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The unique properties-such as biocompatibility, biodegradability, bio-absorbability, low cost, easy fabrication, and high versatility-have made polycaprolactone (PCL) the center of attraction for researchers. The derived introduction in this manuscript gives a pretty detailed overview of PCL, so you can first brush up on it. Discussion on the various PCL-based derivatives involves, but is not limited to, poly(ε-caprolactone-co-lactide) (PCL-co-LA), PCL-g-PEG, PCL-g-PMMA, PCL-g-chitosan, PCL-b-PEO, and PCL-g-PU specific properties and their probable applications in biomedicine. This paper has considered examining the differences in the diverse disease subtypes and the therapeutic value of using PCL. Advanced strategies for PCL in delivery systems are also considered. In addition, this review discusses recently patented products to provide a snapshot of recent updates in this field. Furthermore, the text probes into recent advances in PCL-based DDS, for example, nanoparticles, liposomes, hydrogels, and microparticles, while giving special attention to comparing the esters in the delivery of bioactive compounds such as anticancer drugs. Finally, we review future perspectives on using PCL in biomedical applications and the hurdles of PCL-based drug delivery, including fine-tuning mechanical strength/degradation rate, biocompatibility, and long-term effects in living systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Breast cancer leads to the highest mortality among women resulting in a major clinical burden. Multidrug therapy is more efficient in such patients compared to monodrug therapy. Simultaneous combinatorial or co-delivery garnered significant interest in the past years. Caffeic acid (CFA) (a natural polyphenol) has received growing attention because of its anticarcinogenic and antioxidant potential. Bortezomib (BTZ) is a proteasome inhibitor and may be explored for treating breast cancer. Despite its high anticancer activity, the low water solubility and chemical instability restrict its efficacy against solid tumors. In the present study, we designed and investigated a HP-PCL ( N -2-hydroxypropylmethacrylamide-polycaprolactone) polymeric micellar (PMCs) system for the simultaneous delivery of BTZ and CFA in the treatment of breast cancer. The designed BTZ+CFA-HP-PCL PMCs were fabricated, optimized, and characterized for size, zeta potential, surface morphology, and in vitro drug release. Developed nanosized (174.6 ± 0.24 nm) PMCs showed enhanced cellular internalization and cell cytotoxicity in both MCF-7 and MDA-MB-231 cells. ROS (reactive oxygen species) levels were highest in BTZ-HP-PCL PMCs, while CFA-HP-PCL PMCs significantly ( p < 0.001) scavenged the ROS generated in 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay. The mitochondrial membrane potential (MMP) assay revealed intense and significant green fluorescence in both types of cancer cells when treated with BTZ-HP-PCL PMCs ( p < 0.001) indicating apoptosis or cell death. The pharmacokinetic studies revealed that BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs exhibited the highest bioavailability, enhanced plasma half-life, decreased volume of distribution, and lower clearance rate than the pure combination of drugs. In the organ biodistribution studies, the combination of BTZ+CFA showed higher distribution in the spleen and the heart. Overall findings of in vitro studies surprisingly resulted in better therapeutic efficiency of BTZ-HP-PCL PMCs than BTZ+CFA-HP-PCL PMCs. However, the in vivo tumor growth inhibition study performed in tumor-induced mice concluded that the tumor growth was inhibited by both BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs ( p < 0.0001) more efficiently than pure BTZ and the combination (BTZ+CFA), which may be due to the conversion of boronate ester into boronic acid. Henceforth, the combination of BTZ and CFA provides further indications to be explored in the future to support the hypothesis that BTZ may work with polyphenol (CFA) in the acidic environment of the tumor.

