Curr Pharm Des. 2016;22(11):1506-20.
Pharmacological Drug Delivery Strategies for Improved Therapeutic Effects: Recent Advances
Reema Savaliyaa, Poornima Singhb and Sanjay Singha*
Address for correspondence:
aInstitute of Life Sciences, School of Science and Technology, Ahmedabad University, Ahmedabad, Navrangpura, Ahmedabad-380009, Gujarat, India
bL. J. Institute of Engineering and Technology, S. G. Highway, Sarkhej, Ahmedabad-382210, Gujarat, India
Email to corresponding author: email@example.com
The latest pharmacologic research has resulted number of new molecules with the potential to modernize the prevention or treatment of different complex diseases, including cancer. The therapeutics generally include moieties such as proteins, drugs and genes, etc. Current activities in the pharmacological field include the development of novel drug-delivery systems to overcome pharmacokinetic glitches such as limited bioavailability, unwanted distribution, drug resistant, and stability, etc. Therefore, to address these issues various biotechnological and pharmacological techniques has been introduced. However, effective drug delivery with improved efficacy remains challenging. This review is focused towards different strategies such as physical and biological methods for efficacious delivery at desired tissues and even sub-cellular targeting. Emphasis is also given about nanotechnology based drug or gene delivery strategies and co-delivery of drug-drug; gene-gene or combinations of drug-gene, etc. are the current cutting-edge methods, which are under clinical or pre-clinical stage of research. Uses of biodegradable materials, such as liposomes and polymeric particles are another class of drug delivery vehicles, which have shown tremendous success, are also discussed. Towards the end, future directions of pharmacological drug delivery methods have also been summarized.
Current advancements in molecular and cell biology identified the novel biomolecules, which could be used for the efficacious treatment of several human diseases such as cancer, cardiovascular and diabetes. However, the major hitch to the successful utilization of these molecules lies with the effective delivery and accurate targeting of the disease site. Additionally, bioavailability, unwanted bio-distribution, low stability and drug resistance, etc. are other limiting factors, which affect the pharmacokinetics and pharmacodynamics of the drug molecules. Recent developments within the area of advanced drug delivery and targeting have generated a myriad of strategies to achieve the desired therapeutic consequence. Among several strategies, co-delivery and nanomaterials based, delivery and targeting approaches have shown tremendous success1.
Co-delivery approach: Traditional methods involving single agent/drug for therapeutic applications have found to have limited success due to the development of resistance and side effects. These traits become more obvious due to the use of a high amount of drug in order to achieve elevated efficiency. The famous example is the administration of drug Vemurafenib (PLX4032) used in the treatment of melanoma 2. This drug was effective during the initial course of treatment of advanced melanoma in patients; however, the prolonged used led to the development of resistance. It was found that cancer cells start to create alternate survival pathway and express suitable receptors at the cell surface. It has also been proved that cancer cells develop resistance if treated repeatedly with single drug and targeting individual signaling pathway of cancer cell survival. This is primarily because cancer is multigene abnormality, therefore, the cell survival is controlled by a number of signaling pathways. Consequently, formulations containing multi-drugs (targeting multiple pathways) have been shown better results than corresponding single drug treatment. Such inhibitors can be studied under following sub heads.
Nanomaterials delivering combination of drugs: Multi-drugs have shown limited toxicity and low probability to develop resistance in cancer cells. It has been suggested that the delivered drugs require low amount to achieve the synergy between both the drugs delivered to cancer cells and tissues. Nanomaterials have shown tremendous application in encapsulating two or more drugs in one platform, as it offers more retention time to drugs within the body. Liposomes, micelles, polymeric and other core-shell type nanomaterials have successfully shown the delivery of multiple drugs at the desired site of action 3. Nanomaterials not only encapsulate various drugs, but also exhibit controlled release in the desired ratio, which furthermore increases the treatment efficacy. Additionally, the well characterized surface properties also offer the surface modification with growth factors or antibodies, which could further guide these nanomaterials containing drugs at the cancer site.
Figure 1: Schematic showing encapsulation of two drugs (Paclitaxel and Celecoxib) in a single liposome, which could synergistically inhibit the key survival signaling pathways (MAP Kinase and COX-2) in cancer cells, leading to cell apoptosis.
