Polymeric Micelles in Management of Lung Cancer

C H A P T E R

8 Polymeric Micelles in Management of Lung Cancer Fatemah Bahman, Sara Elkaissi, Khaled Greish, Sebastien Taurin College of Medicine and Medical Sciences, Department of Molecular Medicine, and Nanomedicine Unit, Princess Al-Jawhara Center for Molecular Medicine and Inherited Disorders, Arabian Gulf University, Manama, Kingdom of Bahrain O U T L I N E 1. Introduction

194

2. Biology of Lung Cancer

194

3. Types and Subtypes of Lung Cancer

194

4. Treatment of Lung Cancer

196

5. Challenges Facing Treatment of Lung Cancer

197

6. Polymeric Micelles

198

7. Mechanism of Formation

198

8. Different Types of Polymeric Micelle Systems

198

9. Preclinical Assessment of Polymeric Micelles for Lung Cancer Drug Delivery 9.1 Poly(Styrene-co-Maleic Anhydride) (SMA)

Nanotechnology-Based Targeted Drug Delivery Systems for Lung Cancer https://doi.org/10.1016/B978-0-12-815720-6.00008-3

9.2 Poly(Ethylene Glycol)-BlockPoly(D-L-Lactic Acid) (PEG-b-PLA) 199 9.3 Poly(Ethylene Glycol)-BlockPoly(D,L-Lactic-co-Glycolic-Acid) (PEG-b-PLGA) 203 9.4 Poly(Ethylene-Glycol)-BlockPoly(ℇ-Caprolactone) (PEGePCL) 204 9.5 Poly(N-Vinylpyrrolidone)-BlockPoly(ℇ-Caprolactone) (PVP-b-PCL) 204 9.6 Pluronics 204 9.7 D-a-Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS) 206 9.8 PEG-Poly(Amino Acid) (PEGePAA) 207 10. Polymeric Micelles in Clinical Trials for Treatment of Lung Cancer 207

199 199

11. Conclusion

209

References

209

193

Copyright © 2019 Elsevier Inc. All rights reserved.

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8. POLYMERIC MICELLES IN MANAGEMENT OF LUNG CANCER

1. INTRODUCTION Lung cancer is the second most diagnosed and the leading cause of cancer-related death among both sexes [1,2]. The global number of people dying of lung cancer is expected to nearly double to three million by 2035 due to aging populations, the tobacco pandemic, and air pollution in less developed countries [1]. The majority of lung cancers (80%e85%) arise in former or current smokers, while the risk for passive smokers is increased by 25% [3,4]. For 68% of patients, lung cancer is diagnosed at a late stage (III or IV) and usually in older populations aged between 65 and 70 years [2,5]. The overall 5-year survival of lung cancer patients is only 18.1%, one of the lowest when compared to survival rates of other cancer types [5]. However, the survival rate can be improved to 55% when the disease is detected at an early stage and the cancer is still localized. When cancer has spread to distant sites, the 5-year survival drops to 4% [5]. The standard therapy for patients with lung cancer is usually a combination of chemotherapy, surgery, and/or radiation therapy. As most lung cancers are detected at a late and metastatic stage, systemic chemotherapy is the mainstay option for the majority of patients. However, the efficacy of the treatment of lung cancer is plagued by dose-limited side effects to other organs. In recent years, these limitations have led to the development of strategies involving nanomedicines to improve tumor targeting and decrease systemic toxicity.

2. BIOLOGY OF LUNG CANCER Lung cancer arises principally from the cells lining the bronchi and bronchioles in 90%e95% of patients (see Fig. 8.1). In a few patients, the cancer origin is associated with the pleural mesothelioma and on rare occasions to the tissues supporting the lungs [6,7]. The gene signature of lung cancers differs depending on whether

the patient is or was a smoker or nonsmoker [7]. In addition, most mutations promoting lung cancer are somatic and acquired during the person’s lifetime and involve multiple genes [8]. Some studies have demonstrated a familial aggregation of lung cancer cases independent of smoking; this inherited genetic susceptibility is yet to be defined [9,10]. Overall, different mutations have been reported with genetic and epigenetic changes, including base change (single change), insertions, deletions, amplifications, and DNA methylation.

3. TYPES AND SUBTYPES OF LUNG CANCER Lung cancer is mainly divided into small-cell lung cancer (SCLC) and nonsmall-cell lung cancer (NSCLC), representing 10% and 85% of patient cancer cases, respectively [11]. In 1926, Barnard was the first to recognize the lung origin of small-cell carcinoma [12], while Azzopardi described the histological appearance of SCLC [13,14]. SCLC is mainly related to smoking habits, and while its incidence is reduced in countries with active programs for smoking cessation, it is increasing in low- to middleincome countries. SCLC is the most aggressive type of lung cancer and has a 5-year survival of only 7% [15]. SCLC is characterized by high mitotic count, genomic instability, high vascularization, and early distant metastases [16]. Approximately 70% of patients with SCLC are diagnosed with metastasis to the liver, adrenal gland, bone, bone marrow, or brain [17]. SCLC is in fact a heterogeneous disease, and the majority of SCLC cases were associated with the neurological syndrome and expressed neuroendocrine characteristics [18]. The cell of origin of SCLC has been hypothesized to originate from neuroendocrine cells [19] (Fig. 8.1) but this hypothesis is being challenged [19]. SCLC is believed to be initiated by various genetic defects including the inactivation of TP53 and RB1 genes

3. TYPES AND SUBTYPES OF LUNG CANCER

195

FIGURE 8.1

Schematic representation of the diversity of cells lining the lung and the putative origin of lung cancers. Primary carcinomas of the lung are classified as either small-cell lung cancer (SCLC) or nonsmall-cell lung cancer (NSCLC). NSCLCs represents 80% of lung cancers and are subclassified into squamous-cell carcinoma (SCC), large-cell carcinoma (LCC), and adenocarcinoma. The trachea and main bronchi are lined by a pseudostratified epithelium consisting of ciliated, basal, a few neuroendocrine, and secretory cells including goblet and club cells. The intermediate lung (bronchiole) is mainly lined by club cells, ciliated cells, clusters of neuroendocrine cells called neuroendocrine bodies (NEB), and variant club cells adjacent to NEB. The distal portion of the bronchiole is composed of club cells, ciliated cells, and bronchioalveolar stem cells (BASCs) located at the bronchioalveolar junction (BADJ). The alveoli are composed of alveolar type I (AT1) and II (AT2) cells, lipofibroblast, pericyte, and endothelial cells forming capillaries. Multiple stem cell lineages have been proposed to drive tumorigenesis in the lungs. In the proximal lungs, basal cells have been suggested to contribute to SCC. Recently, BASCs and bronchiolar progenitor cells have been hypothesized to contribute to SCC, but the lineage remains to be established. SCLC were predominantly localized to the intermediate airway, in the bronchiole. Neuroendocrine cells have been hypothesized to be the progenitor of SCLCs. LCCs are localized in the intermediate airway and are principally diagnosed by the exclusion of an SCC, SCLC, or adenocarcinoma diagnosis. Finally, BASC and AT2 cells were hypothesized to be the cells of origin of adenocarcinomas. However, studies have suggested that club and progenitor stem cells of BASCs may also contribute to this subtype of NSCLC.

