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Papers by Harivardhan Reddy L.

Advanced Functional Materials, 2008

Pharmaceutical Development and Technology, 2007

Etoposide-loaded biodegradable microspheres of poly lactic-co-glycolide (PLGA) 50:50, PLGA 75:25,... more Etoposide-loaded biodegradable microspheres of poly lactic-co-glycolide (PLGA) 50:50, PLGA 75:25, and polycaprolactone (PCL) were prepared by simple o/w emulsification solvent evaparation method and characterized by size analysis and microscopy. The influence of drug to polymer ratio on the entrapment of etoposide was studied. Of all the three types of microspheres, polycaprolactone microspheres (PCL MS) showed the highest entrapment efficiency (94.64%), followed by PLGA 75:25 microspheres (PLGA 75:25 MS) (88.64%) and PLGA 50:50 microspheres (PLGA 50:50 MS) (79.19%). The drug to polymer ratio of 1:20 gave the highest entrapment efficiency for all the three types of microspheres. The in vitro release of etoposide from the three microsphere formulations were studied in phosphate buffer pH 7.4 (pH 7.4 PB) containing 0.1% Tween 80. The microspheres showed an initial burst release, which was highest from the PLGA 50:50 MS and least from the PCL MS. PCL MS microspheres showed the lower and slow drug release than the remaining formulations. The release of etoposide from all the three microsphere formulations followed Higuchi's diffusion pattern. The microspheres in the dissolution medium for 28 days appeared irregular in shape and slightly fragmented.

Journal of Pharmacy and Pharmacology, 2005

Despite several advancements in chemotherapy, the real therapy of cancer still remains a challeng... more Despite several advancements in chemotherapy, the real therapy of cancer still remains a challenge. The development of new anti-cancer drugs for the treatment of cancer has not kept pace with the progress in cancer therapy, because of the nonspecific drug distribution resulting in low tumour concentrations and systemic toxicity. The main hindrance for the distribution of anti-cancer agents to the tumour site is the highly disorganized tumour vasculature, high blood viscosity in the tumour, and high interstitial pressure within the tumour tissue. Recently, several approaches such as drug modifications and development of new carrier systems for anti-cancer agents have been attempted to enhance their tumour reach. Approaches such as drug delivery through enhanced permeability and retention (EPR) effect have resulted in a significant improvement in concentration in tumours, while approaches such as drug-carrier implants and microparticles have resulted in improvement in local chemotherapy of cancer. This review discusses different strategies employed for the delivery of anti-cancer agents to tumours, such as through EPR effect, local chemotherapeutic approaches using drug delivery systems, and special strategies such as receptor-mediated delivery, pH-based carriers, application of ultrasound and delivery to resistant tumour cells and brain using nanoparticles.

Molecular Pharmaceutics, 2009

Gemcitabine (2&am... more Gemcitabine (2',2'-difluorodeoxyribofuranosylcytosine) is an anticancer nucleoside analogue active against a wide variety of solid tumors. However, following intravenous administration, this drug is rapidly inactivated by enzymatic deamination and displays a short biological half-life necessitating the administration of high doses leading also to unwanted side effects. To overcome these drawbacks and to improve the therapeutic index of gemcitabine, we have recently developed the concept of squalenoylation which consisted in the bioconjugation of gemcitabine with squalene, a natural lipid. In our preliminary studies, we have shown that this bioconjugate (SQgem) self-organized in water as nanoassemblies with considerable resistance to deamination and significantly higher anticancer activity compared with gemcitabine in an intravenously grafted tumor model in mice. To further establish the candidature of this nanomedicine for clinical trials, in this communication we have tested the preclinical efficacy of squalenoyl gemcitabine nanomedicine on several human tumor cell lines and on the subcutaneously grafted experimental L1210 murine tumor in mice. SQgem nanomedicine displayed an efficient cytotoxicity against a variety of human tumor cell lines in the 60 human tumor cell panel. In vivo, following intravenous administration, SQgem nanomedicine displayed a superior anticancer activity against subcutaneous L1210 tumor, comparatively to gemcitabine. The molecular mechanism behind the anticancer efficacy of SQgem has been investigated by flow cytometry analysis and protein expression profiling of L1210 wt cells treated in vitro with the squalenoyl gemcitabine bioconjugate. It was found that this nanomedicine arrested the cell cycle in G2/M, characterized by an increased cyclin A and cyclin E expression, and activation of caspase-3 and the cleavage of poly(ADP-ribose) polymerase with an increase of cytochrome C level. Taken together, these results suggest that the cell kill by this nanomedicine occurred through mitochondrial apoptotic triggered pathway, similarly to that of gemcitabine free.

