Drug Delivery in Cancer Therapy, Quo Vadis? - ACS Publications

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Drug delivery in cancer therapy, Quo Vadis? Zheng-Rong Lu, and Peter Qiao Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00037 • Publication Date (Web): 19 Mar 2018 Downloaded from http://pubs.acs.org on March 20, 2018

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Molecular Pharmaceutics

Drug delivery in cancer therapy, Quo Vadis?

Zheng-Rong Lu* and Peter Qiao †

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA

Short title: Drug Delivery in Cancer Therapy

* To whom correspondence should be addressed: Dr. Zheng-Rong Lu M. Frank and Margaret Domiter Rudy Professor Wickenden 427, Mail Stop 7207 10900 Euclid Avenue Cleveland, OH 44106 Phone: 216-368-0187 Fax: 216-368-4969 Email: [email protected]

Key words: Drug delivery, cancer therapy, drug delivery systems, cancer, nanomedicine

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Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract The treatment of malignancies has undergone dramatic changes in the past few decades. Advances in drug delivery techniques and nanotechnology have allowed for new formulations of old drugs, so as to improve the pharmacokinetics, to enhance accumulation in solid tumors, and to reduce the significant toxic effects of these important therapeutic agents. Here, we review the published clinical data in cancer therapy of several major drug delivery systems, including targeted radionuclide therapy, antibody drug conjugates, liposomes, polymer drug conjugates, polymer implants, micelles, and nanoparticles. The clinical outcomes of these delivery systems from various phases of clinical trials are summarized. The success and limitations of the drug delivery strategies are discussed based on the clinical observations. In addition, the challenges in applying drug delivery for efficacious cancer therapy, including physical barriers, tumor heterogeneity, drug resistance, and metastasis, are discussed along with future perspectives of drug delivery in cancer therapy. In doing so, we intend to underscore that efficient delivery of cancer therapeutics to solid malignancies remains a major challenge in cancer therapy, and requires a multidisciplinary approach that integrates knowledge from the diverse fields of chemistry, biology, engineering, and medicine. The overall objective of this review is to improve our understanding of the clinical fate of commonly investigated drug delivery strategies, and to identify the limitations that must be addressed in future drug delivery strategies, towards the pursuit of curative therapies for cancer.

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Introduction Cancer is a dynamic and heterogeneous disease with high mortality and morbidity. Selective delivery of therapeutic agents into solid tumors has been considered to be one of the major hurdles in achieving long-term disease remission and cure. Selective increase in the concentration of therapeutic agents in tumors has been the primary goal of a large body of research in drug delivery1-4. This approach is predicated on the assumption that higher drug concentration in tumor tissue results in greater therapeutic efficacy. In past decades, there has been tremendous progress in understanding the biology and mechanisms that underpin cancer drug delivery and, consequently, rapid development of delivery systems for cancer therapeutics57

. Recently, with booming advancements in nanotechnology, a large number of new cancer drug

delivery systems are reported every year8. The search for better delivery systems and nanomedicines to improve the efficacy of cancer therapies has attracted many scientists across disparate disciplines, including chemistry, material sciences, engineering, physics, biology, and medicine. New concepts, ideas, and knowledge have been injected into drug delivery research, and with these, new opportunities have been introduced. Understanding the challenges and limitations of drug delivery for cancer therapy is valuable and imperative to avoid past failures encountered in clinical trials, and to integrate newly acquired knowledge towards designing more efficacious drug delivery systems and therapies for better and curative outcomes. Many different types of drug delivery systems have been developed for cancer therapy since the early 1950s9. Improved tumor drug delivery and therapeutic efficacy have been demonstrated in various animal models and patients. Numerous delivery systems have been tested in clinical trials and some have been approved for clinical use10, Figure 1. Nevertheless, this promising progress in drug delivery has not resulted in curative therapies for the majority of patients, particularly those with aggressive solid tumors11. There is an ongoing discussion in the drug delivery community about the limitations of the existing theory and methods of drug delivery and its future directions in cancer therapy. A tremendous wealth of cancer drug delivery knowledge and experience has been accumulated with the advent and investigation of various drug delivery systems. Many outstanding reviews have recently been published to discuss the challenges and new advances being made in the cancer drug delivery field3, 4, 8, 12-16. Here, we review clinical data on several categories of commonly investigated drug delivery systems, in the context of their results, efficacy, and limitations. We also analyze their successes and limitations



based on observations in clinical trials and clinical applications to identify useful clues for designing better future drug delivery systems.