[16,20]. The lost one allele of the 3p regions is also observed early in the disease and in nearly all SCLC tumors [16]. Furthermore, the amplification or overexpression of oncogenes such as the Myc family members or the downregulation of tumor suppressor such as PTEN were also observed in SCLC tumors [16].

NSCLC is also highly heterogeneous and histologically classified into either adenocarcinoma (w40% of all lung cancers), squamous-cell carcinoma (SqCC) (w30% of all lung cancers), or large-cell carcinoma (LCC) (w15% of all lung cancers) [21]. Most NSCLC patients present in the clinic at a late stage and the 10-year relative

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survival rate remains at a flabbergasting low of 8%e10% [22]. The survival rate is also dependent on the histological subtypes, with an overall 5-year relative survival rate of 14%, 17%, and 9% for SqCC, adenocarcinoma, and LCC, respectively [23]. Lung adenocarcinomas are more common in nonsmokers and are diagnosed more frequently in women [24,25]. The adenocarcinoma tumors are heterogeneous based on pathology, molecular profile, and clinical response [26]. The dynamics of the somatic mutations, copy number alterations, and gene rearrangements constitute a challenge to establish a driver oncogene and define therapeutic target [27]. Eighteen genes were found to be significantly altered, including KRAS, TP53, BRAF, anaplastic lymphoma kinase (ALK), and epidermal growth factor receptor (EGFR), which are among the most commonly mutated genes [27]. Adenocarcinomas have a distal lung distribution and develop in the bronchioalveolar region. The regional segregation of adenocarcinomas suggests that they arise from a specific cell population. The alveolar type II cell (AT2) and bronchioalveolar stem cells (BASCs) are the putative cells of origin of adenocarcinomas [28e30] (Fig. 8.1). SqCC has a stronger association with smoking habits and is more common in men [31]. SqCC is heterogeneous and characterized by a high mutation rate. Several somatic gene alterations distinctive from adenocarcinomas have been identified in SqCC, including sex-determining region Y-box 2 (Sox2), platelet-derived growth factor receptor (PDGFR)-a, fibroblast growth factor receptor-1 (FGFR1), and discoidin domain receptor tyrosine kinase 2 (DDR2) among others [32]. SqCC arises preferentially in the bronchi and less frequently in the trachea [33]. The basal cells or stem cell precursors of these cells have been suggested to be the precursor of SqCC [34] (Fig. 8.1). LCC developed preferentially in the intermediate airway [11,35]. LLC is poorly differentiated and lacks the characteristics of other NSCLC subtypes [36,37]. LCC has a poor prognosis even when diagnosed at an early stage [38].

4. TREATMENT OF LUNG CANCER The choice of therapy for lung cancer patients is dependent on the cancer type, stage, and performance status of the patient [39]. The first-line treatment option for a patient diagnosed in the early stages (IeII) is surgery by either removing the tumor with a safety margin, or by performing a lobectomy [40]. In some cases, combination chemotherapy with radiation therapy may be given after the surgery [41,42]. Patients with SCLC are classified into a twostage system that separates patients into a limited stage or an extensive stage [43]. In the limited stage, the tumor is confined to one hemithorax and the regional lymph nodes, while in the extensive stage, cancer has spread beyond this limit [43]. In the limited stage of SCLC, the treatment involves a combination of platinumbased chemotherapy and thoracic radiation therapy, followed by prophylactic cranial irradiation if the patient has responded to the combination [6,44]. The extensive stage is incurable, and treatment involves combination chemotherapy including platinum-chemotherapy and etoposide or irinotecan [45]. Despite the increased knowledge of the molecular events involved in the development of SCLC, the survival rate has not improved for both stages in the past 30 years [46]. In recent years, new targeted therapeutic strategies have been assessed but demonstrated no effect on the relentless progression of SCLC tumors and patient survival [46]. In comparison to SCLC, NSCLC has more therapeutic options. Surgery is the mainstay treatment for patients with stage I [47,48]. However, when the tumor is not accessible, stereotactic radiotherapy is used [49]. For stage IIeIIIA patients, surgery and in some cases platinum-based chemotherapy, along with radiotherapy, have been shown to improve survival [47,50]. For late stage III and IV patients, the treatment of the NSCLC relies on surgery, a combination of chemotherapeutic drugs, radiation therapy, immunotherapy, and targeted therapies [51]. The current recommended chemotherapeutic

5. CHALLENGES FACING TREATMENT OF LUNG CANCER

treatment is based on the combination of platinum-based chemotherapy with taxanes (paclitaxel or docetaxel), or gemcitabine [6]. In the last two decades, the identification of actionable genes, such as EGFR, ALK, ROS1, or BRAF, has led to the development of targeted therapies, and to the improvement of the survival of identified patients [51]. Tyrosine kinase inhibitors, such as gefitinib, erlotinib, and afatinib targeting EGFR or crizotinib and ceritinib targeting ALK have been shown to improve progression-free survival and response rates when compared to the mainstay platinum-based chemotherapy in a specific subset of patients [52e56]. Furthermore, immunotherapy has now arisen as one of the most promising therapeutic strategies for some cases of NSCLC. Two immune checkpoint pathways targeted by monoclonal antibodies are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) or its ligand PD-L1 [57]. Nivolumab targeting PD-1 was approved by the FDA and improved the survival of NSCLC patients [58e60].

5. CHALLENGES FACING TREATMENT OF LUNG CANCER Lung cancers are highly heterogeneous and characterized by an intricate dynamic succession of genetic alterations. While some subtypes harbor established molecular targets, others remain elusive to identifiable and actionable biomarkers. The vast majority of NSCLC patients harboring somatic mutations in tyrosine kinase receptors experience an initial dramatic response to the tyrosine kinase inhibitors, but inevitably and sometimes rapidly develop resistance to the treatment [61,62]. The acquired resistance is observed by either promoting secondary resistant mutations, shifting cell dependency to alternative pathways, or more significant transformation of SCLC [61e64]. In addition, multiple strategies have been developed to

197

address KRAS mutations observed in 20%e25% of adenocarcinomas, but these have led to little progress to improve the outcome of these patients [65,66]. For patients with no actionable driver gene or genes, the standard treatment regimen relies on systemic chemotherapy. Also, the treatment regimen is generally associated with a cytotoxic response, almost all tumors recur and display resistance to further treatments [16]. Furthermore, the systemic distribution of the drugs limits the efficacy of the treatment and promotes toxicity to the normal tissues [67]. Moreover, subtherapeutic drug concentrations reaching the tumor site may also promote the development of multidrug resistance (MDR) [68,69]. Furthermore, the hydrophobic nature of most anticancer drugs limits their administration and requires higher doses of surfactant-based solubilization to improve the systemic drug availability [70]. Moreover, oral administration of cancer chemotherapeutics suffers limitations due to a multitude of biological barriers, and subsequently, first-pass metabolism in the intestine and liver [71]. Current research efforts are focusing on the discovery of new and potent anticancer agents but also new therapeutic strategies for drug delivery to enhance the anticancer effect and increase patients’ quality of life [72]. In recent years, drug-delivery systems have demonstrated their potential for the treatment of cancers by altering the pharmacokinetics of the drug involved, promoting the tumor accumulation, and minimizing adverse effects to normal tissues [73,74]. Over the last 30 years, few chemotherapeutic nanoparticle formulations have been approved by Food and Drug Administration (FDA) for the treatment of various cancers [75]. All the nanocarriers approved for the treatment of cancers rely on the large molecular size of nanoconstructs to accumulate in the tumor. This phenomenon is based on the enhanced permeability and retention (EPR) effect, where the defective architecture and leakiness of blood vessels promote the extravasation of the nanoparticles and the poor lymphatic

