Current Drug Delivery - Volume 17, Issue 7, 2020

Polymer-drug conjugates are polymers with drug molecules chemically attached to polymer side chains through either a weak (degradable bond) or a dynamic covalent bond. These systems are known as pro-drugs in the inactive form when passing into the blood circulation system. When the prodrug reaches the target organ, tissue or cell, the drug is activated by cleavage of the bond between the drug and polymer, under certain conditions existing in the target organ. The advantages of polymer-drug conjugates compared to other controlled-release carriers and conventional pharmaceutical formulations are the increased drug loading capacity, prolonged in vivo circulation time, enhanced intercellular uptake, better-controlled release, improved therapeutic efficacy, and enhanced permeability and retention effect. The aim of the present review is the investigation of polymer-drug conjugates bearing anti-cancer drugs. The polymer, through its side chains, is linked to the anti-cancer drugs via dynamic covalent bonds, such as hydrazone/imine bonds, disulfide bonds, and boronate esters. These dynamic covalent bonds are cleaved in conditions existing only in cancer cells and not in healthy ones. Thus, ensuring the selective release of drug to the targeted tissue, reducing in this way, the frequent side effects of chemotherapy, leading to a more targeted application, despite the nature of the applied polymer, possessing the ability to aim tumors selectively via incorporation of a relative ligand.

Background: The scope of nanotechnology has been extended to almost every sphere of our daily life. As a result of this, nanocarriers like Carbon Nanotubes (CNTs) are gaining considerable attention for their use in various therapeutic and diagnostic applications. Objective: The objective of the current article is to review various important features of CNTs that make them as efficient carriers for anticancer drug delivery in cancer therapeutics. Methods: In this review article, different works of literature are reported on various prospective applications of CNTs in the targeting of multiple kinds of cancerous cells of different organs via the loading of various anticancer agents. Results: Actually, CNTs are the 3^rd allotropic type of the carbon-fullerenes that are a part of the cylindrical tubular architecture. CNTs possess some excellent physicochemical characteristics and unique structural features that provide an effective platform to deliver anticancer drugs to target specific sites for achieving a high level of therapeutic effectiveness even in cancer therapeutics. For better results, CNTs are functionalized and modified with different classes of therapeutically bioactive molecules via the formation of stable covalent bonding or by the use of supramolecular assemblies based on the noncovalent interaction(s). In recent years, the applications of CNTs for the delivery of various kinds of anticancer drugs and targeting of tumor sites have been reported by various research groups. Conclusion: CNTs represent an emerging nanocarrier material for the delivery and targeting of numerous anticancer drugs in cancer therapeutics.

With the development of nanotechnology, Tumor Physical Stimuli-Responsive Therapies (TPSRTs) have reached a new stage because of the remarkable characteristics of nanocarriers. The nanocarriers enable such therapies to overcome the drawbacks of traditional therapies, such as radiotherapy or chemotherapy. To further explore the possibility of the nanocarrier-assisted TPSRTs, scientists have combined different TPSRTs via the platform of nanocarriers into combination TPSRTs, which include Photothermal Therapy (PTT) with Magnetic Hyperthermia Therapy (MHT), PTT with Sonodynamic Therapy (SDT), MHT with Photodynamic Therapy (PDT), and PDT with PTT. To achieve such therapies, it requires to fully utilize the versatile functions of a specific nanocarrier, which depend on a pellucid understanding of the traits of those nanocarriers. This review covers the principles of different TPSRTs and their combinations, summarizes various types of combination TPSRTs nanocarriers and their therapeutic effects on tumors, and discusses the current disadvantages and future developments of these nanocarriers in the application of combination TPSRTs.

Background: Antiproliferative and cytotoxic effects of lidocaine have been reported in tumor cells. However, the use of these drugs is restricted due to their short action with rapid dispersion from the injected site. The complexation of local anesthetics in 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) is able to improve pharmacological features. Objective: This study evaluated the antitumor effects of lidocaine and the complex HP-β-CD-lidocaine (HP-β-CD-lido). Methods: In vitro, human adenocarcinoma (HeLa) and keratinocytes (HaCaT) were exposed to lidocaine formulations and cell viability, proliferation and apoptosis induction were measured. In vivo, Walker 256 carcinoma cells were subcutaneously injected into the plantar region of the rat right hind paw. The animals were treated with a local application of 5% lidocaine or 5% HP-β-CD-lido. Doxorubicin (3 mg/Kg/day, intraperitoneal) was used as a positive control. Edema sizes were measured daily and the release of cytokines (TNF-α, IL-1α and CXCL-1) and prostaglandin E2 was evaluated. Histological analysis was also performed. Results: HaCaT IG50 values were 846 μM and 2253 μM for lido and HP-β-CD-lido, respectively. In HeLa cells, the IG50 was 1765 μM for lido and 2044 μM for HP-β-CD-lido. Lidocaine formulations significantly reduced the paw edema on day 6 after Walker 256 cells inoculation. However, there were no differences in the release of inflammatory mediators in comparison to the control group. Conclusion: Lidocaine formulations were able to reduce the edema in vivo, without affecting the tumor- induced inflammatory response. The antiproliferative effects of lidocaine formulations may have contributed to tumor reduction.