Clinical observations Maximizing the efficacy of cytotoxic agents such as chemotherapeutics, radioisotopes, and targeted therapeutics in killing cancer cells and minimizing their toxic side effects to normal cells and tissues are the long overdue goals of oncotherapy1, 2. Various delivery technologies, including microspheres, polymer implants, liposomes, proteins, polymers, and nanoparticles have been designed and tested in animal models and clinical trials in the past several decades9, 10, Table 1. A common goal of these drug delivery approaches is to improve the pharmacokinetics and pharmacodynamics of therapeutics. It has been hypothesized that increased concentration and retention of a cytotoxic agent in tumors, while minimizing drug concentration in normal tissues, can achieve high therapeutic efficacy with low toxic side effects9. The clinical data obtained from the investigations of several drug delivery systems are briefly summarized in this section.

1.

Radiolabeled microspheres The use of radioisotopes, such as high-energy beta-emitters, for cancer treatment dates

back to the 1940s17. Loading of therapeutic radioisotopes in microspheres to improve their tumor retention for localized cancer radiotherapy was explored as early as the 1960s18, 19. Microspheres with sizes ranging from 10 to 500 µm have been developed using various materials, including polymers, proteins, resins, and glass, to load therapeutic radioisotopes, including Y-90, Ho-166, or Re-186/Re-188, for cancer treatment20. Radiolabeled microspheres have been investigated for treating liver cancer and colorectal metastases in clinical trials20. Currently, radiolabeled microspheres based on glass and resin are approved for clinical treatment of hepatocellular carcinoma and colorectal metastases21, 22. The microspheres loaded with radioisotopes are locally administered into the artery feeding the tumor under image guidance. The microspheres permanently reside in the microvasculature of the tumor until complete decay of the isotopes. During this time, the ionizing radiation produces extensive DNA damage that is lethal to malignant cells. The encapsulation of radioactive elements in microspheres facilitates delivery of high doses of radioisotopes into the tumor, while reducing their accumulation in healthy tissue.


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As an additional benefit, these particles also block the flow of blood necessary for tumor growth in a process known as embolization. This therapy is known as selective internal radiation therapy and/or radioembolization, because the treatment combines both radiation therapy and embolization. In clinical studies, the treatment of primary liver tumors with radioembolization with Y90 microspheres resulted in necrosis and subsequent shrinkage of hepatocellular carcinoma. The partial response rate to the treatment varied from 4.7% to 82.3%22. However, the complete response rate was relatively low, about 10%. A clinical trial with resin microspheres in patients with liver metastases from colorectal cancer exhibited a dose-dependent response. The response was also affected by the heterogeneity of absorbed radiation dose depending on the tumor size and vascularity23. Treatment of patients with unresectable colorectal cancer and liver metastasis with Y-90-labeled resin microspheres resulted in 10 months median overall survival24. However, the incorporation of Y-90-labeled resin microspheres with standard chemotherapeutic regimen (fluorouracil, leucovorin, and oxaliplatin) in patients with previously untreated metastatic colorectal cancer did not improve the progression-free survival over chemotherapy alone25, 26. It was speculated that the progression of extrahepatic disease contributed to the lack of improvement in overall progression-free survival, despite significant response in observed intrahepatic metastases after radioembolization21. A recent prospective, multicenter, randomized phase III trial investigating Y-90 microsphere radioembolization in unresectable, chemotherapyrefractory, liver-limited metastatic colorectal cancer demonstrated an improvement in both median time to tumor progression and time to liver progression. However, once again, these benefits did not translate into a statistically significant improvement in median overall survival27.

2.

