unbolting new avenues for targeted delivery of cancer therapeutics : A brief overview

Nanotechnology unbolting new avenues for targeted delivery of cancer therapeutics: A brief overview Kunal Pal Debbethi Bera Department of Life Science and Biotechnology, Jadavpur University, Kolkata-700032, India. Division of Molecular Medicine and Centre for Translational Research, Bose Institute, Kolkata700056, India. Centre for Interdisciplinary Research and Education, 404B, Jodhpur Park, Kolkata-700068, India. Department of Physics, Jadavpur University, Kolkata-700032, India. . . . Graphical Abstract Abstract.

Targeted delivery;cancer therapeutics.

Introduction
Nanotechnology can exert immense impact on cancer therapy as it directly aids in the delivery of the chemotherapeutic drugs.The therapeutic efficacy of all the commonly used drugs can be augmented considerably through the proper utilization of nanotechnology[

Barett et al 2004]
.These approaches will help in delivering the drug or therapeutics specifically to the target site without hampering the other cells [Vasir et al 2005,Kipp,2004.Furthermore those drugs which have previously failed clinical trials could be readministered after combining with appropriate nanotechnological measures [Rabinow,2004]. Nano drug delivery system could help in getting over a lot of impediments like hydrophobicity( solubility is low) of major drugs lowers their therapeutic efficacy .The encapsulation of these drugs within the hydrophilic nanovehicles improves their solubility which in turn also enhances their bioavilability and their therapeutic efficiency.Further these drugs could also be encapsulated within the organic or lipid nanoparticles that prolongs their circulation time The half life of a therapeutic agent in the circulation is enhanced by manyfolds after encapsulating it within nano-liposomes. [Hornan and Rieger 2001, Torchilin,2005]. In the case of central nervous system cancers, Different drugs are unable to reach the tumor site by overcoming the blood-brain barrier.On the other hand,drug encapsulated nanoparticles have shown great efficiency in crossing this barrier and transporting the drug to the brain tumors.
The encapsulation of an anticancer drug within a nanoparticle and its subsequent targeting to a particular site helps in enhancing its therapeutic efficacy and also diminishes its toxicity to a graet extent. [Brannon-Peppas and Blanchette 2004;Ravikumar,2000]. For example,the integrin conjugated lipid nanoparticle were able to deliver genes as well as drugs specifically to the angionenic blood vessel in case of tumor induced mice.This targeted nanoparticle was able to induce apoptosis and caused significant primaer and metastatic tumor regression [Hood et al 2002]. The primary attributes of the nanoparticle-mediated drug delivery is their potential to augment bioavailability ,enhance the sustained release of the drugs and also aid in specifically delivering the drug to the target site [Dubin,2004;Dass and Su 2001;Drummond et al 1999]. These delivery could be effectively integrated within the pulmonary therapies [Courrier et al 2002] in the form of emissaries of therapeutic genes [Senior 1998],and also in increasing the stability of the drugs that are prone to degeneration [LaVan et al 2002[LaVan et al ,2003].Different physiological charecteristics like the blood brain barrier,the divaricating pulmonary system and the compact epithelial junctions of the skin pose a steep impediment for the drugs to reach their desired location. These nano drug carriers parvade these obstacles and transport the drug to the target site. The maximum efficacy for pulmonary drug delivery is achieved by particles with size <100 nm [Courrier et al 2002]. The particles around 100 nm exhibit enhanced gastrointestinal absorption [Desai,1996;Hussain et al 2001] and the particles of 50 nm size display very high amount of trancutaneous permeation [Kohli and Alpar, 2004]. These nanoparticles traversing through the pulmonary tract could create a problem if they are exhaled. The use of larger, compartmental or multilayered drug carrier sytem could improve this pulmonary delivery. For example, the outer layers of the nanovehicles could be made in such a way that they erode while traversing the pulmonary tract. As this carrier penetrates furher, the biodegradable components of the carrier will fully degenerate triggering the release of the drugs into the lung. Biodegradable nanoparticles composed of gelatin and humanserum albumin function as promising pulmonary drug carrier [Brzoska et al 2004].
The nanoparticles are able to impregnate the tumor tissue through their characteristic tumor microvasculate which characteristically contains pores from 100-1000 nms. Hence these Nanoscale drug delivery architectures are able to penetrate tumors due to the discontinuous, or"leaky," nature of the tumor microvasculature, which typically contains pores ranging from 100 to 1000 nm in diameter.These pores provide the ideal entry points for the nanoparticles.
These nanoparticles can be fabricated appropriately for attained effective drug delivery.