Journal of Drug Targeting, 2004

The objective of this study is to enhance the delivery of Doxorubicin hydrochloride to Dalton&amp... more The objective of this study is to enhance the delivery of Doxorubicin hydrochloride to Dalton's lymphoma solid tumour through poly(butyl cyanoacrylate) (PBC) nanoparticles. Doxorubicin loaded PBC (DPBC) nanoparticles were prepared by emulsion polymerization and characterized by particle size analysis, zeta potential and scanning electron microscopy. Doxorubicin HCl (Dox) and DPBC nanoparticles were radiolabeled with 99mTc by reduction method using stannous chloride and optimized the labeling parameters to obtain high labeling efficiency. The in vitro stability of 99mTc-labeled complexes was determined by DTPA and cysteine challenge test. The labeled complexes showed very low transchelation and high in vitro and serum stability. 99mTc labeled complexes of Dox and DPBC nanoparticles were administered subcutaneously below the Dalton's lymphoma tumour and biodistribution was studied. The distribution of DPBC nanoparticles to the blood, heart and organs of RES such as liver, lung and spleen was biphasic with a rapid initial distribution, followed by a significant decrease later at 6 h post-injection. The distribution of Dox to tissues was very low initially and increased significantly at 6 h post-injection indicating its accumulation at the injection site for a longer time. The concentration of DPBC nanoparticles was also found high in tissues at 6 h post-injection indicating their accumulation at the subcutaneous site and consequent disposition to tissues with time. A significantly high tumour uptake of DPBC nanoparticles (approximately 13 fold higher at 48 h post-injection) (P <0.001) was found compared to free Dox. The tumour concentrations of both Dox and DPBC nanoparticles increased with time indicating their slow penetration from the injection site into tumour. The concentration of DPBC nanoparticles in the femur bone in the tumour region was also significantly higher (P <0.001) than free Dox and increased with time. The study signifies the advantage of delivering Dox to Dalton's lymphoma through PBC nanoparticles by facilitating enhanced tumour uptake and prolonged tumour retention, which are expected to lead to greater therapeutic effect in the form of tumour regression.

Aaps Pharmscitech, 2005

The aim of the study was to prepare etoposide-loaded nanoparticles with glyceride lipids and then... more The aim of the study was to prepare etoposide-loaded nanoparticles with glyceride lipids and then characterize and evaluate the in vitro steric stability and drug release characteristics and stability. The nanoparticles were prepared by melt emulsification and homogenization followed by spray drying of nanodispersion. Spray drying created powder nanoparticles with excellent redispersibility and a minimal increase in particle size (20-40 nm). Experimental variables, such as homogenization pressure, number of homogenization cycles, and surfactant concentration, showed a profound influence on the particle size and distribution. Spray drying of Poloxamer 407-stabilized nanodispersion lead to the formation of matrix-like structures surrounding the nanoparticles, resulting in particle growth. The in vitro steric stability test revealed that the lipid nanoparticles stabilized by sodium tauroglycocholate exhibit excellent steric stability compared with Poloxamer 407. All 3 glyceride nanoparticle formulations exhibited sustained release characteristics, and the release pattern followed the Higuchi equation. The spray-dried lipid nanoparticles stored in black polypropylene containers exhibited excellent long-term stability at 25 degrees C and room light conditions. Such stable lipid nanoparticles with in vitro steric stability can be a beneficial delivery system for intravenous administration as long circulating carriers for controlled and targeted drug delivery.