Gliomas are the most prevailing intracranial tumors, which account for approximately 36% of the primary brain tumors of glial cells. Glioblastoma multiforme (GBM) possesses a higher degree of malignancy among different gliomas. The blood-brain barrier (BBB) protects the brain against infections and toxic substances by preventing foreign molecules or unwanted cells from entering the brain parenchyma. Nano-carriers such as liposomes, nanoparticles, dendrimers, etc. boost the brain permeability of various anticancer drugs or other drugs. The favorable properties like small size, better solubility, and the modifiable surface of dendrimers have proven their broad applicability in the better management of GBM. However, in vitro and in vivo toxicities caused by dendrimers have been a significant concern. The presence of multiple functionalities on the surface of dendrimers enables the grafting of target ligand and/or therapeutic moieties. Surface engineering improves certain properties like targeting efficiency, pharmacokinetic profile, therapeutic effect, and toxicity reduction. This review will be focused on the role of different surface-modified dendrimers in the effective management of GBM., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Anemia is the most common hematological abnormality of chemotherapy, which is responsible for poor clinical outcomes. To overcome this complication, the present study was aimed for developing a Eudragit/polylactic-co-glycolic acid (PLGA) based nanoparticulate system for a model drug paclitaxel (PTX). The study was planned using a simplex lattice mixture design. PTX nanoparticles (PTXNp) were evaluated in vitro for physicochemical properties, hemolytic effects and cytotoxic effects. Further, the nanoparticles were subjected to in vivo screening using rats for hemocompatibility, pharmacokinetic profile, and biodistribution to the vital organs. The PTXNps were 65.77-214.73 nm in size, showed more than 60% sustained drug release in 360 h and caused less than 8% hemolysis. The parameters like red blood cell count, activated partial thromboplastin time (aPTT), prothrombin time (PT) and C3 complement were similar to the negative control. Cytotoxicity results suggested that all the PTXNp demonstrated drug concentration-dependent cytotoxicity. The in vivo pharmacokinetic study concluded that PTXNp formulations had significantly higher blood AUC (93.194.55-163,071.15 h*ng/mL), longer half-lives (5.80-6.35 h) and extended mean residence times (6.05-8.54 h) in comparison to PTX solution (p < 0.05). Overall, the study provides a nanoparticulate drug delivery system to deliver PTX safely and effectively along with reducing the associated hematological adverse effects., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Poor aqueous solubility of anticancer drug bortezomib (BTZ) still remains a major challenge in the development of a successful formulation. The dendrimeric platform can provide a better opportunity to deliver BTZ with improved solubility. BTZ encapsulated in PEGylated PAMAM dendrimers (BTZ-PEG-PAMAM) was characterized and evaluated comparatively with encapsulated and conjugated dendritic formulations. The particle size of BTZ-PEG-PAMAM was 188.6 ± 4.17 nm, with entrapment efficiency of 78.61 ± 2.91% and drug loading of 39.30 ± 1.98%. The aqueous solubility of BTZ in PAMAM-PEG conjugate was enhanced by 68.11 folds in comparison to pure drug. In vitro drug release profile was found to be sustained up to 72 h. A comparative colorimetric MTT assay against A549 and MCF-7 cancer cells resulted in maximum efficacy from BTZ-PEG-PAMAM with IC 50 value 333.14 ± 15.42 and 152.60 ± 24.56 nM, respectively. Significantly higher cellular internalization was observed in FITC tagged BTZ-PEG-PAMAM. In vivo pharmacokinetic study performed on Sprague Dawley rats resulted in 8.63 folds increase in bioavailability for BTZ-PEG-PAMAM than pure drug. Pharmacokinetic parameters of BTZ-PEG-PAMAM were better and improved over BTZ and other dendritic formulations. In conclusion, the prepared formulation of BTZ-PEG-PAMAM has given significant outcome and this strategy may be further explored for better delivery of BTZ in future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Polymer therapeutics has gained prominence due to an attractive structural polymer chemistry and its applications in diseases therapy. In this review, we discussed the development and capabilities of N-(2-hydroxypropyl) methacrylamide (HPMA) and HPMA-drug conjugates in cancer therapy. The design, architecture, and structural properties of HPMA make it a versatile system for the synthesis of polymeric conjugations for biomedical applications. Research suggests that HPMA could be a possible alternative for polymers such polyethylene glycol (PEG) in biomedical applications. Although numerous clinical trials of HPMA-drug conjugates are ongoing, yet no product has been successfully brought to the market. Thus, further research is required to develop HPMA-drug conjugates as successful cancer therapeutics., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Bortezomib (BTZ) is a proteasome inhibitor used for multiple myeloma and mantle cell lymphoma treatment. BTZ's aqueous in solubility is the main hindrance in its successful development as a commercial formulation. The main objective of the present study is to develop and characterize folic acid-glycine-poly-L-lactic acid (FA-Gly 4 -PLA) based nanoformulation (NPs) to improve solubility and efficacy of BTZ., Methods: BTZ loaded FA-Gly 4 -PLA NPs were prepared and characterized for size, zeta potential, in vitro studies such as release, kinetics modeling, hemolytic toxicity, and cell line-based studies (Reactive Oxygen Species: ROS and cytotoxicity)., Results: BTZ loaded NPs (BTZ-loaded FA-Gly 4 -PLA) and blank NPs (FA-Gly 4 -PLA) size, zeta, and PDI were found to be 110 ± 8.1 nm, 13.7 ± 1.01 mV, 0.19 ± 0.03 and 198 ± 9.01 nm, 8.63 ± 0.21 mV, 0.21 ± 0.08 respectively. The percent encapsulation efficiency (% EE) and percent drug loading (% DL) of BTZ loaded FA-Gly 4 -PLA NPs was calculated to be 78.3 ± 4.1 and 12.38 ± 2.1. The Scanning Electron Microscopy (SEM) showed that NPs were slightly biconcave in shape. The in vitro release of BTZ from FA-Gly 4 -PLA NPs resulted in the sustained manner. The prepared NPs were less hemolytic than BTZ., Conclusions: BTZ loaded Gly 4 -PLA NPs apoptotic index was found to be much higher than BTZ but lesser than BTZ loaded FA-Gly 4 -PLA against breast cancer cell lines (MDA-MB-231). ROS intracellular assessment assay indicated that BTZ and BTZ loaded FA-Gly 4 -PLA NPs exhibited higher ROS production. Conclusively, the BTZ loaded FA-Gly 4 -PLA NPs were able to encapsulate more BTZ than BTZ loaded Gly 4 -PLA NPs and were found to be more effective as per as in vitro anti-cancer effect is concerned.

