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Nanomedicines Based Drug Delivery Systems for Anti-Cancer Targeting and Treatment Vikas Jain*, Shikha Jain and S.C. Mahajan Mahakal Institute of Pharmaceutical Studies, Ujjain (M.P.), India Abstract: Cancer is defined as an uncontrolled growth of abnormal cells. Current treatment strategies for cancer include combination of radiation, chemotherapy and surgery. The long-term use of conventional drug delivery systems for cancer chemotherapy leads to fatal damage of normal proliferate cells and this is particularly used for the management of solid tumors, where utmost tumor cells are not invaded quickly. A targeted drug delivery system (TDDS) is a system, which releases the drug at a preselected biosite in a controlled manner. Nanotechnology based delivery systems are making a significant impact on cancer treatment and the polymers play key role in the development of nanopraticlulate carriers for cancer therapy. Some important technological advantages of nanotherapeutic drug delivery systems (NDDS) include prolonged half-life, improved bio-distribution, increased circulation time of the drug, controlled and sustained release of the drug, versatility of route of administration, increased intercellular concentration of drug and many more. This review covers the current research on polymer based anticancer agents, the rationale for development of these polymer therapeutical systems and discusses the benefits and challenges of cancer nanomedicines including polymer-drug conjugates, micelles, dendrimers, immunoconjugates, liposomes, nanoparticles.

Keywords: Chemotherapy, Immunoconjugates, Nanotechnology, Polymers, polymer therapeutics. INTRODUCTION Cancer, a disease involves uncontrolled cells growth that attack and multiply on nearby cells and tissues of the body by way of lymph system and blood through the process of metastases. The current treatment strategy for cancer includes chemotherapy, surgery, radiation and/or the combination of said treatment options. The localized therapies i.e. radiotherapy and surgery, are successful when wicked cells are limited to localized area. Systemic treatment of metastases via chemotherapy is thus important to prevent local growth of tumor cell and tissues. The medicaments used in the chemotherapy are agents that preferentially destroy the proliferative dividing cells. These are anti-metabolites, enzymes, plant alkaloids, alkylating agents, mitosis inhibitors, antibiotics, DNA-complexing agents, hormones etc. These agents exert their activity either by cell division and repair or by interfering with DNA replication and translation. Long term cancer chemotherapy via conventional systems leads to fatal damage of normal proliferate cells and this is particularly used for the management of solid tumors, where utmost tumor cells are not invaded quickly. Even though numerous researches, chemotherapy discourages the patient’s outlook, and there is a need of novel anticancer systems that target the drug directly on cancer cells, reduce toxicity, improve bioavailability and therapeutical drug level as well. *Address correspondence to this author at the Mahakal Institute of Pharmaceutical Studies, Ujjain (M.P.), India; Tel:/Fax: 07344050773; E-mail: [email protected]

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Table 1 describes the barriers that limit the use of conventional systems bearing anticancer agents applied to tumors. Table 1.

Barriers those limiting conventional systems bearing anticancer agents applied to tumors [1].

Barriers to drug delivery to tumors Anatomical barriers:- Vascular endothelium, Peri-vascular space, Cellular membrane, Blood brain barrier, Nuclear membrane. Physiological barriers:- High interstitial fluid pressure, Hepatic degradation, Renal filtration, Drug efflux pumps, High tumor cell density. Chemical barriers:- Large volume of distribution, Low stability, Low solubility, Charge interactions, Low molecular weight. Clinical barriers:- High toxicity, Need for hospitalization, Low efficacy, Low cost-effectiveness.

PRINCIPLES OF DRUG TARGETING The concept of designing site specific drug delivery systems to achieve selective targeting is conceived by Paul Ehrlich, who proposed a system that act as magic bullet. It was the very first statement published on targeting describing targeted delivery as an incident where carriers conjugate and/or complex with drug and delivers it exclusively to preselected and/or target cells in a specific manner. Targeted drug delivery systems are defined as systems, which target the drug selectively and effectively at pre-identified and/or © 2014 Bentham Science Publishers

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pre-selected target site in therapeutic concentration, while restricting the movement of drug to normal cells, thus minimizing undesirable effects and maximizing therapeutic concentration at target site. A targeted drug delivery system (TDDS) is a system that releases the drug at a pre-selected bio-site in a controlled way. OBJECTIVES OF TARGETED DRUG DELIVERY SYSTEM

Jain et al.