Nanovehicles that are commonly used for the delivery of therapeutics
The nanocarriers that are widely used as vehicles for the delivery of therapeutics comprises are usually conjugated with a targeting moiety.Different varieties of nanocarriers are widely used like liposomes, micelles, carbon nanotubes, dendrimers, nanoshells etc. The therapeutic agent can be attached with the nanocarrier through the proceeses of entrapping,covalent binding,encapsulation or adsorption.  [Cui,2003;Ai,2002]. Liposomes having a single lipid bilayer contain an aqueous core for entrapping the hydrophilic drugs. Liposomes that possesses more than a single bilayer can encapsulate the hydrophobic(lipid soluble)drugs [Rosiak et

Targeted drug delivery Systems
The concept of designing a targeted delivery was first conceived by a microbiologist Paul Ehrlich. Targeted drug delivery involves the transport and accumulation of therapeutic agent to a desired site in without hampering the normal cells, thus enhancing the therapeutic efficacy of that agent . The primary features of targeted delivery are:  It should be nontoxic, biocompatible, biodegradable, and exhibit physicochemical stability in both in vivo and in-vitro environments.
 The distribution of the drug should be limited to the desired site(cells,tissues,organs or uniform capillary distribution.)  The rate of drug release should be controllable and predictable.  The drug distribution should be affected by the drug release.
 The amount of drug released by the system should be sufficient for therapy in the desired site.
 The drug leakage during transport should be restricted.
 The carriers must be biodegradable or readily eliminated from the body without exerting any hazardous effect and they should not temper the diseased site.
 The synthesis of these drug delivery system should be reasonably facile, high yielding and cost effective.  Targeted drug delivery has been segregated into different categories considering the attributes of the target cells and also the type of targeting ligand.

Active Targeting.
In case of active targeting, nanoparticles containing the chemotherapeutic agents are designed in such a way such that they directly interact with the diseased cells. The active targeting is solely based on the recognition of the cellular biomolecules. Henceforth the nanoparticle are fabricated by attaching with the targeting agents in order to recognize the molecular patterns of the cancer cells which in turn helps in the delivery of the therapeutics to the desired site. Double Targeting: When temporal and spatial methodologies are combined to target a carrier system, then that targeting strategy is regarded as double targeting. Spatial placement relates to targeting drugs to specific organs, tissues, cells.On the other hand, the temporal delivery refers to the regulation of the drug delivery rate to the desired site.   MOL2NET, 2020, 6, ISSN: 2624-5078 14 http://sciforum.net/conference/mol2net-06

Conclusions
These targeted nanoparticles face a steep challenge in releasing the drugs to the cancer cells since the hydrolytic enzymes residing in the lysosomes of the cells cause damage to both the nanoparticles and the encapsulated drugs.The tumors characteristically have a lower pH and this attribute can be exploited while designing the carriers.Thus the carriers which are responsive to the alterations in the pH and change their solubility at lower pH is quite conducive for drug delivery. A pH responsive nanoparticle typically comprises of a shell and a core The core-shell nanoparticles are designedth in a way that their lower critical solution temperature (LCST) is dependent on the ambient pH. The lower pH near the tumor cells causes a drastic alteration in the LCST of the coreshell nanoparticles which leads to its structural degradation that eventually stimultes the unleashing of the therapeutics.The conjugation of a targeting moity helps in specifically targeting these nanoparticles to the cancer cells. [Neerman et al 2004]. A wide range of biodegradable nanoprticles have been designed from the the copolymers of poly(d,l-lactide-co-glycolide) which are endowed with the ability to deliver different therapeutic agents like DNA.The researchers have also developed thermoresponsive, pH-responsive by combining biodegradable poly (d,l-lactide)