The aim of the study is to determine and compare the pharmacokinetics and tissue distribution of ... more The aim of the study is to determine and compare the pharmacokinetics and tissue distribution of Doxorubicin (Dox) delivered as solution or through nanoparticles after intravenous (i.v.) and intraperitoneal (i.p.) injection. Doxorubicin loaded poly(butyl cyanoacrylate) nanoparticles were synthesized by dispersion polymerization (DP) and emulsion polymerization (EP) techniques. The drug loaded DP and EP nanoparticles were administered by i.v. or i.p. routes and the respective pharmacokinetics and tissue distribution were determined. Both types of nanoparticles significantly enhanced the elimination half-life (T 1/2 ), mean residence time (MRT) AUC 0-8 , AUC 0-∞ and AUMC 0-8 of Dox in blood after i.v. injection. Dox delivered through DP nanoparticles rapidly disappeared from blood and distributed to the organs of reticuloendothelial system (RES). But, the clearance of Dox delivered through EP nanoparticles from blood was slower than this of the DP nanoparticles and Dox solution. After i.p. injection, the Dox loaded into DP nanoparticles quickly appeared in blood and undergone rapid distribution to the organs of RES, while the Dox loaded into EP nanoparticles absorbed slowly into blood and remained in the circulation for longer time. The absorption into blood of Dox delivered through DP and EP nanoparticles after i.p. injection was relatively rapid and higher than Dox solution. The T 1/2 , MRT, AUC 0-8 , AUC 0-∞ and AUMC 0-8 of Dox in blood were significantly higher and the clearance (Cl) was lower than for the Dox solution after i.p. injection. The tissue concentrations of Dox delivered through nanoparticles after i.p. injection were significantly lower than after i.v. injection. The bioavailability (F) of Dox was greatly enhanced by DP (∼1.9 fold) and EP nanoparticles (∼2.12 fold) compared to Dox solution after i.p. injection. EP nanoparticles significantly enhanced the bioavailability, MRT, T 1/2 , AUC 0-8 , AUC 0-∞ and AUMC 0-8 of Dox than DP nanoparticles. This signifies the advantage of EP nanoparticles in increasing the elimination half-life of Dox both after i.v. and i.p. injection and enhanced bioavailability after i.p. injection, which is expected to improve the therapeutic efficacy of Dox and reduce the Dox-associated systemic toxicity. Importantly, both DP and EP nanoparticles greatly reduced the distribution of Dox to heart both after i.v. and i.p. injection, suggesting their potential in reducing Dox-associated cardiotoxicity.

Langmuir, 2008

Gemcitabine is widely used against a variety of solid tumors; however, it possesses some importan... more Gemcitabine is widely used against a variety of solid tumors; however, it possesses some important drawbacks such as rapid deamination leading to short biological half-life and induction of tumor resistance. We have shown previously that the covalent coupling of squalene (a precursor of cholesterol in sterol biosynthesis) to gemcitabine resulted in a potent nanomedicine, squalenoyl gemcitabine (SQdFdC), which displayed appreciable anticancer activity. Now, the present study describes the concept of magnetic responsiveness of SQdFdC nanoparticles obtained by the nanoprecipitation of SQdFdC around magnetite nanoparticles. To investigate these new core/shell nanoparticles, we have compared their structure, chemical composition and surface properties with those of either the magnetic core alone or of the SQdFdC coating material. X-ray diffraction and infrared spectroscopy studies have shown that the composite core/shell particles displayed an intermediate behavior between that of pure magnetite and of pure SQdFdC nanoparticles, whereas dark-field, high-resolution transmission electron microscopy allowed clear demonstration of the core/shell structure. Electrophoresis measurements as a function of both pH and ionic strength, as well as thermodynamic consideration, showed similar behavior of core/shell and pure SQdFdC nanoparticles, suggesting again the coating of the magnetite core by the SQdFdC prodrug. The two important parameters to be controlled in the efficient adsorption of SQdFdC onto magnetite nanocores were the magnetite/SQdFdC weight ratio and the pluronic F-68 concentration. Pluronic F-68 was found to play a key role as a surfactant in the generation of stable composite core/shell nanoparticle suspensions. Finally, the characterization of the magnetic properties of these core/shell nanoparticles revealed that if the squalenoyl shell reduced the magnetic responsiveness of the particles, it kept unchanged their soft ferrimagnetic character. Thus, the heterogeneous structure of these nanoparticles could confer them both magnetic field responsiveness and potential applicability as a drug carrier for active targeting to solid tumors.

