Nanotherapeutic Intervention in Cancer Disease

Introduction
Cancer is second most prevalent and lethal disease after cardiovascular disorder, despite of advances in tumor biology research and chemotherapy. The nanotechnology tremendously growing with due advances in nanomedicine and drug delivery system. The mantra of nanotherapy in cancer based on right medicine, right dose, right target, right time of exposure, patient safety and right therapeutic output. Nanotherapy intended for targeting payload of chemotherapeutic agent to the specific site in due time and at right dose [1]. Nanotechnology based delivery system could be capable of bearing one or more nano-sized therapeutics as conjugates, and release controlled medication for prolong time period as per the dosage form design and therefore, patients more benefitted. The nanomedicine offers precise and effective drug dosing at low dose, delivers fewer side effects, and gets rid of disease condition evidently. The marketing of nanomedicine such as Doxil, Abraxane, as DaunoXome, Myocet brings hope in cancer patients. The term cancer means carcinoma was first introduced by Hippocrates in late 370 BC. The cancer prognosis starts with uncontrolled cell division due to genetic defect, chromosomal alteration that leads to abnormality of biological system. The cancer cell physiology differs from normal cells. The conventional therapeutic regimen remains questionable in this disease due to dose dumping, systemic toxicity, and low therapeutic outcomes. The cells/tissue/organ selectivity has been a melodic theme since back still a captivating approach for cancer cells targeting. Based on this technology nanomedicine therapy is the forefront and taking lead role in intervention of cancer disease. The significant improvements in cancer mortality were first detected in the late 20th century and thereafter field of targeted cancer therapies blossomed with new discoveries in cancer signaling pathways involved in tumor development, proliferation, and metastasis. Human genome project in 2003 led the foundation of revolutionary advances by thorough understanding of several human diseases including cancer. Through genetic analysis of tissues form several part of the body of the patients, scientist uplift knowledge in precise prognosis of cancer of different stages that could highly helpful in the rational design of nanomedicine. Based on the 2013 report, the survival rate among the cancer patient has increased to 66.7 per cent. Despite these cancers is the leading cause of death across the US with more than 1.6 million cases and 580000 deaths each year.

Tumor biology and rational drug design
In 1847, R. Virchow an oncologist examined blood samples from leukemia patients under microscopy. Now, the pathogenesis in cancer disease is a multistep process that involves genetic alteration due to ambiguity in codon or gene expression. The cancer causing gene may be oncogenes, defective genes, and or tumor suppressor gene. The genetic alteration in turn causes defective signaling pathways results in cell invasion and metastasis. The developed tumors cells interact with stroma of adjacent cells, their immune system stimulate cell proliferation, and tumorigenic inflammation.

Several molecular pathways involves in cancer pathogenesis such as MAP kinase, PI3 pathway, B-raf, and C-raf pathways etc. Therapies based on molecular genetics, customised medicine helpful to monitor, detect, and cure cancer effectively. The rational drug design requires apprehension on cancer pathogenesis, signaling pathways like up-regulation of EGFR receptor has translated more promised clinical therapy. The multiple pathways involved in cancer therapy it further complicated the design of effective therapeutic system. Thence, a paradigm shift is underway as researchers are working to analyse individual tumors in order to design therapies for specific cancer phenotypes.

Tumor heterogeneity and challenges in cancer therapy
Due to instability and biological diversity in tumor cells, only few cells are sensitive to the therapy, while other cells develop resistance. The resistance tumor cells receive less or no drug uptake due erratic drug influx or aberrant cell cycle. The signaling cascades involved in the tumor cells can diminish efficacy of targeted therapies if the new mutation overrides the targeted factor in the signaling cascade. For example, due to mutations in the tumor suppressor gene or inactivation of TP53, and PTEN, the efficacy of anti-HER2 immunotherapy can minimises. The hierarchy of cancer cells comprised of multiple cell subpopulations have wide spectrum of proliferation and regeneration tendencies had well explained in myeloid leukemia cells. The primary tumor initiating cells implicit in dormant state, chemotherapy is less susceptible to these rapidly proliferating cells. Further studies identified the tumor initiating cells in various tumors including brain tumors. Therefore, effective therapies will require targeting of these primary initiating cells since traditional chemotherapies target only the proliferative subset of the cancer.