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8. POLYMERIC MICELLES IN MANAGEMENT OF LUNG CANCER

drainage contributes to their retention [76,77]. The circulation time of the nanocarriers and accumulation levels in tumor tissue are influenced by the characteristics of the carrier, such as the stability, size, shape, and surface charge [74,78]. In addition, modification of the surface of the nanocarrier by peptides, antibodies, or aptamers can further enhance the active targeting of tumor cells [79].

6. POLYMERIC MICELLES Over the years, biocompatible and biodegradable polymeric micelles have demonstrated their potential as nanocarriers of therapeutic drugs for the treatment of various cancers [80]. Polymeric micelles are defined by the self-assembly of amphiphilic polymers or by the aggregation of block copolymers in selective solvents [81,82]. Polymeric micelles are characterized by a hydrophobic core and a hydrophilic shell or corona [81]. Triblock copolymers and to a lesser extent tetra-, penta-, ionic, grafted, or star-block copolymers have also been created [79]. The choice of polymer is dependent on its compatibility with the drug incorporated to promote high loading capacity and stability of the complex [74]. The hydrophobic core is usually biodegradable and serves as a reservoir for poorly soluble drugs and protects it from the aqueous environment and rapid metabolism; while the shell is biocompatible, it protects the loaded drug, prolongs time in the blood circulation, and determines the biodistribution [74,83]. Polymeric micelles have an optimum diameter between 20 and 200 nm, which allows them to extravasate from the leaky tumor vasculature but they are large enough to escape glomerular filtration in the kidneys [84]. The stealth nature of the corona of most polymeric micelles is sufficient to escape from the reticuloendothelial system (RES) composed of macrophages and present in the liver, spleen, bone marrow, and lymph nodes and prolongs time in the blood circulation [74].

The polymeric micelles are also thermodynamically and kinetically stable because of their relatively low critical micelle concentration (CMC) [85e87]. The high molecular weight and hydrophobicity of the core is determinant in lowering the CMC [88]. Furthermore, the internalization of the polymeric micelles at the cellular level is achieved through endocytosis and involves multiple pathways dependent or independent of major endocytosis-associated proteins, caveolin or clathrin [89,90]. The internalization mechanism is essential to overcoming multidrug resistance by bypassing the efflux transporters located at the membrane.

7. MECHANISM OF FORMATION The formation of polymeric micelles is determined by two approaches; the first relies on a direct dissolution approach where the copolymer is added to an aqueous solution at a concentration above the CMC and the drug is allowed to interact with the hydrophobic core [91]. The second approach is a film-casting method, where the polymer and drug are dissolved in the appropriate volatile solvent to form a film which is later processed by either direct water dissolution, dialysis, or oil-in-water emulsion [91]. Several studies have reported the different shapes of polymeric micelles ranging from vesicles, rods, worms, stars, and spheres with regards to the solvent environment and the relative length of hydrophilic and hydrophobic blocks [79]. The spherical micelles are the most frequently used (Table 8.1).

8. DIFFERENT TYPES OF POLYMERIC MICELLE SYSTEMS Most of the polymeric micelles developed rely on a diblock copolymer structure (AeB). The hydrophilic block that forms the shell or corona consists mainly of polyethylene glycol (PEG)

9. PRECLINICAL ASSESSMENT OF POLYMERIC MICELLES FOR LUNG CANCER DRUG DELIVERY

TABLE 8.1

Morphological Shapes of Polymeric Micelles

Polymeric Micelle Morphology

References

Star shapes

[92]

Vesicles and helices

[93]

Spherical supramolecular

[94]

Worm shapes

[95]

Flower-like

[96]

which is commonly used to form the shell. PEG is nontoxic, water-soluble, biocompatible, and neutrally charged [88]. PEG has emerged as a common strategy to reduce opsonization through the RES and to prolong the circulation of the nanoparticles [88,97,98]. As an alternative to PEG, hydrophilic polymers such as poly(N-vinyl pyrrolidone) (PVP), poly(N-isopropyl acrylamide) (pNIPAM), and chitosan have also been considered [99e101]. The core of the polymeric micelle mainly involves biodegradable hydrophobic polyesters such as poly(D, L-lactide) (PLA), poly(d-valerolactone) (PVL), and poly(εcaprolactone) (PCL). Other polymers, such as polyethers and polypeptides, have also been used. Poly(propylene oxide) (PPO), poly(D,L-lactic acid) (PDLLA), poly(L-aspartate), poly(L-histidine), poly(DL-lactic-co-glycolic acid) (PLGA), poly(beta-benzyl-L-aspartate) (PBLA), and poloxamers are a few examples [79,88,102,103].

9. PRECLINICAL ASSESSMENT OF POLYMERIC MICELLES FOR LUNG CANCER DRUG DELIVERY Several polymeric micelles have been engineered and tested in preclinical studies for the treatment of lung cancers. The various formulations improve the solubility, alter the pharmacokinetics, and enhance a tumor-favorable biodistribution of drugs that are otherwise poorly soluble, rapidly cleared, and broadly toxic (Table 8.2).

199

9.1 Poly(Styrene-co-Maleic Anhydride) (SMA) SMA is a synthetic copolymer where the hydrophobic styrene moiety is covalently coupled to the hydrophilic maleic acid segment. The carboxylic groups constituting the corona may noncovalently bind to the albumin which therefore acts as a secondary biocompatible transporter to the tumor tissue [104]. The SMA micelles are highly stable in biological fluids and characterized by a CMC of 4 mg/L [105]. SMA conjugated to neocarzinostatin (SMANCS) was the first approved nanomedicine and used for the treatment of hepatocellular carcinoma [105,106]. Neocarzinostatin has been shown to induce single- and double-strand DNA breaks [107]. The conjugation of neocarzinostatin to SMA drastically increases the half-life of the peptide and decreases its toxicity to the bone marrow [108]. Further to the amide bond between the NCS and SMA, the SMA inherently assumes the micellar configuration in eques solutions. The anticancer effect of SMANCS was also assessed in a pilot study for various human tumors including lung cancer and demonstrated clinical benefits [76,108]. The conjugation of paclitaxel to SMA was assessed in vitro using the adenocarcinoma human alveolar epithelial A549 cells and displayed significant cytotoxicity [109] (Table 8.2). Paclitaxel has been approved by the FDA for the treatment of NSCLC but is limited by its poor solubility or toxicity in its Taxol form. Recently, the FDA approved Abraxane, an albumin-bound form of paclitaxel, for the treatment of NSCLC [110].