Pharmaceutical Development and Technology, 2006

Solid lipid nanoparticles (SLN) were prepared by emulsification and high pressure homogenization ... more Solid lipid nanoparticles (SLN) were prepared by emulsification and high pressure homogenization technique and characterized by size analysis and differential scanning calorimetry. The influence of experimental factors such as homogenization pressure, time, and surfactant concentration on the nanoparticle size and distribution were investigated to optimize the formulation. Homogenization at 15,000 psi for 3 cycles was found to be optimum and resulted in smaller sized nanoparticles. In case of tristearin SLN (TSSLN), tripalmitin SLN (TPSLN), and glycerol behenate SLN (GBSLN), the relatively smaller sized nanoparticles were obtained with 3% sodium tauroglycocholate. The SLN were loaded with an anticancer agent, tamoxifen citrate (TC). The TC-loaded TSSLN shown lower entrapment efficiency (78.78%) compared to the TPSLN (86.75%) and GBSLN (98.64%). Short term stability studies indicated a significant increase in size of nanoparticles when stored at 500C, compared to those stored at 30 degrees C and 4 degrees C. The particle destabilization upon storage in case of all the types of nanoparticles studied was in the order of day light > artificial light > dark. An ultraviolet (UV) spectrophotometric method of estimation of tamoxifen in rat plasma was developed and validated. The TC-loaded TSSLN was administered to the rats intravenously and the pharmacokinetic parameters in the plasma were determined. The t(1/2) and mean residence time of TC-loaded TSSLN in plasma was about 3.5-fold (p < 0.001) and 3-fold (p < 0.001) higher, respectively, than the free tamoxifen, indicating the potential of TC-loaded TSSLN as a long circulating system in blood. Thus the above mentioned solid lipid nanoparticles can be a beneficial system to deliver tamoxifen to cancer tissues through enhanced permeability and retention (EPR) effect.

Advanced Functional Materials, 2008

Pharmaceutical Development and Technology, 2007

Etoposide-loaded biodegradable microspheres of poly lactic-co-glycolide (PLGA) 50:50, PLGA 75:25,... more Etoposide-loaded biodegradable microspheres of poly lactic-co-glycolide (PLGA) 50:50, PLGA 75:25, and polycaprolactone (PCL) were prepared by simple o/w emulsification solvent evaparation method and characterized by size analysis and microscopy. The influence of drug to polymer ratio on the entrapment of etoposide was studied. Of all the three types of microspheres, polycaprolactone microspheres (PCL MS) showed the highest entrapment efficiency (94.64%), followed by PLGA 75:25 microspheres (PLGA 75:25 MS) (88.64%) and PLGA 50:50 microspheres (PLGA 50:50 MS) (79.19%). The drug to polymer ratio of 1:20 gave the highest entrapment efficiency for all the three types of microspheres. The in vitro release of etoposide from the three microsphere formulations were studied in phosphate buffer pH 7.4 (pH 7.4 PB) containing 0.1% Tween 80. The microspheres showed an initial burst release, which was highest from the PLGA 50:50 MS and least from the PCL MS. PCL MS microspheres showed the lower and slow drug release than the remaining formulations. The release of etoposide from all the three microsphere formulations followed Higuchi's diffusion pattern. The microspheres in the dissolution medium for 28 days appeared irregular in shape and slightly fragmented.