Nanomaterials delivering combination of genes: Since drugs can induce non-specific side effects in cancer patients, RNA interference technology has been shown minimum of such effects, therefore, remains the most promising tool for targeted treatment of disease through gene delivery. Nevertheless, the lack of appropriate transfection method limits its successful usage in clinics. Several approaches have been introduced over past few decades, which mainly include viral vectors, electroporation, gene gun method, chemical methods and lipid based transfection 4. The use of viral vectors offered best transfection efficiency, however, poses a high risk of infection among mammalian systems. In other methods, transfection efficiency is compromised along with cytotoxicity and safety issues. Nanomaterials based gene delivery is an upcoming field and variety of materials such as polymers, dendrimers, liposomes, carbon nanotubes, graphene, fullerenes, metals and metal-oxide nanoparticles have been designed. Along with genes, the unique optical and physicochemical properties of nanomaterials have also been exploited to destroy the targeted cancer cells and tissues, which make the gene therapy more effective. Nanomaterials, such as gold nanoparticles (AuNPs), exhibit near-infra red (NIR) light absorption and can produce photo thermal effect, due to which they can produce heat in their surrounding environment 5. Heating effect may disintegrate the nanoparticles which help in the release of genes to the targeted tissues. Gold nano-shells could raise the temperature of surrounding up to 55 °C, which cancer cells cannot withhold but normal cells can easily tolerate this temperature.
Figure 2: Schematic diagram showing nanoparticle carrying two genes (AKT-siRNA and PTEN plasmid) together. These genes could synergistically inhibit the key survival signaling pathways (AKT and MMP) in cancer cells, leading to cell apoptosis.
Nanomaterials delivering combination of drugs and genes: Drug resistance has been known to be caused by malfunctioning of genes in cancer cells, which results in inactivation of drugs. In order to correct the drug resistance, siRNAs or other antitumor genes has been used, which further sensitize the cancer cells to anticancer drugs6. These mechanisms of antitumor activity involve a combination of drugs with genes. Doxorubicin, a well-known anticancer drug, has been combined with several genes, peptides, miRNAs and siRNAs. These genes can be the one targeting proteins responsible for effluxing drugs form cancer cells or silencing multiple drug resistance genes. It has been observed that such combination treatment prolongs median survival compared with single anticancer agent treatment7.
Figure 3: Schematic diagram showing nanoparticle encapsulating a drug (plumbagin) and carry one gene (MMP-2 siRNA). These genes could synergistically inhibit the key survival signaling pathways (COX-2 and MMP) in cancer cells, leading to cell apoptosis.
This strategy has the potential to be successfully translated into a new, more effective therapy for all types of cancer.
Conclusions and future directions: A plethora of research in the area of biomedical sciences has enriched our understanding about the identification of biological targets present on the cancer cells along with the pharmacokinetics and pharmacodynamics of the drug in the human body. Despite these advancements, many drugs fail into clinical trials either due to undesirable side effects or limited efficacy. This could be because of the fact that the efficacy largely depends on the route of administration, dose to the body and response from the body to drugs, which vary from person to person. A concept of “personalized medicine” has been given, which may help in reducing side effects and present improved therapeutic index. Further, advancement in the design of nanomaterials for biomedical applications can also surmount the challenges faced by clinicians. However, the full potential of nanotechnology and nanomedicines has not yet been explored, which possibly needs a close effort from the experts of field of biology, physics, chemistry and medicines. It may not be surprising if a concept of “personalized nanomedicine” comes into the existence in near future and probably would be a better alternative.
Acknowledgements: The financial assistance for the Centre for Nanotechnology Research and Applications (CENTRA) by The Gujarat Institute for Chemical Technology, and the funding from the Department of Science and Technology-Science and Engineering Research Board (SERB), India (Grant No.: ILS/SERB/2015-16/01) to Dr Sanjay Singh under the scheme of Start-Up Research Grant (Young Scientists)-Life Sciences are gratefully acknowledged. Authors also thank to University Grant Commission (UGC), New Delhi for providing Junior Research Fellowship.
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