Purpose: Combinatorial approach can be beneficial for cancer treatment with better patient recovery. Co-delivery of natural and synthetic anticancer drug not only valuable to achieve better anticancer effectivity but also to ascertain toxicity. This study was aimed to co-deliver berberine (natural origin) and doxorubicin (synthetic origin) utilizing conjugation/encapsulation strategy through poly (lactic-co-glycolic acid) (PLGA) nanoparticles., Methods: Doxorubicin was efficiently conjugated to PLGA via carbodiimide chemistry and the PLGA-doxorubicin conjugate (PDC) was used for encapsulation of berberine (PDBNP)., Results: Significant anti-proliferative against MDA-MB-231 and T47D breast cancer cell lines were observed with IC 50 of 1.94 ± 0.22 and 1.02 ± 0.36 μM, which was significantly better than both the bio-actives (p < 0.05). The ROS study revealed that the PDBNP portrayed the slight increase in the reactive oxygen species (ROS) pattern in MDA-MB-231 cell line in a dose-dependent manner, while in T47D cells, no significant change in ROS was seen. PDBNP exhibits significant alteration (depolarization) in mitochondrial membrane permeability and arrest of cell cycle progression at sub G1 phase while the Annexin V/PI assay followed by confocal microscopy resulted into cell death mode to be because of necrosis against MDA-MB-231 cells. In vivo studies in Sprague Dawley rats revealed almost 14-fold increase in half life and a significant increase in plasma drug concentration., Conclusion: The overall approach of PLGA based co-delivery of doxorubicin and berberine witnessed synergetic effect and reduced toxicity as evidenced by preliminary toxicity studies.

The intention of present research work is to formulate usnic acid (UA) loaded heparin modified gellan gum (HAG) nanoparticles (NPs). HAG copolymer based conjugation was synthesized and characterized by 1 H NMR and FT-IR spectroscopy. Plain and UA loaded HAG NPs were prepared via nanoprecipitation technique. NPs were typified and further characterized for particle size, polydispersity index, entrapment efficiency, zeta potential, atomic force microscopy, differential scanning calorimetry, X-ray diffraction analysis, and in-vitro release. In-vitro tube formation assay, tumorsphere assay, autophagy assay, DNA cleavage assay, internalization by confocal and FACS based internalization analysis, caspase assay and cell cycle assay were performed for biological activity. Obtained experimental results explored that HAG NPs displayed a sustained release of UA (95.67% in 48 h) compared to gellan gum NPs (96.12% in 8 h). In cytotoxicity studies, UA loaded HAG NPs exhibited an enormous cytotoxic potential against A549 cancer cells. In the in vivo bio-distribution study, using albino rat model the free UA concentration was found 7.09 ± 0.9%, 2.7 ± 1.5%, 7.5 ± 2.1, 9.2 ± 2%, and 6.25 ± 1.3% post two hours of intravenous administration, however, in the case of UA loaded HAG NPs the obtained level was 4.1 ± 1.10, 7.7 ± 1.30%, 2.21 ± 0.29%, 1.85 ± 0.25%, 2.2 ± 0.78%, 2.9 ± 1.21% respectively, in heart, lung, liver, spleen, intestine and kidney. The overall anticancer study and result of internalization deciphered the higher anticancer potential of UA loaded HAG NPs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Bendamustine is an important drug for the treatment of chronic lymphatic leukaemia (CLL), non-Hodgkin lymphoma (NHL). However, its delivery is challenging due to its instability. Current approach reports the development and characterization of bendamustine encapsulated PLGA nanoparticles for the effective targeting to leukemic cells., Methods: The prepared, bendamustine loaded PLGA nanoparticles (BLPNP) were developed and characterized for particle size, zeta potential and polydispersity index. The formed nanoparticles were further characterized with the help of electron microscopy for surface morphology. The formed nanoparticles were evaluated for cytotoxicity, cell uptake, ROS and cell apoptosis against THP-1 leukemic cells as a part of in vitro evaluation. In vivo organ bio-distribution and tumor regression studies were performed to track in vivo behaviour of BLPNP., Results: The average particle size was 138.52 ± 3.25 nm, with 0.192 ± 0.036 PDI and - 25.4 ± 1.38 mV zeta potential. TEM images revealed the homogeneous particle size distribution with uniform shape. In vitro release exhibited a sustained drug-release behaviour up to 24 h. Cytotoxicity against THP-1 cells through MTT assay observed IC 50 value of 27.8 ± 2.1 μM for BLPNP compared to pure drug, which was 50.42 ± 3.4 μM. Moreover, in vitro studies like cell-uptake and cell apoptosis studies further confirmed the higher accumulation of BLPNP in comparison to the pure drug. Organ distribution and tumor regression studies were performed to track in vivo behaviour of bendamustine loaded nanoparticles., Conclusion: The overall study described a promising approach in terms of safety, least erythrocytic toxicity, better IC 50 value with enhance tumor targeting and regression.