Besides tumor cell biology, heterogeneity, tumor microenvironment is the critical challenges in chemotherapeutic regimes. The abnormal vasculature, organisation of cells, abrupt endothelial cells is making trouble for drug retention i.e., impede drug uptake or increase drug clearance. The drug delivery in necrotic tumor is largely impaired due to rapid metabolism, reduced absorption; increased clearance can lower the serum drug concentration. Moreover particle size, drug solubility can hinder the tumor drug delivery. The patient factor further has variable tolerance and drug induced side effect could significantly impede the treatment regimens.  

Targeted therapy in cancer disease
The modes of drug targeting categorises into two groups; active targeting and passive targeting. The concept of tumour targeting is synonymous to active targeting but cannot be separated from passive targeting as active transport of drug occurs after passive accumulation in tumor site.

The nanoparticle is excellent nanocarrier for tumors targeting both by EPR effect and receptor based active targeting to tumor cells. Due to up-regulation of proangiogenic factors, abnormal architecture of new blood vessel, hyper-vasculature in solid tumor, poor lymphatic drainage nanoparticles got the advantage of this features in targeting. The nanoparticles of size ranges 10 to 200 nm ideally accumulated nearby tumor region, too small particles cleared from renal portal system and too large size will not adequately penetrate the tumor vasculature and interstitial space.

Polymer based nanoparticles yet not been approved as nanomedicine in targeted therapy. The prostate-specific membrane antigen coated Docetaxel nanoparticles under the name of AccurinTM/BIND therapeutics now under phase II of clinical trial indicated for head and neck cancer, gall bladder, cervical and non-small cell lung cancer. AstraZeneca filed a product for clinical approval AZD2811 (Accurin™) nanoparticle (Aura B-kinase inhibitor) for advanced solid tumors now in phase I of clinical trial.

Lipid nanocarrier based nanomedicine first came in the market for cancer therapy. Many nanomedicines have been approved and marketed so far with ameliorated efficacy in various tumors. For example, liposomal preparation of doxorubicin under trade name of MyocetTM credited to UK based Teva Pharmaceutical and DoxilTM of Janseen product approved for treatment in metastatic breast cancer, Kaposi's sarcoma, multiple myeloma and ovarian cancer.

The other approved liposomal preparation of chemotherapeutic agent Vincristine invented by Spectrum Pharmaceuticals, under trade name of Marqibo™ for indication in acute lymphoblastic leukaemia; Daunorubicin loaded DaunoXome™ by Galen for the treatment of HIV-related Kaposi's sarcoma; Depocyt™/Pacira Pharmaceuticals containing Cytarabine used in Lymphomatous meningitis and Irinotecan loaded Onivyde™/Merrimack Pharmaceuticals for 2nd line metastatic pancreatic cancer.  

Polymeric conjugate of Asparaginase under the trade name of Oncaspar™ discovered by Baxalta Pharma indicated for acute lymphoblastic leukaemia. Samyang Biopharmaceuticals of product Genexol-PM™ containing Paclitaxel moiety formulated as polymeric micelles has approved in therapy of breast cancer.

The nanomedicine committed significant steps towards developing insight into the novel engineering of biopharmaceuticals that turn out advantages in health care system. Several nanomedicines developed or under developing stage aimed to perform well both in vitro and in vivo that assured improved stability, uniform dissolution/solubility, better pharmacokinetic profiles or biodistribution, efficacious, high payload and reported low toxicity. The physicochemical properties of delivery system such as size, surface charge, morphology, surface functionalisation, and biocompatibility as well as biodegradability have significant effect on the biodistribution and clearance of the nanomedicine.

References
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