9.2 Poly(Ethylene Glycol)-BlockPoly(D-L-Lactic Acid) (PEG-b-PLA) The diblock copolymer PEG-b-PLA, an FDAapproved pharmaceutical excipient, has been widely used for the encapsulation and delivery of anticancer drugs to treat various cancers over the past 20 years [111]. PLA is a synthetic biocompatible and biodegradable polymer,

200 TABLE 8.2

8. POLYMERIC MICELLES IN MANAGEMENT OF LUNG CANCER

Preclinical Studies Using Micelles for Drug Delivery

Polymers

Drugs

Model (Cells, Cancer Type, Origin)

Study Type (Tumor Site)

SMA

Paclitaxel

A549 cells, NSCLC, human

In vitro

PEG-b-PLA

Paclitaxel 17-AAG Rapamycin

A549 cells, NSCLC, human

In vitro/in vivo (subcutaneous)

Intravenous

[117,124]

PEG-b-PLA

b-Lapachone

A549 cells, NSCLC, human

In vitro/in vivo (orthotopic)

Intravenous

[125]

PEG-b-PLA

b-Lapachone Paclitaxel

A549 cells, NSCLC, human

In vitro

[127]

PEG-b-PLA

Quercetin

A549 cells, NSCLC, human

In vitro

[128]

mPEG-PLA

Curcumin

A549 cells, NSCLC, human

In vitro

[129]

mPEG-b-PLGA

Paclitaxel Doxorubicin

A549 cells, NSCLC, human

In vitro

[133]

PEG-b-PLGA

Paclitaxel Cisplatin

344SQ, H460 and A549 cells, NSCLC, human H69AR cells, SCLC, human

In vitro/in vivo (subcutaneous)

Intravenous

[134]

PLGA CS-PLGA PEG-b-PLGA PEG-CS-PLGA

D9-THC

MRC-5 cells, embryonic lung In vitro/in vivo fibroblast, human (subcutaneous) A549 cells, NSCLC, human Lewis lung carcinoma, NSCLC, murine

Peritumoral

[135]

PEG-b-PCL

Doxorubicin Curcumin

A549 cells, NSCLC, human

In vitro

PEG-b-PCL

Cisplatin

A549 cells, NSCLC, human NCI-H460, NSCLC, human

In vitro In vivo (subcutaneous)

PEG-PCL-PEG

Honokiol

A549 cells, NSCLC, human

In vitro

[147]

PVP-b-PCL

Paclitaxel

A549 cells, NSCLC, human NCI-H1975, NSCLC, human

In vitro

[149]

PVP-b-PCL

Tetrandrine

A549 cells, NSCLC, human

In vitro

[150]

PVP-b-PCL

Curcumin

A549 cells, NSCLC, human

In vitro In vivo (subcutaneous)

Pluronic P123

ruthenium(II) A549 cells, NSCLC, human complexes with aminomethyl (diphenyl)phosphine (RuPCp and RuPNr)

In vitro

Pluronic P85

( )-Gossypol

In vitro In vivo (subcutaneous)

A549 cells, NSCLC, human

Delivery Route

References [109]

[145] Intravenous

Intravenous

[129]

[152]

[160]

Intravenous

[161]

201

9. PRECLINICAL ASSESSMENT OF POLYMERIC MICELLES FOR LUNG CANCER DRUG DELIVERY

TABLE 8.2

Preclinical Studies Using Micelles for Drug Deliverydcont'd

Polymers

Drugs

Model (Cells, Cancer Type, Origin)

Study Type (Tumor Site)

Delivery Route

References

Pluronic P105/F127

Docetaxel

A549 cells, NSCLC, human

In vitro In vivo (subcutaneous)

Intravenous

[162]

Pluronic P123/F127

Paclitaxel

A549 cells, NSCLC, human

In vitro In vivo (subcutaneous)

Intravenous

[163]

Pluronic F127-Selenium

Paclitaxel

A549 cells, NSCLC, human

In vitro

[164]

Pluronic P123-chitosan

Acetylthevetin B

A549 cells, NSCLC, human

In vitro Intravenous In vivo (orthotopic)

[156]

Pluronic P123/F127-biotin

Niclosamide

A549 cells, NSCLC, human

In vitro

[166]

Pluronic P85-PEI/TPGS

Paclitaxel shRNAsurvivin

A549 cells, NSCLC, human

In vitro/in vivo (subcutaneous)

Intravenous

[168]

Pluronic P85-PEI/ TPGS-iRGD

Paclitaxel shRNAsurvivin

A549 cells, NSCLC, human

In vitro/in vivo (subcutaneous)

Intravenous

[171]

Pluronic P105 TPGS

Oleanolic acid

A549 cells, NSCLC, human PC-9 cells, NSCLC, human

In vitro/in vivo (subcutaneous)

Intravenous

[173]

PEG-b-PCLpluronic P105

Doxorubicin

A549 cells, NSCLC, human

In vitro

TPGS-modified doxorubicin

Chlorin e6

A549 cells, NSCLC, human

In vitro/in vivo (subcutaneous)

TPGS-b-Soluplus

Piperine

A549 cells, NSCLC, human

In vitro

TPGS-b-PLA Transferrin-PLA

Cisplatin

A549 cells, NSCLC, human

In vitro/in vivo (subcutaneous)

TPGS-b-PLA Transferrin-TPGS

Docetaxel

A549 cells, NSCLC, human

In vitro

TPGS/PEG-b-PCL

Ginsenoside compound K

A549 and PC-9 cells, NSCLC, human

In vitro/in vivo (subcutaneous)

Intravenous

[184]

TPGS PEG-b-PLA

Paclitaxel

A549 cells and A549paclitaxel resistant, NSCLC, human

In vitro/in vivo (subcutaneous)

Intravenous

[186]

TPGS-b-PLA

Crizotinib

NCI-H3122 cells, NSCLC, human

In vitro

[187]

TPGS-b-PLA

Crizotinib, palbociclib, sildenafil

A549 cells, NSCLC, human

In vitro

[188]

TPGS-b-Solutol HS 15

Baohuoside _

A549 cells, NSCLC, human

In vitro/in vivo (subcutaneous)

[174] Intravenous

[180] [181]

Intravenous

[176] [175]

Intravenous

[191] (Continued)

202 TABLE 8.2

8. POLYMERIC MICELLES IN MANAGEMENT OF LUNG CANCER

Preclinical Studies Using Micelles for Drug Deliverydcont'd Model (Cells, Cancer Type, Origin)

Study Type (Tumor Site)

Paclitaxel parthenolide

A549 cells and A549-T24 taxol resistant, NSCLC, human

In vitro

TPGS-PVPS630

Paclitaxel

A549 cells, NSCLC, human Lewis lung carcinoma cells, NSCLC, murine

In vitro/in vivo (subcutaneous)

PEG-b-poly (aspartic acid)

Doxorubicin

A549 cells, NSCLC, human

In vitro

PEG-b-poly (glutamic acid)