8) Offers maximum drug concentration at the site of action and minimum concentration at non-target tissue and/or organ. Fig. (1) depicts the principle and rationale of drug targeting to tumors. TYPES OF DRUG TARGETING TO TUMORS [2-4] Passive Targeting

3) Minimize the entry of drug to non-target cells.

Passive targeting involves drug-carrier complex and/ or drug delivery vectors that can deliver the drug directly on tumor cells or tissues. In case of cancer nanotherapeutic, size of nanomedicines and behavior of tumor tissue vasculature play an important role in passive targeting. Since, there is an increased metabolic requirement of growing tumor cells, preexisting blood vessels are exposed to pressure that leads to the development of new capillaries to the tumor by the process of angiogenesis. Accumulation of nanomedicines in tumor tissues is dependant of interstitial fluid pressure which is elevated in tumor tissues than the normal tissues. In particular, interstitial pressure is higher at the centre and diminishing towards the periphery which is responsible for inducing drugs to outflow from the cells leading to redistribution of drug in the cancer tissues and/or cells. Accumulation of nanomedicines in proliferating tissues is also dependant of size, surface characters, and circulation half-life.

4) Targeted delivery to previously in-accessible domains, e.g., intracellular sites, virus, bacteria and parasites offers distinctive therapeutic benefits.

ENHANCED PERMEABILITY AND RETENTION (EPR) EFFECT [5]



To prevent the drug from going into cells/tissues/organs where it is not needed.



To prevent drug degradation and elimination that is done by the body defense system such as opsonins in blood, liver and kidney.



To increase bioavailability and drug accumulation at the target site.

ADVANTAGES OF DRUG TARGETING 1) Delivery of drugs to specific pre-identified compartments of the body. 2) Maximize the intrinsic activity of the drug.

5) Delivery of the drug in controlled manner to pharmacological receptors and its binding specifically with target cells. 6) Offers protection of the drug inside the body. 7) It en route the drug to extravascular site of drug action

Fig. (1). Principle and rationale of tumor targeting.

In cancer tissue, the vasculature found is extensively different from normal tissue in respect of size, density, permeability and flexibility. It is mostly heterogeneous in distribution, larger in size, has high vascular density and is more permeable and leaky, unlike the tight endothelium of normal blood vessels. This leaky and defective architecture of tumor

Polymeric Conjugated System for Anti-Cancer Targeting and Treatment

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vasculature could be due to elevated levels of vascular mediators such as bradykinins, nitric oxide, and vascular endothelial growth factor (VEGF), basic fibroblast growth factor(bFGF), prostaglandins, etc. The leaky vasculature permits diapedesis (extravasation) of circulating nanocarriers within the tumor interstitium. This phenomenon coupled with the impaired lymphatic drainage of macromolecules in solid tumors, allows an enhanced accumulation and retention of high molecular weight drugs in or around neoplastic tissue. This property of accumulation for macromolecular drugs in tumor tissue much more than they execute in normal tissues is called the enhanced permeability and retention (EPR) effect. The EPR effect is predominantly used for passive targeting of drugs encapsulated in carriers

jugates which are used in polymeric nanomedicines. Polymeric nanomedicines include different variety of architectures i.e. liposomes, niosomes, micelles, micro and nanospheres, nanogels, other vesicular systems, and dendrimers. Some important technological advantages of nanotherapeutic drug delivery systems (NDDS) are as follows:- [15, 16].

ACTIVE TARGETING

5) Optimized size and surface characteristics of nanopraticlulate carrier systems increase circulation time of the drug.

Active targeting is an important process involves conjugation of targeting molecules (like antibodies, ligands, peptides, polymers, nucleic acids etc.) on the surface of nanocarriers with receptors. Tumor targeting molecules on the nanocarriers bind to tumor tissues via an endosome-dependent mechanism that bypasses the drug efflux pump leading to high intracellular concentration. The distribution pattern of the drug-carrier complex is altered by physical, chemical and biological means, so that it identified and reached only through particular biosite. NANOMEDICINES FOR TUMOR TARGETING There is an increasing attention on nanotechnology based drug delivery systems. Nanomedicines are used for diagnosis and treatment of the tumor with great accuracy and effectiveness. Nanotechnology literally means nanoscale performed technology. The nanoscaleparticles/ nanoparticles are ultrafine particles in the nanometer size ranging from 1 nm to 1000 nm. Nanomedicine is an important area in nanotechnology which refers diagnosis, prevention and treatment of diseases to specific medical intervention at the molecular level [3]. Polymers play an important role in the development of nanocarriers based cancer drug delivery. The word “polymer therapeutics” [7, 8] includes polymer-drug [9-11], polymer–protein [12, 13], and/or polymer-micelles [14] con-

Table 2.