Journal of Pharmacy and Pharmacology, 2005

Despite several advancements in chemotherapy, the real therapy of cancer still remains a challeng... more Despite several advancements in chemotherapy, the real therapy of cancer still remains a challenge. The development of new anti-cancer drugs for the treatment of cancer has not kept pace with the progress in cancer therapy, because of the nonspecific drug distribution resulting in low tumour concentrations and systemic toxicity. The main hindrance for the distribution of anti-cancer agents to the tumour site is the highly disorganized tumour vasculature, high blood viscosity in the tumour, and high interstitial pressure within the tumour tissue. Recently, several approaches such as drug modifications and development of new carrier systems for anti-cancer agents have been attempted to enhance their tumour reach. Approaches such as drug delivery through enhanced permeability and retention (EPR) effect have resulted in a significant improvement in concentration in tumours, while approaches such as drug-carrier implants and microparticles have resulted in improvement in local chemotherapy of cancer. This review discusses different strategies employed for the delivery of anti-cancer agents to tumours, such as through EPR effect, local chemotherapeutic approaches using drug delivery systems, and special strategies such as receptor-mediated delivery, pH-based carriers, application of ultrasound and delivery to resistant tumour cells and brain using nanoparticles.

Molecular Pharmaceutics, 2009

Gemcitabine (2&am... more Gemcitabine (2',2'-difluorodeoxyribofuranosylcytosine) is an anticancer nucleoside analogue active against a wide variety of solid tumors. However, following intravenous administration, this drug is rapidly inactivated by enzymatic deamination and displays a short biological half-life necessitating the administration of high doses leading also to unwanted side effects. To overcome these drawbacks and to improve the therapeutic index of gemcitabine, we have recently developed the concept of squalenoylation which consisted in the bioconjugation of gemcitabine with squalene, a natural lipid. In our preliminary studies, we have shown that this bioconjugate (SQgem) self-organized in water as nanoassemblies with considerable resistance to deamination and significantly higher anticancer activity compared with gemcitabine in an intravenously grafted tumor model in mice. To further establish the candidature of this nanomedicine for clinical trials, in this communication we have tested the preclinical efficacy of squalenoyl gemcitabine nanomedicine on several human tumor cell lines and on the subcutaneously grafted experimental L1210 murine tumor in mice. SQgem nanomedicine displayed an efficient cytotoxicity against a variety of human tumor cell lines in the 60 human tumor cell panel. In vivo, following intravenous administration, SQgem nanomedicine displayed a superior anticancer activity against subcutaneous L1210 tumor, comparatively to gemcitabine. The molecular mechanism behind the anticancer efficacy of SQgem has been investigated by flow cytometry analysis and protein expression profiling of L1210 wt cells treated in vitro with the squalenoyl gemcitabine bioconjugate. It was found that this nanomedicine arrested the cell cycle in G2/M, characterized by an increased cyclin A and cyclin E expression, and activation of caspase-3 and the cleavage of poly(ADP-ribose) polymerase with an increase of cytochrome C level. Taken together, these results suggest that the cell kill by this nanomedicine occurred through mitochondrial apoptotic triggered pathway, similarly to that of gemcitabine free.

Journal of Drug Targeting, 2004

The objective of this study is to enhance the delivery of Doxorubicin hydrochloride to Dalton&amp... more The objective of this study is to enhance the delivery of Doxorubicin hydrochloride to Dalton's lymphoma solid tumour through poly(butyl cyanoacrylate) (PBC) nanoparticles. Doxorubicin loaded PBC (DPBC) nanoparticles were prepared by emulsion polymerization and characterized by particle size analysis, zeta potential and scanning electron microscopy. Doxorubicin HCl (Dox) and DPBC nanoparticles were radiolabeled with 99mTc by reduction method using stannous chloride and optimized the labeling parameters to obtain high labeling efficiency. The in vitro stability of 99mTc-labeled complexes was determined by DTPA and cysteine challenge test. The labeled complexes showed very low transchelation and high in vitro and serum stability. 99mTc labeled complexes of Dox and DPBC nanoparticles were administered subcutaneously below the Dalton's lymphoma tumour and biodistribution was studied. The distribution of DPBC nanoparticles to the blood, heart and organs of RES such as liver, lung and spleen was biphasic with a rapid initial distribution, followed by a significant decrease later at 6 h post-injection. The distribution of Dox to tissues was very low initially and increased significantly at 6 h post-injection indicating its accumulation at the injection site for a longer time. The concentration of DPBC nanoparticles was also found high in tissues at 6 h post-injection indicating their accumulation at the subcutaneous site and consequent disposition to tissues with time. A significantly high tumour uptake of DPBC nanoparticles (approximately 13 fold higher at 48 h post-injection) (P <0.001) was found compared to free Dox. The tumour concentrations of both Dox and DPBC nanoparticles increased with time indicating their slow penetration from the injection site into tumour. The concentration of DPBC nanoparticles in the femur bone in the tumour region was also significantly higher (P <0.001) than free Dox and increased with time. The study signifies the advantage of delivering Dox to Dalton's lymphoma through PBC nanoparticles by facilitating enhanced tumour uptake and prolonged tumour retention, which are expected to lead to greater therapeutic effect in the form of tumour regression.