SN-38

SBC-3, SCLC, human H69, SCLC, human H82, SCLC, human

In vitro/in vivo (subcutaneous)

Intravenous

[214]

PEG-b-poly (glutamic acid)

SN-38

A549, PC-9, PC-14, EBC-11 and H520 cells, NSCLC, human

In vitro/in vivo (subcutaneous)

Intravenous

[201]

PEG-b-poly (glutamic acid)

SN-38

A549, PC-14 cells, NSCLC, human

In vitro/in vivo (subcutaneous)

Intravenous

[202]

Polymers

Drugs

TPGS PEG2000-DSPE

Delivery Route

References [193]

Oral

[197]

[200]

17-AAG: 17-N-allylamino-17-demethoxygeldanamycin; CS: chitosan; mPEG-PCL: methoxypoly(ethylene-glycol)-block-poly(ℇ-caprolactone); PAM-PGlu-b-PEG: poly(amidoamine)-poly(glutamic acid)-b-poly(ethylene glycol); PCL: (ℇ-caprolactone); PEG: poly(ethylene glycol); PEG2000DSPE1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]; PEG-b-PLA: poly(ethylene glycol)-block-poly(Llactic acid); PLGA: poly(D,L-lactic-co-glycolic-acid); PVP-b-PCL: poly(N-vinylpyrrolidone)-block-poly(ε-caprolactone); PVPS630: PlasdoneS-630 Copovidone; THC: tetrahydrocannabinol; TPGS: D-a-tocopherol polyethylene glycol 1000 succinate.

while PEG is a biocompatible hydrophilic stealth polymer eluding opsonization [112]. The copolymerization of PLA and PEG promotes the encapsulation of poorly soluble anticancer drugs and improves their solubility by two to three orders of magnitude [111]. The release rate of the drugs can be controlled by the molecular weight of PEG and PLA and PEG/PLA ratio [112]. The low molecular weights of PEG and PLA tend to promote a rapid release of the drug without significantly affecting its pharmacokinetics when compared to the free drug. Meanwhile a higher molecular weight of both polymers promotes stability and alters the pharmacokinetics of the drug encapsulated [111e113]. The PEGb-PLA micelles have a diameter between 10 and 200 nm and are generally internalized into the cells via a lipid raft/caveolae-mediated endocytic pathway [114e116]. PEG-b-PLA

micelles have been assessed for drug delivery to treat lung cancer. Shin et al. developed a PEG-b-PLA micelle encapsulating paclitaxel, 17-allylamino-17-demethoxygeldanamycin (17AAG), and rapamycin [117]. Paclitaxel is a mainstay chemotherapeutic drug approved for the treatment of lung cancers [118,119]. A PEG-bPLA encapsulating paclitaxel is currently approved in Korea and Europe and is undergoing a phase II clinical trial for the treatment of NSCLC under the trade name of Genexol-PM [120,121]. 17-AAG is an inhibitor of heat shock protein 90, a protein chaperone involved in the regulation of multiple oncogenic signaling pathways and was shown to increase the efficacy of paclitaxel [122]. Rapamycin is an inhibitor of mTOR, a protein essential for cell proliferation and survival [123]. The cytotoxicity of the PEGb-PLA micelle encapsulating the three drugs

9. PRECLINICAL ASSESSMENT OF POLYMERIC MICELLES FOR LUNG CANCER DRUG DELIVERY

was assessed in human A549 NSCLC cells in vitro and in vivo [124] (Table 8.2). The activities of the drugs demonstrated synergy in vitro and antitumor activity in a xenograft A549 NSCLC mouse model without significant toxicity [124]. Another study used PEG-b-PLA micelles to encapsulate b-lapachone, a drugdependent NAD(P)H:quinone oxidoreductase 1(NQO1) to achieve cytotoxicity [125]. NQO1 is found overexpressed in the majority of NSCLC [126], b-lapachone undergoes a redox cycle catalyzed by NQO1 and leading to the production of reactive oxygen species (ROS) [125]. The encapsulation of b-lapachone prodrug into PEG-bPLA micelle improves its pharmacokinetics and decreases the adverse effects of the drug, such as methemoglobinemia, while decreasing A549 cells viability in vitro and orthotopic tumor size in vivo [125]. Furthermore, the coencapsulation of paclitaxel and b-lapachone improved the drug loading of the PEG-b-PLA micelle and synergistically decreased the viability of A549 cells and warrants further investigation in vivo [127]. Additional studies have used PEG-b-PLA or mPEG-b-PLA to encapsulate quercetin [128] and curcumin [129], respectively. Methoxypoly(ethylene glycol) (mPEG) was shown to accelerate the clearance of the micelle in vivo by inducing anti-PEG antibodies [130] (Table 8.2).

9.3 Poly(Ethylene Glycol)-BlockPoly(D,L-Lactic-co-Glycolic-Acid) (PEGb-PLGA) PLGA is a biocompatible and biodegradable polymer approved by the FDA and exhibits mechanical properties adjustable to drug delivery. The stability and release rate of the encapsulated material from the PEGePLGA micelles can be modified by altering the molecular weight of the polymers, the ratio of lactide to glycolide, as well as the molecular weight and ratio of PEG as described with PEGePLA copolymer [131]. The PEG conjugation improved the release kinetic of the drugs loaded when compared to

203

PLGA micelle [131]. PEG-b-PLGA nanoparticles were used in two studies for the treatment of NSCLC. PEG-b-PLGA micelles were loaded with paclitaxel and doxorubicin; both drugs are commonly used for the treatment of various solid tumors and characterized by dose-limited systemic adverse effects [132]. These polymeric micelles had an average diameter of 227 nm and zeta potential of 25 mV [133]. The PEG-bPLGA loaded with paclitaxel and doxorubicin (1:2 ratio) was stable and the release rate reached 90% after 300 h [133]. The simultaneous release of paclitaxel and doxorubicin had a synergistic toxic effect against multiple cell lines including A549 cells [133]. More recently, a study coencapsulated paclitaxel and cisplatin in PEG-b-PLGA micelles. The particles had an average diameter of 83 nm and a zeta potential of 1.8 mM [134]. The cytotoxicity of the particles was evaluated in multiple NSCLC cell lines and one SCLC cell line (Table 8.2). The nanoparticles loaded with a 1:1 ratio of paclitaxel and cisplatin were cytotoxic against all the lung cancer cell lines tested in vitro and sensitized cells to subsequent radiotherapy [134]. Furthermore, the dual-drugloaded nanoparticles demonstrated a higher cytotoxicity in vivo in two mouse xenograft models of NSCLC [134]. Another group loaded various PLGA-based micelles with D9-tetrahydrocannabinol (D9-THC) [135] (Table 8.2). Previously, D9-THC has been shown to have an antinociceptive effect and cytotoxic and antiangiogenic effects in several cancer types, including lung cancers [136e138]. The authors encapsulated D9-THC in either PLGA, PEG-bPLGA, chitosanePLGA (CSePLGA), and PEGe CSePLGA generating nanoparticles with diameters of 290, z590 nm, z745, and z790 nm, respectively [135]. Chitosan is a linear cationic polysaccharide consisting of 2-acetamide-2deoxy-b-D-glucopyranose (GlcN) and 2-amino2-deoxy-b-D-glucopyranose (GlcNAc) residues [139]. Chitosan is a biodegradable and nontoxic polymer, immunostimulating and mucoadhesive [140e142]. The release rate of D9-THC was

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decreased when CS was added to the micelle formulation. The effect of the different formulations on cell viability was measured in different lung cancer cell lines, A549 cells and murine LL2 lung adenocarcinoma cells, and human embryo lung fibroblastic MRC-5 cells. The cytotoxicity of the PEG-b-PLGA formulation was superior to the PEGeCSePLGA in both lung cancer cell lines and attenuated in MRC-5 cells in vitro. However, D9-THC encapsulated PEGb-PLGA micelle peritumoral injection failed to show an antitumor effect in a syngeneic mouse model of NSCLC in vivo [135].