Targeted radionuclide therapy The concept of using antibodies as carriers to specifically deliver radioisotopes into

tumor tissues for radioimmunotherapy or targeted radionuclide therapy was first reported in the 1950s28. Radioisotopes were conjugated to antibodies to utilize their tumor binding ability for targeted delivery of high doses of radioactivity into malignant tumors. Early studies showed that intravenous injection of I-131-labeled antibodies specific to fibrin resulted in preferential localization of the radioisotopes in animal tumor models, including spontaneous tumor models29, 30

. Since the publication of these seminal studies, numerous tumor-specific antibody and peptide



radioisotope conjugates have been developed and investigated for cancer therapy. Several peptide and antibody targeted radionuclides have been tested in clinical trials for cancer therapy31, 32. Y-90 and Lu-177 conjugates of somatostatin analogues have shown great promise for treating neuroendocrine tumors in clinical trials. For example, a clinical trial of Lu-177Dotatate in patients with well-differentiated, metastatic midgut neuroendocrine tumors showed a higher rate (65.2%) of progression-free survival at 20 months than a control group (10.8%) and a significantly higher response rate at 18%33. In another trial in patients with metastatic bronchial and gastroenteropancreatic neuroendocrine tumors, treatment with Lu-177-Dotatate resulted in progression-free survival of 29 months and overall survival of 63 months with no long-term renal and hepatic failure34. The development of hybridoma technology for the production of monoclonal antibodies has significantly facilitated the clinical translation of radiolabeled antibodies. Anti-CD20 monoclonal antibodies labeled with I-131 and Y-90 chelates were approved in the early 2000s for the treatment of refractory non-Hodgkin’s lymphoma. Radioimmunotherapy has shown good therapeutic efficacy in treating hematopoietic cancer with an overall response rate of 60-80% and complete response rate of 15-40%. In some cases, prolonged survival for 10+ years after therapy has been documented31. However, radioimmunotherapy via systemic administration did not exhibit the same efficacy in treating solid tumors when compared to hematopoietic cancer in clinical trials. One large challenge facing successful radioimmunotherapy approaches for the treatment of solid tumors is the poor tumor uptake of radiolabeled antibodies after intravenous injection due to the heterogeneity of antibody epitope expression within the tumor and poor vascularity of some tumor regions31, 35.

3. Antibody drug conjugates Investigation of tumor-binding antibodies as a way to facilitate targeted delivery of chemotherapeutics was initiated in the early 1970s36. Chemotherapeutics were loaded onto the antibodies via chemical bonds to form antibody drug conjugates that were hypothesized to better target malignant tissue. Targeted cytotoxic effects to tumors were first observed with antitumor antibody conjugates of chlorambucil, adriamycin (aka doxorubicin) and daunomycin in early studies37-39. The effect of the specific chemistry utilized to conjugate cytotoxic agents to targeting antibodies on the therapeutic efficacy of the conjugate was also noted. For example, the