Berberine (BBR) is a nitrogenous cyclic natural alkaloid with potential anticancer activity. However it has been less explored due to its poor pharmacokinetic profile. Dendrimers (e.g. PAMAM) have promising potential to deliver anticancer drugs/bio-actives because of their well-defined architecture, monodispersity and tailor-made surface functionality. In the present study it was attempted to deliver berberine through G4 PAMAM dendrimers by conjugation (BPC) as well as encapsulation (BPE) approach. The developed encapsulated and conjugated berberine formulations were found to have size in the approximate range of 100-200nm while zeta potential was almost same as PAMAM G4 dendrimer. The entrapment efficiency in BPE was found to be 29.9%, whereas, the percentage conjugation in BPC was found to be 37.49% indicating high drug payload in conjugation. The developed nano-formulations were characterized through 1 H NMR, FT-IR as well as electron microscopy (SEM and TEM). The in vitro release study in different media (water and PBS 7.4) showed sustained release pattern of BBR. Almost 72% and 98% drug was released within 24h respectively; whereas in PBS almost 80% and 98% release was observed within 24h, respectively. The formulations followed Higuchi release and first order release as best fit release kinetic model. MTT assay results showed significantly higher anticancer activity for the PAMAM-BBR (BPC) (p<0.01) against MCF-7 and MDA-MB-468 breast cancer cells. The time dependent ex vivo hemolytic toxicity of the BPC and BPE was significantly less (<5%) even after 24h, which indicated that the formulations can be regarded as significantly safe and biocompatible. Similarly, the in vivo hematological parameters were analyzed through auto-analyzer and the formulations were found to be safer and biocompatible with very least but insignificant (p>0.05) effects. The in vivo pharmacokinetic parameters were found to be impressively improved in albino rat model. The pharmacokinetic parameters such as half-life (t 1/2 ) and AUC of berberine were impressively improved in the plasma level time in vivo studies in albino rat model. The obtained t 1/2 was 14.33h for BPC compared to 6.7h for BBR alone. The overall conclusion says that among both the developed formulations the conjugated formulation (BPC) was found to be more prominent than the encapsulated one (BPE). Therefore conclusively conjugation can be a better option for the delivery of natural bio-actives through dendrimers., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The cluster-determinant 44 (CD44) receptor has a high affinity for hyaluronic acid (HA) binding and is a desirable receptor for active targeting based on its overexpression in cancer cells compared with normal body cells. The nanocarrier affinity can be increased by conjugating drug-loaded carriers with HA, allowing enhanced cancer cell uptake via the HA-CD44 receptor-mediated endocytosis pathway. In this review, we discuss recent advances in HA-based nanocarriers and micelles for cancer therapy. In vitro and in vivo experiments have repeatedly indicated HA-based nanocarriers to be a target-specific drug and gene delivery platform with great promise for future applications in clinical cancer therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Bortezomib (BTZ) is the first proteasome inhibitor approved by the US-FDA is majorly used for the treatment of newly diagnosed and relapsed multiple myeloma including mantle cell lymphoma. BTZ is hydrophobic in nature and is a major cause for its minimal presence as marketed formulations. The present study reports the design, development and characterization of dendrimer based formulation for the improved solubility and effectivity of bortezomib. The study also equally focuses on the mechanistic elucidation of solubilization by two types of dendrimers i.e. fourth generation of poly (amidoamine) dendrimers (G4-PAMAM-NH 2 ) and fifth generation of poly (propylene) imine dendrimers (G5-PPI-NH 2 ). It was observed that aqueous solubility of BTZ was concentration and pH dependent. At 2mM G5-PPI-NH 2 concentration, the fold increase in bortezomib solubility was 1152.63 times in water, while approximately 3426.69 folds increase in solubility was observed at pH10.0, respectively (p<0.05). The solubility of the drug was increased to a greater extent with G5-PPI-NH 2 dendrimers because it has more hydrophobic interior than G4-PAMAM-NH 2 dendrimers. The release of BTZ from G5-PPI-NH 2 complex was comparatively slower than G4-PAMAM-NH 2 . The thermodynamic treatment of data proved that dendrimer drug complexes were stable at all pH with values of ΔG always negative. The experimental findings were also proven by molecular simulation studies and by calculating RMSD and