and paclitaxel in a cross-linking NP, the cellular uptake of coloading NPs in 4T1 cells was significantly increased compared with free drug combination or single drug–loaded NPs.

Repurposing drugs with nanomedicine in cancer therapy: Repurposing old medicines in cancer therapy is a cost-efficient way and is now gathering its momentum. The discovery of new pharmacological targets has extended the life of some centenary-old medicines [ ]. Some examples of repurposing old drugs in nanomedicine are listed in Table 13.1 . Suramin (SM) has been explored in many clinical trials for cancer treatment. However, SM was withdrawn from the market due to its narrow therapeutic window and side effects. To overcome the obstacle for the application SM, we introduced the concept of encapsulating both SM and DOX as a combinational nanomedicine for the prevention of metastatic triple-negative breast cancer (TNBC).

Table 13.1

List of NPs of repurposed drugs in cancer therapy.

Drug category	Drug	New mechanism of actions/indication	Types of NP	Disease model	References
CNS	Perphenazine	Disrupting cancer cell cholesterol homeostasis	Liposome	Xenografted melanoma tumor	[ ]
Iron deficiency anemia	Ferumoxytol	MRI of brain tumors, accumulation in tumor lesions	Inorganic	Patients with advanced solid tumor	[ ]
NSAID	Celecoxib	Decrease levels of key cyclin	Liposome	Xenografted melanoma tumor	[ ]
Antidiabetic	Metformin	Decrease glucose metabolites	Polymer	Patient-derived orthotopic pancreatic tumor	[ ]
Alcohol aversion	Disulfiram	Degrades to diethyldithiocarbamate and forms a copper complex	Polymer	Xenografted ovary tumor	[ ]
Metabolic bone diseases	Bisphosphonate	Cytotoxic effects	Metal-organic	Xenografted lung and prostate tumor	[ ]

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