Aaps Pharmscitech, 2005

The aim of the study was to prepare etoposide-loaded nanoparticles with glyceride lipids and then... more The aim of the study was to prepare etoposide-loaded nanoparticles with glyceride lipids and then characterize and evaluate the in vitro steric stability and drug release characteristics and stability. The nanoparticles were prepared by melt emulsification and homogenization followed by spray drying of nanodispersion. Spray drying created powder nanoparticles with excellent redispersibility and a minimal increase in particle size (20-40 nm). Experimental variables, such as homogenization pressure, number of homogenization cycles, and surfactant concentration, showed a profound influence on the particle size and distribution. Spray drying of Poloxamer 407-stabilized nanodispersion lead to the formation of matrix-like structures surrounding the nanoparticles, resulting in particle growth. The in vitro steric stability test revealed that the lipid nanoparticles stabilized by sodium tauroglycocholate exhibit excellent steric stability compared with Poloxamer 407. All 3 glyceride nanoparticle formulations exhibited sustained release characteristics, and the release pattern followed the Higuchi equation. The spray-dried lipid nanoparticles stored in black polypropylene containers exhibited excellent long-term stability at 25 degrees C and room light conditions. Such stable lipid nanoparticles with in vitro steric stability can be a beneficial delivery system for intravenous administration as long circulating carriers for controlled and targeted drug delivery.

The aim of the study is to determine and compare the pharmacokinetics and tissue distribution of ... more The aim of the study is to determine and compare the pharmacokinetics and tissue distribution of Doxorubicin (Dox) delivered as solution or through nanoparticles after intravenous (i.v.) and intraperitoneal (i.p.) injection. Doxorubicin loaded poly(butyl cyanoacrylate) nanoparticles were synthesized by dispersion polymerization (DP) and emulsion polymerization (EP) techniques. The drug loaded DP and EP nanoparticles were administered by i.v. or i.p. routes and the respective pharmacokinetics and tissue distribution were determined. Both types of nanoparticles significantly enhanced the elimination half-life (T 1/2 ), mean residence time (MRT) AUC 0-8 , AUC 0-∞ and AUMC 0-8 of Dox in blood after i.v. injection. Dox delivered through DP nanoparticles rapidly disappeared from blood and distributed to the organs of reticuloendothelial system (RES). But, the clearance of Dox delivered through EP nanoparticles from blood was slower than this of the DP nanoparticles and Dox solution. After i.p. injection, the Dox loaded into DP nanoparticles quickly appeared in blood and undergone rapid distribution to the organs of RES, while the Dox loaded into EP nanoparticles absorbed slowly into blood and remained in the circulation for longer time. The absorption into blood of Dox delivered through DP and EP nanoparticles after i.p. injection was relatively rapid and higher than Dox solution. The T 1/2 , MRT, AUC 0-8 , AUC 0-∞ and AUMC 0-8 of Dox in blood were significantly higher and the clearance (Cl) was lower than for the Dox solution after i.p. injection. The tissue concentrations of Dox delivered through nanoparticles after i.p. injection were significantly lower than after i.v. injection. The bioavailability (F) of Dox was greatly enhanced by DP (∼1.9 fold) and EP nanoparticles (∼2.12 fold) compared to Dox solution after i.p. injection. EP nanoparticles significantly enhanced the bioavailability, MRT, T 1/2 , AUC 0-8 , AUC 0-∞ and AUMC 0-8 of Dox than DP nanoparticles. This signifies the advantage of EP nanoparticles in increasing the elimination half-life of Dox both after i.v. and i.p. injection and enhanced bioavailability after i.p. injection, which is expected to improve the therapeutic efficacy of Dox and reduce the Dox-associated systemic toxicity. Importantly, both DP and EP nanoparticles greatly reduced the distribution of Dox to heart both after i.v. and i.p. injection, suggesting their potential in reducing Dox-associated cardiotoxicity.