intermolecular hydrogen bonding through Schrodinger software. It was concluded that PPI dendrimers were able to solubilize the drug more effectively than PAMAM dendrimers through electrostatic interactions., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Dendrimers are novel nanoarchitectures with unique properties including a globular 3D shape, a monodispersed unimicellar nature and a nanometric size range. The availability of multiple peripheral functional groups and tunable surface engineering enable the facile modification of the dendrimer surface with different therapeutic drugs, diagnostic agents and targeting ligands. Drug encapsulation, and solubilizing and passive targeting also equally contribute to the therapeutic use of dendrimers. In this review, we highlight recent advances in the delivery of anticancer drugs using dendrimers, as well as other biomedical and diagnostic applications. Taken together, the immense potential and utility of dendrimers are envisaged to have a significant positive impact on the growing arena of drug delivery and targeting., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Delivery of chemotherapeutic drugs for the diagnosis and treatment of cancer is becoming advanced day by day. However, the challenge of the effective delivery system still does exist. In various types of cancers, breast cancer is the most commonly diagnosed cancer among women. Breast cancer is a combination of different diseases. It cannot be considered as only one entity because there are many specific patient factors, which are involved in the development of this disease. Nanotechnology has opened a new area in the effective treatment of breast cancer due to the several benefits offered by this technology., Methods: Polymeric nanocarriers are among one of the effective delivery systems, which has given promising results in the treatment of breast cancers. Nanocarriers does exert their anticancer effect either through active or passive targeting mode., Results: The use of nanocarriers has been resolute about the adverse effects of chemotherapeutic drugs such as poor solubility and less penetrability in tumor cells., Conclusion: The present review is focused on recent developments regarding polymeric nanocarriers, such as polymeric micelles, polymeric nanoparticles, dendrimers, liposomes, nanoshells, fullerenes, carbon nanotubes (CNT) and quantum dots, etc. for their recent advancements in breast cancer therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Unlabelled: Poly(amidoamine) dendrimers (PAMAM) are well-defined, highly branched, nanoscale macromolecules with numerous active amine groups on the surface. PAMAM dendrimer can enhance the solubility of hydrophobic drugs, and with numerous reactive groups on the surface PAMAM dendrimer can be engineered with various functional groups for specific targeting ability. However, in physiological conditions, these amine groups are toxic to cells and limit the application of PAMAM. In the recent years, polyethylene glycol (PEG) conjugation has been the most widely used approach to reduce the toxicity of the active group on dendrimer surface. PEG molecules are known to be inert, non-immunogenic, and non-antigenic with a significant water solubility. PEGylated PAMAM-mediated delivery could not only overcome the limitations of dendrimer such as drug leakage, immunogenicity, hemolytic toxicity, systemic cytotoxicity but they also have the ability to enhance the solubilization of hydrophobic drugs and facilitates the potential for DNA transfection, siRNA delivery and tumor targeting. This review focuses on the recent developments on the application and influence of PEGylation on various biopharmaceutical properties of PAMAM dendrimers., Statement of Significance: It is well established that dendrimers have demonstrated promising potentials for drug delivery. However, the inherent toxicity poses challenges for its clinical translation. In this regard, PEGylation has helped mitigate some of the toxicity concerns of dendrimers and have paved the way forward for testing its translational potentials. The review is a collection of articles demonstrating the utility of PEGylation of the most studied PAMAM dendrimers. To our knowledge, this is a first such attempt to draw reader's attention, specifically, towards PEGylated PAMAM dendrimers., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Nanotechnology, in health and medicine, extensively improves the safety and efficacy of different therapeutic agents, particularly the aspects related to drug delivery and targeting. Among various nano-carriers, polymer based macromolecular approaches have resulted in improved drug delivery for the diseases like cancers, diabetes, autoimmune disorders and many more. Polymeric micelles consisting of hydrophilic exterior and hydrophobic core have established a record of anticancer drug delivery from the