Background: Screening of multiple methods is worthless for formulators due to material losses, wastage of time, and expenditures. It is imperative to make a quick decision. Objective: The present investigation describes the systematic approach to select the best suitable method for the development of nanoliposomes (NL), the precursor of nanocochleates encapsulating curcumin using Analytic Hierarchy Process (AHP). Methods: Pair-wise comparison matrices were used to achieve the overall priority weight and ranking for the selection of appropriate technique. Furthermore, Plackett-Burman screening Design (PBD) was exploited to investigate specific effects of associated formulation and process variables on particle size (Y1), drug content (Y2), and entrapment efficiency (Y3), while fabricating NL. Results: Results revealed the reliability of the pair-wise comparison matrices and selected the ethanol injection method with the highest priority weight (0.337). Bland-Altman plot and control chart validated the results of AHP. The preparation of vesicles with the preferred diameter and size distribution was essentially fulfilled. Stirring speed (X5), amount of phospholipid (X4), and cholesterol (X8) showed significant influence (p<0.05) on Y1 and Y3, PBD revealed. These factors can be further optimized using the design of experiments. Conclusion: AHP being an effective tool, has assisted in selecting the best alternative for fabricating NL, whilst PBD enabled a clear understanding of the effects of diverse formulation variables on responses studied. Results ensure that NL is a riveting candidate for modulating effectively into tailormade diverse shaped nanoformulations for further in vitro and in vivo studies.

Background: Amongst various cancer diseases, breast cancer is frequently diagnosed malignancy in women. Existing treatments are inadequate, painful and toxic. New ways of treatments need to be explored. Methods: The present work proposes preparation and targeted delivery of a formulation, F-1, for MCF-7 breast cancer treatment. The formulation, colloidal silver (0.76 ppm), was prepared by electrolytic deposition technique and multi surface coatings. Black tea extract (2.25%v/v) was used as a capping agent to tune the morphology of silver nanoparticle and potato extract (6.25%v/v) as a functionalizing agent for targeting MCF-7 breast cancer site. Results: Characterization results show highly pure spherical silver nanoparticles with an average particle size of 15nm. The shift of peaks in the FTIR spectra of formulation confirms the interaction between nanoparticles and extracts. The UV-visible peak was obtained at 525nm, a typical characteristic of silver nanoparticles. In-vivo anti-cancer study of formulation gave a moderate therapeutic effect in Non-Obese Diabetic Severe Combined Immune Deficiency (NOD-SCID) mice. Conclusion: It is observed that tumor volumes obtained in the case of Formulation-1 were moderately inhibited from days 5 to 9. However, one of the mice in the Formulation-1 group inhibited tumor volume to 1.52 cc similar to one of the mice of positive control group (Adriamycin 1.42cc).

Background: Compared to polymeric nanoparticles prepared using non-lipid surfactants, lecithin addition forms larger nanoparticles and exhibits higher drug loading and the stability of nanoparticles can be conferred by adding Vitamin E Polyethylene Glycol Succinate (TPGS) into the formulation. Aim: The aim of this study is to prepare Gemcitabine (Gem) loaded lecithin/PLGA nanoparticles. Moreover, the effect of TPGS and sodium cholate (SK) on the preparation of lecithin/PLGA nanoparticles was compared. Methods: It was found that while PC addition into PLGATPGS nanoparticles formed larger particles (251.3± 6.0 nm for Gem-PLGATPGS NPs and 516,9 ± 3.9 nm for Gem-PLGA-PCTPGS NPs), the particle size of PLGASK nanoparticles was not affected by lecithin addition (p>0.05). Results: In cytotoxicity studies, it was found that the SK-MES-1 cell inhibition rates of Gem-PLGATPGS NPs, Gem-PLGA-PCTPGS NPs, Gem-PLGASK NPs, Gem-PLGA-PCSK NPs were similar with free Gem (p>0.05). In cytotoxicity studies, it was found that the encapsulation into nanoparticles did not change the cytotoxicity of the drug. However, higher cellular uptake has been observed when the lecithin was used in the preparation of PLGA nanoparticles. Conclusion: Compared with free Gem, the Gem-loaded nanoparticles enhanced the uptake of the drug by SK-MES-1 cells which can increase the effect of gemcitabine for non-small cell lung cancer therapy.

Background: Extensive loss of skin in burn patients can have devastating consequences, both physically and mentally. Adipose-Derived Stem Cells (ADSCs) and fibroblasts are known to play significant roles in the process of wound healing. Recently, bioengineered skin has been considered for wound healing purposes. Methods: Investigate the effect of Integra seeded with ADSCs, fibroblasts, or both on wound healing. Results: We found that when Integra is seeded with ADSCs and fibroblasts, both types of cells incorporate and proliferate, the phenomenon becoming more robust when the cells are co-cultured on Integra, both in vitro and in vivo. In addition, when these cells are seeded on Integra, they stimulate epithelization with no signs of inflammation and skin necrosis being observed when transplanted on animals for 7 days. Conclusion: ADSCs and fibroblasts seeded on Integra could decrease the number of α-SMA positive myofibroblasts, leading to scarless wound healing. The evidence from this study is strongly supportive that Integra seeded with ADSCs and fibroblasts is an appropriate and effective bioengineered skin for wound healing.