9.4 Poly(Ethylene-Glycol)-BlockPoly(ℇ-Caprolactone) (PEGePCL) Diblock copolymer PEGePCL or triblock copolymer PEGePCLePEG have been evaluated in several studies for anticancer drug delivery to lung cancer cells (Table 8.2). PCL is a biodegradable and biocompatible aliphatic polyester [143]. In comparison to PLA or PLGA, PCL is highly hydrophobic and has a slow degradation rate [144]. PEG-b-PCL has been used for the encapsulation of various hydrophobic drugs for the treatment of NSCLC such as a combination of doxorubicin and curcumin [145]. The codelivery of both drugs demonstrated an enhanced synergistic effect when compared to the free drug combination in vitro using A549 cells [145]. Another study used the PEG-b-PLC micelle conjugated to cisplatin to improve the cytotoxicity of cisplatin in vitro and tumor suppression in two mouse xenograft models of NSCLC using A549 and NCI-H460 cells [129]. To increase the hydrophilicity of the micelle, a triblock copolymer PEG-PPCL-PEG was used to encapsulate honokiol, a bioactive compound which has demonstrated anticancer properties [146]. The multiblock polymeric micelle was only evaluated in vitro and demonstrated cytotoxicity against A549 cells [147].

9.5 Poly(N-Vinylpyrrolidone)-BlockPoly(ℇ-Caprolactone) (PVP-b-PCL) PVP is a hydrophilic polymer used as an alternative to PEG; PVP showed a longer circulation time when compared to PEG but a lower volume distribution in the tissue [148]. PVP has been extensively used with various hydrophobic copolymers for the delivery of anticancer drugs [149]. Several in vitro studies used PVP-b-PCL to deliver drugs to NSCLC cells (Table 8.2). Paclitaxel loaded into the polymeric micelles achieved a high loading of 17%, a sustained release rate over a period of days, and a cytotoxicity comparable to free paclitaxel in A549 and NCI-H1975 NSCLC cell lines [149]. A previous study developed a tetrandrine-loaded PVP-bPCL and assessed the delivery of the drug to A549 cells and the cytotoxicity as a result [150]. Tetrandrine, a bis-benzylisoquinoline alkaloid, is a calcium channel blocker and prevents multidrug resistance by binding to P-glycoprotein [151]. The tetrandrine-loaded PVP-b-PCL micelles decreased the migration and invasion, and reduced the viability of A549 cells [150]. More recently, curcumin-loaded PVP-b-PCL proved to have higher cytotoxicity when compared to free curcumin using A549 cells and enhanced the sensitivity to radiation in a murine xenograft model of A549 NSCLC [152].

9.6 Pluronics Pluronic or poloxamer is a synthetic amphiphilic copolymer based on hydrophilic poly(ethylene oxide) (PEO) block and hydrophobic poly(propylene oxide) (PPO) block organized in a triblock structure PEOePPOePEO. In general, PEG refers to polyols of molecular weight below 20,000, while PEO is relevant to polyols with higher molecular weight [153]. The properties of the pluronic copolymers can be altered by modifying the molar mass ratio between the

9. PRECLINICAL ASSESSMENT OF POLYMERIC MICELLES FOR LUNG CANCER DRUG DELIVERY

PEO and PPO blocks, more than 50 pluronics have been developed [154]. Pluronics are biocompatible and form polymeric micelles with a diameter under 100 nm [154]. Pluronics increase the solubility and modify the pharmacokinetics of poorly soluble drugs [155,156]. Pluronics were also described to overcome multidrug resistance by inhibiting drug efflux transporters such as P-glycoprotein transporters [157e159]. Various pluronics have been assessed for the treatment of lung cancers (Table 8.2). Pluronic P123 was used to improve the solubility of organometallic Ru(II) complexes with phosphine derivatives of fluoroquinolones [160]. The micelles were efficiently internalized in A549 cells and induced DNA damage [160]. Tomoda et al. encapsulated ( )-gossypol into the pluronic P85 micelle, the authors demonstrated the higher toxicity of the micelle in vitro using A549 cells and enhanced the radiationinduced cancer cell death in a murine xenograft model of lung cancer [161]. Chen et al. used a mixed pluronic micelle composed of P105 and F127 to encapsulate docetaxel and evaluate its efficiency in A549 and A549 taxol-resistant cell lines [162]. The authors demonstrated that the mixed micelle formulation efficiently delivers docetaxel to A549 taxol-resistant cells and improves cytotoxicity in vitro and antitumor effects in vivo [162]. Zhang et al. also used a mixed micelle composed of Pluronic P123 and F127 to deliver paclitaxel to A549 cells and xenograft A549 tumors [163]. The authors demonstrated the in vivo efficacy of the mixed micelle for the delivery of paclitaxel, improving the cytotoxicity and anticancer effect in vivo [163]. Several studies have also developed mixed polymeric micelles. Bidkar et al. developed a Pluronic F127 stabilized selenium nanoparticle to encapsulate paclitaxel and demonstrated cytotoxicity using A549 cells [164]. Zhu et al. encapsulated Acetylthevetin B into chitosanepluronic P123 micelles [156]. Acetylthevetin B is a cardiac glycoside that demonstrated cytotoxicity in multiple cell lines including lung cancer cells [165].