laboratory to commercial reality. The nanometric size, tailor made functionality, multiple choices of polymeric micelle synthesis and stability are the unique properties, which have attracted scientists and researchers around the world to work upon in this opportunistic drug carrier. The capability of polymeric micelles as nano-carriers are nowhere less significant than nanoparticles, liposomes and other nanocarriers, as per as the commercial feasibility and presence is concerned. In fact polymeric micelles are among the most extensively studied delivery platforms for the effective treatment of different cancers as well as non-cancerous disorders. The present review highlights the sequential and recent developments in the design, synthesis, characterization and evaluation of polymeric micelles to achieve the effective anticancer drug delivery. The future possibilities and clinical outcome have also been discussed, briefly.

Nanotechnological advancement has become a key standard for the diagnosis and treatment of several complex disorders such as cancer by utilizing the enhanced permeability and retention effect and tumor-specific targeting. Synthesis and designing the formulation of active agents in terms of their efficient delivery is of prime importance for healthcare. The use of nanocarriers has resolved the undesirable characteristics of anticancer drugs such as low solubility and poor permeability in cells. Several types of nanoparticles (NPs) have been designed with the use of various polymers along or devoid of surface engineering for targeting tumor cells. All NPs include polymers in their framework and, of these, polylactide-co-glycolide (PLGA) is biodegradable and Food and Drug Administration approved for human use. PLGA has been used extensively in the development of NPs for anticancer drug delivery. The extensive use of PLGA NPs is promising for cancer therapy, with higher efficiency and less adverse effects. The present review focused on recent developments regarding PLGA NPs, the methods used for their preparation, their characterization, and their utility in the delivery of chemotherapeutic agents.

Poly-L-lysine (PLL) dendrimers are currently being investigated as antiangiogenic agent for therapy of cancer. In this study, we report folate conjugated poly-l-lysine dendrimers (FPLL) as an efficient carrier for model anticancer drug, doxorubicin hydrochloride (Dox); for pH sensitive drug release, selective targeting to cancer cells, anticancer activity and antiangiogenic activity. This nanoconjugate of Dox showed initial rapid in vitro release followed by gradual slow release, and the drug release was found to be pH sensitive with greater release at acidic pH. In the CAM assay and tubule formation assay with HUVEC, Dox-FPLL formulation showed the significant antiangiogenic activity confirming that activity of PLL was not compromised by the presence of Dox and folic acid. The ex vivo investigations with human breast cancer cell lines MCF-7 showed enhanced cytotoxicity of Dox-FPLL with significantly enhanced intracellular uptake (p<0.001). The in vivo therapeutic potential of nanoconjugate was determined in MCF-7 breast cancer xenograft model in tumor-bearing mice. Dox-FPLL increased the concentration of Dox in tumor by 121.5-fold after 24 h in comparison with free Dox formulation. The folate conjugated dendrimeric Dox showed superior anti-tumor activity in tumor xenograft model with significantly prolonged survival determined by Kaplan Meier survival analysis (p<0.001)., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In the present study we developed the novel kind of triazine dendrimers by utilizing differential reactivity of the cyanuric chloride (triazine trichloride) which overcome the limitations associated with the others classes of dendrimers like toxicity, low yield, high synthesis cost etc. Triazine dendrimers were synthesized by divergent method using triazine trichloride as core and diethanolamine as branching unit to avoid the use of protecting group and functional group interconversion up to third generation. These hydroxyl terminated dendrimers were characterized by FTIR, 1HNMR, 13CNMR, ES mass spectroscopy, and by elemental analysis. The yield of pure G3 dendrimers was 63%. This novel dendrimers increases the aqueous solubility of hydrophobic drug Paclitaxel up to 0.562 mg/ml as well as showed control release behavior. Hemolytic and toxicology studies of this dendrimer in mice showed no adverse toxicity to the kidneys and the liver up to 200 mg/kg dose (i.p). Triazine being a hydrophobic compound, the core of this dendrimer is hydrophobic and supposed to easily incorporate the hydrophobic guest while presence of hydroxyl group on periphery increases its water solubility and reduces its toxicity; and thus it is useful in various fields like gene delivery, MRI contrasting agents, vaccines or as solubilization tool.