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conjugation of adriamycin (aka doxorubicin) and daunomycin via a degradable imine bond exhibited better pharmacological activity than a non-degradable amide bond38. The development of high target specificity of monoclonal antibodies has greatly facilitated research activities in antibody drug conjugates in both academia and industry. Numerous antibody drug conjugates have been developed for specific delivery of chemotherapeutic agents into cancer cells via specific binding of the antibodies to the antigen epitopes overexpressed on cancer cells. Many of them have been tested in clinical trials40, 41. The first antibody drug conjugate, an anti-CD33 monoclonal antibody calicheamicin conjugate (gemtuzumab, ozogamicin, or Mylotarg®), was approved in 2001 for treating acute myelogenous leukemia. However, it did not provide a significant improvement in therapeutic outcome as compared to conventional treatment and was withdrawn from the market in 2010. Patients were also found to suffer from various toxic side effects, including severe myelosuppression, venous occlusion, etc.42. It was reintroduced to the US market in 2017 because the conjugate was found to be beneficial to a subpopulation of the patients43. New generations of antibody drug conjugates have been designed and developed to address the limitations observed in the early generation. Currently, approximately 70 clinical trials with various antibody drug conjugates are ongoing for cancer therapy. Brentuximab vedotin (Adcetris®) and trastuzumab emtansine (Kadcyla®) are approved for treating Hodgkin’s lymphoma and metastatic breast cancer, respectively41. Brentuximab vedotin is a chimeric monoclonal antibody conjugate of monomethyl auristatin E targeting the cell membrane protein CD30. Similar to radioimmunotherapy for lymphoma, brentuximab vedotin showed good therapeutic efficacy in treating advanced Hodgkin’s lymphoma. The treatment of patients with relapsed Hodgkin’s lymphoma with brentuximab vedotin resulted in an overall response rate of 48.3%, disease free survival rate of 26.35% at 3 years and progression-free survival rate of 31.9% at 4.5 years, as reported in a recent study44. The incorporation of brentuximab vedotin as a first-line treatment in an escalated therapy regimen (eBEACOPP: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) resulted in an impressive 90% complete remission45. Trastuzumab emtansine is a monoclonal antibody drug conjugate targeting human epidermal growth factor receptor (HER2) for treating HER2-positive breast cancer46. Trastuzumab emtansine treatment resulted in longer median progression-free survival (14.2



months) than treatment with trastuzumab plus taxane (9.8 months) in patients with previously untreated HER2-postive metastatic breast cancer, when trastuzumab emtansine was used in the first-line setting47. Recently published clinical studies showed mixed results in therapeutic efficacy when the conjugate was used as the second-line and third-line treatments in settings of HER2-postive metastatic breast cancer48-50. One of the studies showed that when the conjugate was used as second- and third-line treatment, the median progression-free survival improved to 9 and 12 months, respectively, as compared to 7 months in the overall population49. However, the antibody-conjugated drug has been less effective in treating solid tumors than brentuximab vedotin in treating Hodgkin’s lymphoma. It is believed that tumor heterogeneity and development of drug-resistant disease are the main causes of the low efficacy of these conjugates51.

4.

Liposomal drug delivery systems The use of liposomes as a carrier to entrap an anticancer drug was first reported in 1973

with the goal to achieve specific drug delivery to the tumors and to address the challenges in cancer therapy, including drug resistance, non-specific tissue accumulation, and toxicity1, 52, 53. Prolonged circulation and improved therapeutic efficacy of drug-loaded liposomes was observed in animal models54. However, issues of high non-specific liver and spleen accumulation and drug leakage of the small drugs from liposomes were also observed in the early studies54. With continuous efforts of many dedicated scientists, pegylated liposomes were later developed to address the limitations of early generations of liposomal delivery systems6. Several drug-loaded pegylated liposomes have been approved for cancer treatment55. Of these systems, the most extensively investigated agent is a liposomal formulation of doxorubicin (Doxil®). The efficacy of Doxil® has been and is currently under investigation across a wide variety of solid malignancies, both in monotherapy and in combination with other traditional chemotherapeutic agents56, 57. Initial clinical trials of Doxil® were performed in a population of HIV-positive patients suffering from a rare form of cancer known as Kaposi’s sarcoma, and found a beneficial therapeutic effect58. Additional Phase II clinical trials also established efficacy of Doxil® in breast and ovarian cancers59, 60. Of particular note, these early experiences with Doxil® showed an improved safety profile, and thus achieved widespread clinical acceptance.