205

Chitosan efficiently adheres to lung cancer cells through an H-bonding interaction and biotic stickiness [165]. Acetylthevetin B-encapsulated micelles improve the therapeutic effect of the cardiac glycoside by enhancing cellular uptake, cytotoxicity, and localization into the orthotopic tumor tissue, while minimizing its accumulation in the heart, liver, and spleen, and anticancer effect [156]. Russo et al. tagged pluronic F127 with biotin in a mixed micelle preparation with P123 to increase the delivery of niclosamide [166]. Niclosamide is an inhibitor of breast cancer resistance protein and a suppressor of the lipoprotein receptor-related protein (LRP) associated with the WNT/b-catenin pathway and involved in cisplatin resistance [167], The authors showed that the mixed micelle tagged with biotin improved the delivery and cytotoxicity of niclosamide in A549 cells [166]. Shen et al. designed mixed polymeric micelles using pluronic P85, D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), PEG 1000, and polyethyleneimine (PEI). The micelle encapsulated paclitaxel and shRNA-survivin targeting a protein inhibitor of apoptosis [168]. Pluronic P85 was been shown to reverse multidrug resistance and is a potent inhibitor of glutathione S-transferase (GST) activity in lung cancer [169]. GST is an enzyme involved in detoxification of compounds leading to drug resistance [170]. PEI was conjugated to P85 to facilitate the delivery of shRNAesurvivin, TPGS, a derivative of vitamin E, and PEG 1000 were used to increase the solubility and absorption [168]. The study shows that shRNAe survivin and paclitaxel were efficiently delivered to NSCLC A549 cells, increasing sensitivity to paclitaxel and lowering survivin expression in vitro as well as decreasing the growth of A549 tumors in a murine xenograft model of NSCLC [168]. A later study attached a cyclic tripeptide with an arginineeglycineeaspartic sequence (iRGD) to TPGS [171]. iRGD is a tumor-homing peptide binding preferentially to integrin avb3 [172]. The authors demonstrated improved cytotoxicity and anticancer effects

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in vivo [171]. Wu et al. used a pluronic P105 and TPGS to encapsulate oleanolic acid and assessed its effect in vitro and in vivo [173]. The oleanolic acid micelle reduced the viability of two NSCLC cell lines, A549 and PC-9 cells, and tumor development of A549 murine xenograft model of NSCLC [173]. Xu et al. developed a mixed synthetic micelle combining PEGePCL and Pluronic P105 to encapsulate doxorubicin [174]. The authors showed that the micelle delivery of doxorubicin improved cellular uptake and drug retention, and enhanced doxorubicin radiosensitivity in A549 multicellular spheroids [174].

9.7 D-a-Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS) TPGS is a semisynthetic nonionic and amphipathic surfactant formed by esterification of vitamin E succinate with polyethylene glycol 1000 (PEG) and has been approved by the FDA [175e177]. TPGS is a biocompatible solubilizer and absorption enhancer, able to inhibit Pglycoprotein and reverse multidrug resistance as well as facilitate permeation through a biological barrier such as the intestine wall [178,179]. Hou et al. used TPGS conjugated to cis-aconitic anhydride-modified doxorubicin to obtain selfassembling pH-sensitive nanoparticles and used it to encapsulate chlorin e6, a photosensitizer [180]. The authors assessed chlorin e6-loaded TPGS nanoparticles using A549 cells in vitro and in vivo and demonstrated the theranostic potential of the nanoparticles for the diagnosis and treatment of lung cancers [180]. Most micelle preparations used TPGS in combination with other formulations (Table 8.2). Ding et al. developed a mixed micelle preparation consisting of TPGS and Soluplus to encapsulate piperine, an alkaloid extracted from black pepper which showed an anticancer effect in various studies [181]. Soluplus is a polyvinyl caprolactame polyvinyl acetateepolyethylene glycol graft copolymer (PCLePVAcePEG), this new excipient is designed to improve the solubility of

hydrophobic drugs [182]. This mixed micelle preparation improved the cytotoxicity of piperine in A549 cells and its pharmacokinetics [181]. Xu et al. developed dual-labeled nanoparticles using PLAeTPGS and PLAetransferrin copolymers to encapsulate cisplatin [176]. TPGS is attractive based on the inhibition of multidrug-resist efflux proteins while transferrin is a glycoprotein the receptor of which is generally overexpressed in various cancers including lung cancer [183]. The combination of both in one nanoparticle improved the targeted delivery and cytotoxicity of cisplatin to A549 lung cancer cells in vitro, decreased the tumor size, and improved the biodistribution of cisplatin in vivo [176]. An earlier study by Singh et al. developed a mixed micelle PLAeTPGS and TPGSetransferrin to encapsulate docetaxel [175]. The study demonstrated the improve targeting and delivery of docetaxel to A549 cells in vitro [175]. Yang et al. created a TPGS mixed PEGePCL micelle to encapsulate ginsenoside compound K [184]. Ginsenoside compound K is a metabolite of ginseng that demonstrated an anticancer effect in various studies [185]. The encapsulation of this compound into a TPGSePCLePEG mixed micelle improved its anticancer effect in vitro and in vivo [184]. Huang et al. prepared a mixed micelle TPGS/PLAePEG to encapsulate paclitaxel [186]. The authors demonstrated that encapsulation into the mixed micelle improved the cytotoxicity of paclitaxel intro against A549 and A549-paclitaxel-resistant cells in vitro as well as prolonging the blood circulation and anticancer effect in vivo in a murine xenograft model of A549 paclitaxel-resistant NSCLC [186]. Jiang et al. used PLAeTPGS to encapsulate crizotinib, a tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC [187]. The authors demonstrated the increased cytotoxicity of the micelle formulation [187]. de Melo-Diogo et al. encapsulated in a similar micelle crizotinib, palbociclib, and sildenafil [188]. Palbociclib is a selective cyclin-dependent kinase 4/6 (CDK 4/6)

10. POLYMERIC MICELLES IN CLINICAL TRIALS FOR TREATMENT OF LUNG CANCER

inhibitor resulting in G1 cell cycle arrest [189]and sildenafil is a phosphodiesterase 5 (PDE5) inhibitor and inhibitor of several ATP-binding cassette (ABC) drug efflux transporters [190]. The combination of the three drugs synergistically increased the cytotoxicity against A549 cells [188]. Yan et al. developed TPGS/solutol HS15 mixed micelles for the delivery of baohuoside I to A549 cells and assessed the potential of the mixed micelles in vitro and in vivo [191]. Solutol HS15 (polyoxyethylene esters of 12hydroxystearic acid) is an amphiphilic nonionic surfactant made by fusing fatty acids and endcapped methoxy polyethylene glycol (mPEG) and demonstrated biocompatibility [192]. Baohuoside I is an active flavonoid demonstrating anticancer activity against multiple cell lines [191]. The encapsulation of baohuoside I improved antitumor activity against NSCLC, decreased toxic effects on normal tissues, and achieved effective drug delivery [191]. Gill et al. used TPGS/PEG2000-DSPE mixed micelles to encapsulate paclitaxel and parthenolide and assessed the cytotoxicity in A549 and A549 taxol-resistant cell lines [193]. DSPE forms a lipid tail and provides a hydrophobic driving force for self-assembly, while PEG forms the hydrophilic headgroup [194]. Parthenolide suppresses NFkB activity by preventing DNA binding [195], a protein with activity which promotes paclitaxel resistance [196]. The mixed micelle coencapsulation of paclitaxel and parthenolide improved the cytotoxicity against A549 and A549 taxolresistant cells [193]. Recently, a TPGSe PlasdoneS-630 Copovidone (PVPS630) polymeric micelle was evaluated for the oral absorption and anticancer activity of paclitaxel [197]. TPGS is a known enhancer of absorption and permeation [178], while PVPS630 is an amphiphilic random copolymer consisting of N-vinyl-2-pyrrolidone and vinyl acetate [197]. The polymeric micelles improved the bioavailability and anticancer effects of paclitaxel in vitro and in vivo following oral absorption in a syngeneic murine model of lung cancer [197].