The purpose of the present investigation was to evaluate the potential of surface engineered polypropylene imine (PPI) dendrimers as nanoscale drug delivery units for site-specific delivery of a model anti-cancer agent, doxorubicin.hydrochloride (DOX). Dextran conjugated PPI dendrimers were synthesized, characterized and further loaded with DOX. The developed formulation was characterized by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR) and transmission electron microscopic (TEM) studies. Dendrimer formulation was evaluated for in vitro drug release and haemolytic studies under various pH conditions. Cell uptake and cytotoxicity studies were performed on A549 cell lines using MTT cell proliferation assay. In vivo studies were conducted for evaluation of various pharmacokinetic parameters and tissue distribution pattern. In vitro, formulation displayed initial rapid release of the drug followed by rather slow release. Further, the dextran conjugated dendrimer formulation was found to be least haemolytic but more cytotoxic as compared to free drug. Cell uptake studies depicted that the formulation was preferably taken up by the tumor cells when compared to free drug. The conjugation of oxidized polyaldehyde dextran imparts macromolecular nature to the dendritic carrier, consequently the formulation was found to selectively enter highly porous mass of tumor cells at the same time precluding normal tissues. Thus it was concluded that the drug loaded dendrimer formulation would selectively localize in the tumor mass, increasing the therapeutic margin of safety while reducing the side effects associated with anti-cancer agents.

Ligand-mediated targeting of drugs especially in anticancer drug delivery is an effective approach. Dendrimers, due to unique surface topologies, can be a choice in this context. In the present study, PAMAM (polyamidoamine) dendrimers up to fourth generation were synthesized and characterized through infrared (IR), nuclear magnetic resonance (NMR), electrospray ionization (ESI) mass spectrometric, and transmission electron microscopic (TEM) techniques. Primary amines present on the dendritic surface were conjugated through folic acid and folic acid-PEG (poly(ethylene glycol))-NHS (N-hydroxysuccinimide) conjugates. Tumor in mice was induced through the use of KB cell culture. Prepared dendritic conjugates were evaluated for the anticancer drug delivery potential using 5-FU (5-fluorouracil) in tumor-bearing mice. Approximately 31% of 5-FU was loaded in folate-PEG-dendritic conjugates. Results indicated that folate-PEG-dendrimer conjugate was significantly safe and effective in tumor targeting compared to a non-PEGylated formulation. Tailoring of dendrimers via PEG-folic acid reduced hemolytic toxicity, which led to a sustained drug release pattern as well as highest accumulation in the tumor area.

Tumour is a morbid state, characterized by spontaneous outgrowth of an abnormal mass of cells. The evolution of tumours is random, disorganized, a condition of numerous mutations. The properties are biased and incompletely comprehended. It is a malignant or benign condition that encompasses its own rules of morphogenesis, an immortal state that elucidates different physiology. It is a pathological crisis that still haunts the minds of scientists, physicians and patients, a complete cure of which is still a dream to be realized. The unpredictable microenvironment of cancerous cells in all of its existing forms i.e. leukaemic cells, solid tumours and sarcomas is well documented. This phenomenon expressed by cancerous sites in the body poses various obstacles towards drug efficacy. Thus, it has become necessary to address briefly the issues relating to tumour physiology, its vasculature and angiogenesis. The information could provide insight towards the development of tumour-targeted drug delivery. The salient features regarding these have been discussed.