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However, more recent clinical data suggest that the improvement in patient outcomes provided by Doxil® is largely limited to the improved side effect profiles and improved patient response to therapy. In a 2015 meta-analysis of 10 studies in advanced breast cancer, liposomal doxorubicin was associated with over a 50% reduction in risk of cardiotoxicity, and a 25% improvement in response rate when compared to conventional doxorubicin formulations. However, this meta-analysis found no improvement in progression-free survival or overall survival61. In the PELICAN phase III clinical trial published in 2017, Doxil® displayed no statistically significant improvement in overall survival, time to disease progression, or time to treatment failure62. Further clinical trials testing the effect of Doxil® as part of a combination chemotherapy regimen returned similarly disappointing survival data, with two studies in multiple myeloma showing little to no effect on overall survival or disease-free progression63. Lastly, it appears that modification of the liposomes to enable the attachment of targeting moieties also shows very little benefit. The HERMIONE trial utilizing liposomal formulations of doxorubicin functionalized with an anti-HER2 antibody was terminated before completion due to a lack of improvement of therapeutic effect64. Other liposomal formulations of cytotoxic agents are also beginning to penetrate the market, decades after Doxil gained the initial FDA approval. Vyxeos, a liposomal formulation of a cytarabine-daunorubicin mixture, was approved by the FDA in 2017 for use in hematological malignancies, including acute myeloid leukemia65, 66. Phase III clinical trials of this drug in acute myeloid leukemia patients demonstrated a clear improvement in overall survival and response to therapy in the Vyxeos treated group, when compared to those treated with a free drug cocktail67.

5.

Polymer drug conjugates The first reported polymer drug conjugate intended for cancer treatment was a soluble

dextran methotrexate (MTX) conjugate68. The conjugate was designed to prevent rapid drug excretion via the kidneys, to increase the blood circulation, and to facilitate sustained drug release. The concept of polymer drug conjugate for targeted drug delivery was elegantly depicted in a review paper in 197569. Water soluble polymers were used as carriers for chemotherapeutic drugs, most of which are hydrophobic, to improve their water solubility and pharmacokinetics. A targeting agent was attached to the polymers for target-specific drug delivery. The drug was covalently conjugated to the polymers via a cleavable spacer to facilitate drug release at a target



site. Various natural and synthetic polymers, including dextran, carboxylmethylcellulose, polyethylene glycol (PEG), poly-N-(2-hydroxypropyl)methacrylamide (pHPMA), polyglutamic acid, and dendrimers, have been used as carriers to prepare polymer drug conjugates for cancer therapy70-74. More than a dozen different polymer conjugates of chemotherapeutics, including doxorubicin, camptothecin, paclitaxel, and palatinate, have been tested in clinical trials75-77. HPMA copolymer conjugates have been tested in clinical trials for treating breast cancer, nonsmall cell lung cancer, and colorectal cancer76, 78. These drug conjugates have shown prolonged blood circulation and better tolerance at higher doses. However, clinical trials of pHPMA drug conjugates were terminated at different stages due to limited therapeutic response or unexpected toxicity, e.g., neurotoxicity for pHPMA-paclitaxel conjugates and bladder toxicity for pHPMAcamptothecin conjugates possibly due to unexpectedly high drug concentration in these organs76, 78

. Although a polyglutamic acid paclitaxel conjugate progressed to phase III clinical trials, they

were also terminated due to a lack of significant improvement over the standard treatment and unexpected neurotoxicity74. Currently, no polymer chemotherapeutic conjugate has obtained approval for clinical use. Biocompatible polymers have also been conjugated to protein therapeutics to increase their stability and to minimize the potential immunogenicity. Some polymer protein conjugates, including SMANCS and pegylated asparagenase, have been approved for cancer treatment79, 80. SMANCS is a conjugate of polystyrene-maleic anhydride copolymers and neocarzinostatin. Its Lipiodol formulation was approved in Japan for treating hepatocellular carcinoma via transarterial infusion. A clinical study with 30 patients showed a 40% overall response rate, including a 27% complete response rate and a 13% partial response rate for localized disease81. Another clinical study also showed that 47.1% the patients with hepatocellular carcinoma had at least 25% tumor regression82. A multicenter phase III clinical trial in patients with newly diagnosed unresectable hepatocellular carcinoma showed that the treatment with SMANCS resulted in an estimated 2-year survival rate of nearly 50% with a median overall survival time of approximately 650 days83. SMANCS is locally administrated for treating localized disease and is not useful for the treatment of metastatic disease. PEG is commonly used in the conjugation of therapeutic proteins to enhance their efficacy by minimizing immunogenicity, to improve protein stability, and to increase circulation.