1) Prolonged half-life. 2) Improved biodistribution of anti-cancer drugs. 3) Versatility of route of administration (NDDS can be administrated through oral, nasal, parenteral, intraocular routes etc.) 4) Both hydrophilic and lipophilic compounds can be delivered efficiently.

6) Release of the drug in controlled and sustained manner during the transportation and at the site of drug action. 7) Increased intercellular concentration of drug either by better permeability and retention effect or by endocytosis mechanism. For quick and successful clinical translation, the nanocarriers should exhibit following characteristics [17]:•

Made-up by biocompatible, well characterized and simple in use material;



Have high uptake in the proliferating tissues over normal tissues;



Soluble and/or colloidal under aqueous condition with better efficiency;



Have a long shelf life and extensive circulating half-life, and



Have a low aggregation rate

Fig. (2) narrates some imminent anticancer therapeutical systems. Fig. (3). illustrates the different types of cancer nanomedicines.

Types of drug targeting to tumors.

Passive Targeting

Active Targeting

Targeting occurs because of the body’s natural response to the physiological characteristics of the drug or drug carrier system

Targeting involves modification or manipulation of the drug carriers to redefines its biofate.

Prototypic examples of nanomedicines formulations are liposomes, polymers, micelles, nanoparticles and antibodies

Examples of targeting ligandsroutinely used for actively targeting nanomedicines formulations to tumor cells are folate, transferrin and galactosamine.

Less selective

Highly selective

Restricted in use

Very versatile

More likely to produce side effects

Less likely to induce side effects

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Fig. (2). Imminent anticancer polymer therapeutics.

Fig. (3). Types of cancer nanomedicines.

Polymer Drug Conjugate as Cancer Nanomedicines Ringsdorf’s vision [18] and ‘Trouet and De Duve’s realization pathway for successful lysosome based drug delivery [19] led to the concept of polymeric- drug conjugation for

targeted drug delivery to cancer tissues. Fig. (4) shows outline of a polymer conjugate systems designed for better pharmacodynamic and pharmacokinetic properties of the drug.

Polymeric Conjugated System for Anti-Cancer Targeting and Treatment

In general, polymer conjugates and/ or complex with drug have improved solubility in aqueous medium and prolonged circulation half-life compared to free drugs [20].The aims of polymeric conjugation of drug are •

Attaining better targeting of the drug to tumor tissues,



Overcoming toxicity of the drug and the mechanisms of drug resistance.

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The drug-polymer composite must release the drug at a pre-determined rate within tumor tissues.



It should be appropriate for industrial-scale production.

The various polymer conjugates based drug delivery system for cancer therapies are mentioned in Table 3. Polymers exhibiting preclinical success for polymeric-drug conjugations are as follows [21]:•

N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer



Polyethlene glycol (PEG)



Poly(glutamic acid) (pGlu)



Dextran



Cyclodextrin- based polymer



Poly lactic acid,



Poly(styrene-co-maleic acid/anhydride),



Poly(N-(2-hydroxypropyl) methacrylamide) copolymer,

Fig. (4). Outline of a polymer- drug conjugate.



Poly(ethyleneimine

Fig. (5) explain the mechanisms of action of drugpolymer conjugates.



Poly(acroloylmorpholine),



Poly(vinylpyrrolidone),



Poly(vinylalcohol),



Poly(amidoamines),



Divinylethermaleic anhydride/acid copolymer



Poly(L-lysine),



Poly(malic acid),



Poly(aspartamides),



Poly((N-hydroxyethyl)-L glutamine),



Poly hydroxyl ethyl methacrylate.

IDEAL CHARACTERISTICS OF POLYMERS USED FOR CONJUGATION •

They should be non-toxic and non-immunogenic.



Molecular weight of the polymer must be high in order to attain long circulation time.



Molecular weight of non-biodegradable polymeric drug conjugates must be