Langmuir, 2008

Gemcitabine is widely used against a variety of solid tumors; however, it possesses some importan... more Gemcitabine is widely used against a variety of solid tumors; however, it possesses some important drawbacks such as rapid deamination leading to short biological half-life and induction of tumor resistance. We have shown previously that the covalent coupling of squalene (a precursor of cholesterol in sterol biosynthesis) to gemcitabine resulted in a potent nanomedicine, squalenoyl gemcitabine (SQdFdC), which displayed appreciable anticancer activity. Now, the present study describes the concept of magnetic responsiveness of SQdFdC nanoparticles obtained by the nanoprecipitation of SQdFdC around magnetite nanoparticles. To investigate these new core/shell nanoparticles, we have compared their structure, chemical composition and surface properties with those of either the magnetic core alone or of the SQdFdC coating material. X-ray diffraction and infrared spectroscopy studies have shown that the composite core/shell particles displayed an intermediate behavior between that of pure magnetite and of pure SQdFdC nanoparticles, whereas dark-field, high-resolution transmission electron microscopy allowed clear demonstration of the core/shell structure. Electrophoresis measurements as a function of both pH and ionic strength, as well as thermodynamic consideration, showed similar behavior of core/shell and pure SQdFdC nanoparticles, suggesting again the coating of the magnetite core by the SQdFdC prodrug. The two important parameters to be controlled in the efficient adsorption of SQdFdC onto magnetite nanocores were the magnetite/SQdFdC weight ratio and the pluronic F-68 concentration. Pluronic F-68 was found to play a key role as a surfactant in the generation of stable composite core/shell nanoparticle suspensions. Finally, the characterization of the magnetic properties of these core/shell nanoparticles revealed that if the squalenoyl shell reduced the magnetic responsiveness of the particles, it kept unchanged their soft ferrimagnetic character. Thus, the heterogeneous structure of these nanoparticles could confer them both magnetic field responsiveness and potential applicability as a drug carrier for active targeting to solid tumors.

Pharmaceutical Development and Technology, 2006

Solid lipid nanoparticles (SLN) were prepared by emulsification and high pressure homogenization ... more Solid lipid nanoparticles (SLN) were prepared by emulsification and high pressure homogenization technique and characterized by size analysis and differential scanning calorimetry. The influence of experimental factors such as homogenization pressure, time, and surfactant concentration on the nanoparticle size and distribution were investigated to optimize the formulation. Homogenization at 15,000 psi for 3 cycles was found to be optimum and resulted in smaller sized nanoparticles. In case of tristearin SLN (TSSLN), tripalmitin SLN (TPSLN), and glycerol behenate SLN (GBSLN), the relatively smaller sized nanoparticles were obtained with 3% sodium tauroglycocholate. The SLN were loaded with an anticancer agent, tamoxifen citrate (TC). The TC-loaded TSSLN shown lower entrapment efficiency (78.78%) compared to the TPSLN (86.75%) and GBSLN (98.64%). Short term stability studies indicated a significant increase in size of nanoparticles when stored at 500C, compared to those stored at 30 degrees C and 4 degrees C. The particle destabilization upon storage in case of all the types of nanoparticles studied was in the order of day light > artificial light > dark. An ultraviolet (UV) spectrophotometric method of estimation of tamoxifen in rat plasma was developed and validated. The TC-loaded TSSLN was administered to the rats intravenously and the pharmacokinetic parameters in the plasma were determined. The t(1/2) and mean residence time of TC-loaded TSSLN in plasma was about 3.5-fold (p < 0.001) and 3-fold (p < 0.001) higher, respectively, than the free tamoxifen, indicating the potential of TC-loaded TSSLN as a long circulating system in blood. Thus the above mentioned solid lipid nanoparticles can be a beneficial system to deliver tamoxifen to cancer tissues through enhanced permeability and retention (EPR) effect.