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Pegylated asparaginase and interferon α-2b have been approved as adjuvant therapy for acute lymphoblastic leukemia and resected stage III melanoma, respectively84. The improved in vivo stability and prolonged circulation of pegylated proteins significantly reduced the injection frequency that was needed for the original proteins. Pegylated asparaginase demonstrated similarly high disease-free remission rate as the unmodified protein in treating both newly diagnosed and relapsed acute lymphoblastic leukemia, but with fewer and less frequent injections required85-87.

6. Polymer implants The use of drug loaded polymer implants for sustained local release of therapeutics into tumor tissues was reported in the early 1970s. Polymeric hydrogel implants loaded with 5fluorouracil were utilized for sustained drug release at tumor sites88. The anticancer drug cytarabine was loaded into silicone implants for prolonged drug release and sustained therapeutic effects in cancer treatment89. In vivo study in animal models showed that silicone implants loaded with cytarabine exhibited prolonged drug release. Although good biocompatibility and prolonged drug release were observed for these implants, no improvement in therapeutic effect was observed90, 91. Application of biodegradable polymers facilitated the development of bioabsorbable drug loaded implants. A wafer implant of poly[bis(p-carboxyphenoxy)propane sebacic acid] loaded with carmustine was approved by the FDA for treating brain cancer92, 93. A 2015 multicenter case-control study compared the outcomes of adult patients treated with carmustine wafers after surgical resection to those not receiving carmustine wafer implantation in a cohort of high-grade glioblastoma (GBM) patients94. This trial, one of the largest ever performed in glioblastoma patients, found that median progression-free survival was increased from 10 months to 12 months by carmustine wafer implantation. Despite this result, overall survival was not improved (p=0.574), and a higher rate of postoperative infection was observed in the implanted group, although this did not contribute to a reduction in survival94. Similarly, another study investigating the benefit of carmustine wafer implantation in patients receiving 5-aminolevlinic acid (5-ALA) image-guided surgical resection of high-grade GBM also demonstrated no significant survival benefit (p=0.836)95. Interestingly, while studies of GBM cohorts have shown relatively little benefit, a study of an older cohort (more than 65 years



of age) found an approximately 3 month improvement in overall survival96. This suggests that such an approach could prove beneficial in certain patient populations.

7.

Polymeric micelles Polymeric micelles take a variety of forms and several formulations are now being

investigated in clinical trials. Most formulations utilize block copolymers with both hydrophilic and hydrophobic units, in either a diblock, triblock, or grafted copolymer configuration97, 98. These polymers can self-assemble into micelles with hydrophobic cores capable of carrying large amounts of hydrophobic drugs utilized in cancer therapy. Several polymer micelle drug delivery systems have progressed to various phases of clinical trials99. NK105 is a PEG-b-poly(aspartate4-phenyl-1-butanolate) micelle formulation loaded with paclitaxel. When investigated in a Phase III clinical trial enrolling patients with metastatic or recurrent breast cancer, NK105 demonstrated no statistically significant difference in progression-free survival, and no substantial improvement in overall survival or overall response rate, although NK105 did demonstrate reduced incidence of peripheral neuropathy100. SP1049C is a Pluronic L61 and F127 mixed micelle formulation incorporating doxorubicin as a drug payload. SP1049C completed Phase II clinical trials in 2011, and is now entering Phase III clinical trials99, 101. Overall, the Phase II trials reported a response rate of approximately 53%. However, out of the 21 patients evaluated at the end of the trial, no patients achieved a complete response to the therapy. Approximately 25% of patients achieved survival for over 1 year. The clinical pipeline is full of additional polymeric micelles that have not yet reached Phase III trials. The data available on these constructs is less clear, but several have demonstrated improved delivery of chemotherapeutic payloads. First reported in 2003, NC-6004 is a micelle based on poly(ethylene glycol)-poly(glutamic acid) block copolymers utilized to deliver cisplatin102. A Phase Ib/II clinical trial investigating the efficacy of NC-6004 across a variety of advanced solid tumors was completed in 2017, and showed that NC-6004 delivered therapeutic concentrations of cisplatin with a more favorable side effect profile when compared to the free drug103. Whether newer polymer micelles such as NC-6004 can outperform the currently available therapies remains to be seen.