207

9.8 PEG-Poly(Amino Acid) (PEGePAA) PEG-b-PAA is a unique carrier owing to the PAA nonpolar core which can encapsulate poorly soluble drugs. PAA is highly biocompatible, nontoxic, and harbors multiple functional moieties including amine, carboxylic acid, hydroxyl, and thiol that allow the encapsulation of drugs, DNA, or RNA [116]. PEG-b-PAA has been prepared using different amino acids including poly(lysine), poly(aspartic acid), poly(glutamic acid), and poly(cysteine) [198]. The size of the polymeric micelles can be controlled within a diameter range from 20e100 nm [199]. Eckman et al. developed a PEG-b-poly(aspartic acid) encapsulating doxorubicin and assessed its cytotoxicity in vitro using A549 cells [200] (Table 8.2). The release rate was dependent on the pH and efficiently decreased A549 cell viability [200]. Nagano et al. developed NK-012, a PEG-b-poly(glutamic acid) block copolymer encapsulating 7-ethyl-10hydroxycamptothecin (SN-38), an active metabolite of irinotecan. NK-012 combined with cisplatin demonstrated the improved cytotoxicity and anticancer effect of the combination. Later, the same group evaluated NK-012 in combination with S1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine and bevacizumab, a humanized antivascular endothelial growth factor (VEGF) monoclonal antibody, against NSCLC cell lines, and demonstrated the increased cytotoxicity of NK-012 combined with S-1 or bevacizumab in vitro and in vivo [201,202].

10. POLYMERIC MICELLES IN CLINICAL TRIALS FOR TREATMENT OF LUNG CANCER Only five polymeric micelles were evaluated in the clinic, and among them only one was approved for the treatment of locally advanced

208 TABLE 8.3

8. POLYMERIC MICELLES IN MANAGEMENT OF LUNG CANCER

Nanomicelles Drug in Clinical Trials

Brand Name 2Polymer

Drug

Indication

Approval/Phase

Genexol-PM

PEG-b-PLA copolymer

Paclitaxel

Locally advanced or metastatic NSCLC

Approved in South Korea (2007) and Europe (2013) Phase II (FDA, USA)

NK-012

PEG-b-poly SN-38 (glutamic acid)

NC-4016

Clinical Trial References Numbers [120,121]

NCT01770795 NCT01023347

SCLC, sensitive Phase II relapsed and refractory relapsed SCLC

[206,213]

NCT00951613

PEG-b-poly DACHPt (glutamic acid)

Advanced solid tumors

Phase I

[210]

NCT03168035

Nanoplatin (NC-6004)

PEG-b-poly Cisplatin (glutamic acid)

NSCLC

Phase Ib/II

[211]

NCT02240238

NC-6300 (K-912)

PEG-b-poly (aspartic acidhydrazone)

Phase I

[212]

JapicCTI132221

Epirubicin Solid tumors (lung cancer)

DACHPt: dichloro(1,2-diaminocyclohexane)platinum(II); FDA: Food and Drug Administration; NSCLC: nonsmall-cell lung cancer; PEG: poly(ethylene glycol); PLA: poly(D,L-lactide); SCLC: small-cell lung cancer.

or metastatic NSCLC (Table 8.3). Genexol-PM is manufactured by Samyang Pharmaceuticals and was approved in South Korea in 2007 and in Europe in 2013 and is currently being evaluated in phase II clinical trials in the USA for the treatment of locally advanced or metastatic NSCLC [121,203] (Table 8.3). Genexol-PM is a PEG-bPLA polymeric micelle encapsulating paclitaxel (16% wt%) forming particles with a diameter of 20e50 mm [81]. The maximum tolerated dose was established at 180 mg/m2 as a 1-h infusion weekly for 3 weeks followed by a resting week in a phase I study involving 24 patients [204]. Genexol-PM and Taxol share similar pharmacokinetics, but Genexol-PM has a lower incidence of adverse effects suggesting that the adverse effects are mainly due to Cremophor EL [205]. In patients with advanced NSCLC, Genexol-PM combined with cisplatin demonstrated a potent anticancer activity and a tolerability that allowed the administration of a higher dose when compared to Taxol [203]. Genexol-PM demonstrated favorable overall response rates of from 37.7% to 46.5% [121,203].

NK-012 is a polymeric micelle manufactured by Nippon Kayaku, Co. NK-012 consists of a block copolymer of PEG and poly(glutamic acid) conjugated to SN-38 [206]. Irinotecan is a topoisomerase I inhibitor approved for the treatment of multiple cancers including SCLC [207]. Approximately only 10% of the irinotecan dose is converted into SN-38 by the liver [208]. In a phase I trial, the maximum tolerated dose was established at 37 mg/m2 SN-38 equivalent [209]. The efficacy and safety of NK-012 were further evaluated in a phase II clinical trial in SCLC patients (Table 8.3). NC-4016 is a polymeric micelle manufactured by Nanocarrier, Co. NC-4016 consists of a block copolymerofPEGandpoly(glutamicacid)encapsulating dichloro(1,2-diaminocyclohexane) platinum (II) (DACHPt) [210]. The encapsulation of DACHPt improved the solubility and decreased the systemic toxicity. NC-4016 was assessed in a phase I dose-escalation and pharmacokinetics study in patients with advanced solid tumors to determine the maximum tolerated dose (Table 8.3). Nanoplatin (NC-6004) is a polymeric micelle manufactured by Nanocarrier, Co. Nanoplatin

REFERENCES

consists of a block copolymer of PEG and poly(glutamic acid) encapsulating cisplatin that was evaluated in a phase Ib/II clinical trial in combination with gemcitabine in patients with solid tumors [211] (Table 8.3). NC-6300 is a polymeric micelle manufactured by Nanocarrier, Co. This consists of a block copolymer of PEG and poly(aspartic acid hydrazone) encapsulating epirubicin [212]. NC-6300 was assessed in a phase I dose-escalation and pharmacokinetic study in patients with advanced or recurrent solid tumors to determine the maximum tolerated dose (Table 8.3).

11. CONCLUSION In summary, multiple combinations of block polymers have been developed and assessed in preclinical studies for the treatment of lung cancers. All these studies have demonstrated that versatile polymeric micelle-based drug delivery is advantageous over the delivery of poorly soluble and often toxic free drug when assessed in vitro and in a murine xenograft model of lung cancers. The polymeric micelles improved the tumor accumulation of the drug encapsulated or conjugated while decreasing the adverse effects on normal tissue. The overwhelming majority of these studies rely on passive targeting and the EPR effect to achieve tumor accumulation. However, until now, only five (passively targeted) polymeric micelles have been investigated in clinical trials, of which Genexol-PM was approved in Korea and Europe for the treatment of patients with locally advanced or metastatic NSCLC. In addition to the ongoing research to extend the circulation time and immune compatibility, the nanocarriers will improve their therapeutic efficacy. A better understanding of the cellular mosaic of lung cancers and tumor environment is required to develop clinical opportunities for a new generation of targeted polymeric micelles.

209

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