Taxanes have established and proven effectivity against different types of cancers; in particular breast cancers. However, the high hemolytic toxicity and hydrophobic nature of paclitaxel and docetaxel have always posed challenges to achieve safe and effective delivery. Use of bio-degradable materials with an added advantage of nanotechnology could possibly improve the condition so as to achieve better and safe delivery. In the present study paclitaxel loaded chitosan nanoparticles were formulated and optimized using simple w/o nanoemulsion technique. The observed average size, pdi, zeta potential, entrapment efficiency and drug loading for the optimized paclitaxel loaded chitosan nanoparticle formulation (PTX-CS-NP-10) was 226.7 ± 0.70 nm, 0.345 ± 0.039, 37.4 ± 0.77 mV, 79.24 ± 2.95% and 11.57 ± 0.81%; respectively. Nanoparticles were characterized further for size by Transmission Electron Microscopy (TEM). In vitro release studies exhibited sustained release pattern and more than 60% release was observed within 24 h. Enhanced in vitro anticancer activity was observed as a result of MTT assay against triple negative MDA-MB-231 breast cancer cell lines. The observed IC 50 values obtained for PTX-CS-NP-10 was 9.36 ± 1.13 μM and was almost 1.6 folds (p < 0.05) less than the pure drug. Similarly, PTX-CS-NP-10 were extremely biocompatible and safe as observed for haemolytic toxicity which was almost 4 folds less (p < 0.05) than the naïve drug. Anticancer activity was further evaluated using flow cytometry for apoptosis. Cell apoptosis study revealed that PTX-CS-NP-10 treatment resulted into enhanced (almost double) late cell apoptosis than naïve paclitaxel. Hence the developed nanoparticulate formulation not only reduced the overall toxicity but also resulted into improved anticancer efficacy of paclitaxel. It can be concluded that a robust, stable and comparatively safe nanoformulation of paclitaxel was developed, characterized and evaluated. [ABSTRACT FROM AUTHOR]

Although paclitaxel is a front-line chemotherapeutic agent for the treatment of metastatic breast cancer, its intravenous therapy produces deleterious adverse effects. In an attempt to address the issue, the present study aimed to develop a paclitaxel loaded thermosensitive/thermoresponsive hydrogel (PTXNp-TGel) for loco-regional administration to breast tumors to provide dose-dense chemotherapy. Poloxamer and xanthan gum were used to prepare TGel by the cold method. In vitro and in vivo performance of PTXNp-TGel was compared with TGel, pure drug loaded TGel (PTX-TGel) and marketed formulation, Taxol®. The formulated PTXNp-TGel showed acceptable gelation temperature and time (37 °C and 57 s), lower viscosity at room temperature and higher viscosity at body temperature to support sol-gel transition with increasing temperature, and sustained drug release up to 21 days. Additionally, PTXNp-TGel showed negligible hemolytic toxicity as compared to PTX-TGel and Taxol®. Intratumoral administration of PTXNp-TGel produced significantly higher antitumor activity as indicated by lowest relative tumor volume (1.50) and relative antitumor proliferation rate (27.71 %) in comparison with PTX-TGel, Taxol®, and PTXNp (p < 0.05). Finally, insignificant body weight loss during the experimental period, lack of hematotoxicity, nephrotoxicity, and hepatotoxicity imply improved therapeutic performance of the locally administrated dose-dense therapy of PTXNp-TGel as compared to Taxol®. • Paclitaxel loaded thermoresponsive hydrogel (PTXNp-TGel) provided dose dense chemotherapy in breast cancer model. • Xanthan gum provided mucoadhesive character to PTXNp-TGel and helped in retention of gel at the tumor site. • Loco regional administration of PTXNp-TGel exhibited remarkable antitumor activity without any significant side effects. • Same delivery system can be used for other cytotoxic agents to improve their therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Bendamustine is a drug of choice for the treatment of several cancers including non- Hodgkin lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL). The unstable nature of the drug, however, offers a major obstacle in its effective formulation development. The present study was aimed to achieve improved stability and efficacy of bendamustine via co-polymeric PEG-PLGA nanoparticulate approach. PEG-PLGA co-polymeric conjugate was synthesized and characterized by FT - IR and 1 H NMR spectroscopy. Bendamustine loaded nanoparticles (PLGA and PEG-PLGA) were prepared, optimized and characterized for size, zeta and electron microscopy (SEM and TEM). The average size, pdi (polydispersity index), zeta potential and entrapment efficiency for bendamustine loaded PEG-PLGA nanoparticles (PPBNP 15) was 297.3 ± 2.055 nm, 0.256 ± 0.012, −6.62 ±0.081 mV and 52.30 ± 3.66%, respectively. The in vitro release studies displayed sustained release nature of bendamustine. The Krosmeyer-Peppas model was the best fit model as a result of kinetic modelling for in vitro release. The ex vivo hemolytic toxicity of the PPBNP 15 was significantly less (approx. 11%; 4 folds) compared to pure drug (p < 0.05). The cytotoxicity study showed significantly higher anticancer activity against MCF - 7, T47D and PC-3 cells (p < 0.05) compared to naïve bendamustine. The developed biodegradable nanoparticles improved the stability of bendamustine and were equally stable, less toxic and highly effective against different cancerous cells. [ABSTRACT FROM AUTHOR]