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8.

Nanoparticle-based delivery systems Recent developments in materials science and nanotechnology have greatly enriched the

stockpile of nanosized materials available for drug delivery in cancer treatment104. Various synthetic materials, including inorganic, organic, and natural materials, have been developed, modified and used as nanosized carriers for the delivery of anticancer therapeutics, especially for systemic delivery105. The hyperpermeability or enhanced permeability of the tumor vasculature to nanosized materials has also greatly contributed to the drastic expansion of the research activities on nanosized drug delivery systems for cancer therapy in the last two decades. Nanosized drug delivery systems have now become an important branch of nanomedicine. One such construct that has received great interest is nab-paclitaxel (Abraxane). Nabpaclitaxel is an albumin-bound paclitaxel nanoparticle formulation, which was designed to improve paclitaxel solubility while eliminating the need for solvents such as Cremophore EL, which have significant adverse effects in clinical use106. A Phase III clinical trial comparing the efficacy of nab-paclitaxel to the free drug in locally recurrent or metastatic breast cancer found that nab-paclitaxel is not superior to paclitaxel in progression-free survival107. Of particular note, this trial found that treatment with nab-paclitaxel resulted in a shorter period of tumor response (as measured by imaging and the RECIST 1.0 scoring system), when compared to paclitaxel (5.2 versus 6.6 months, p25% reduction in tumor Polymer Drug Conjugates volume . 37 Approved, additional PEGylated asparaginase Similar disease free remission rate as unmodified protein, Resected stage III melanoma trials in progress for 38 (Oncaspar®) but with less frequent injections . other indications 39 Median progression improvement vs unimplanted (12 vs 10 Carmustine wafers (Gliadel®) Post-resection glioblastoma Approved Polymer Implants months) . No improvement in overall survival . 40 Paclitaxel PEG-b-poly(aspartate-4No statistically significant improvement in progression-free Metastatic and recurrent breast pheyl-1-butanolate) micelle Phase III clinical trials survival, overall survival, and overall response rate . 41 cancer (NK105) Improvement in side effect profile . 42 Doxorubicin pluronic L61-F127 Esophageal and gastroesophageal Response rate of 53% with no complete response to Phase III clinical trials mixed micelles (SP1049C) adenocarcinoma therapy, 25% 1 year survival . Polymeric Micelles 43 Lung cancer, head and neck cancer, Cisplatin poly(ethylene glycol)Favorable side effect profile, tumor shrinkage in 55% of endocrine cancer, sarcoma, Phase II clinical trials 44 poly(glutamic acid) micelles (NCpatients, with partial response in 15% and stable disease in colorectal cancer, gastoesophageal completed 6004) 70% of patients . cancer, breast cancer 45 Not superior to paclitaxel in progression-free survival and 46 shorter period of tumor response in Breast Cancer . 10% Metastatic breast cancer, non-small increase in progression-free survival and 1 month increase Albumin-paclitaxel (Abraxane®) cell lung cancer, metastatic Approved 47 in overall survival in Lung Cancer . Improvement in pancreatic adenocarcinoma suvivial at both 1 year (35% vs 22%) and at 2 years (9% vs Nanoparticles 48 4%) . 49 Ocular melanoma, colorectal PEGylated gold-TNFα Phase II clinical trials Well tolerated on administration, preferential trafficking to adenocarcinoma, pancreatic nanoparticles (CYT-6091) ongoing diseased tissue and liver . 50 adenocarcinoma, breast cancer 51 52 53 54 55 56 57 58 59 ACS Paragon Plus Environment 60 21

Improved Side Effect Profile Yes

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Figure 1: The drug delivery platforms that have been extensively investigated in clinical trials. Red hexagons and purple diamonds represent drugs, blue and green represent polymers and other biological macromolecules.


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Figure 2: The areas of drug delivery research need to be explored to achieve curative outcomes in cancer therapy.


Drug Delivery in Cancer Therapy, Quo Vadis? - ACS Publications

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